Squamous cell carcinoma of the eyelid

Abstract Eyelid squamous cell carcinoma is a major type of rare eyelid cancer, together with basal cell carcinoma and sebaceous gland carcinoma. It is a painless disease that progresses slowly and is often detected by the appearance of nodules or plaques. Risk factors include exposure to ultraviolet light, fair skin, radiation and human papillomavirus infection. The standard treatment is surgical removal, and in cases of orbital invasion, orbital content removal is required. If sentinel node biopsy reveals a high risk of lymph node metastasis, adjuvant radiotherapy may be considered. Local chemotherapy, such as imiquimod and 5-fluorouracil, may be used for eyelid squamous cell carcinoma in situ. When surgery or radiotherapy is not recommended for distant metastases or locally advanced disease, drug therapy is often according to head and neck squamous cell carcinoma in Japan. The treatment often requires a multidisciplinary team to ensure the preservation of function and cosmetic appearance.


Introduction
Eyelid cancer, specifically eyelid squamous cell carcinoma (SCC), is an uncommon type of cancer that may require a team of specialists, such as ocular oncologists, medical oncologists, radiation oncologists, pediatricians, psychologists and other experts, to maintain functionality and cosmetic appearance (1).However, there have been limited comprehensive reports on eyelid SCC from Japan.This review is aimed at oncologists and focuses on eyelid carcinomas, particularly eyelid skin SCC.

Classification of eyelid cancers
Periocular tumors are classified as eyelid/conjunctival or orbital tumors, each of which has different approaches for diagnosis and treatment (2).The eyelids are divided into anterior and posterior lamellae.The anterior lamella is composed of skin and orbicularis oculi muscle, whereas the posterior lamella is composed of the tarsal plate and palpebral conjunctiva (3).Eyelids possess specialized adnexal structures including (i) meibomian glands in the tarsal plate, (ii) sebaceous glands of Zeis, which open into eyelash follicles and (iii) glands of Moll, which are modified sweat glands that also open into eyelash follicles (4,5).Eyelid cancers can arise from any tissue.Basal cell carcinoma (BCC) arising from skin, sebaceous gland carcinoma (SGC) arising from the meibomian or Zeis glands and SCC arising from skin or ocular conjunctiva are the three most common types.Melanoma, Merkel cell carcinoma and malignant lymphoma are also seen (6).
The TNM Classification of Malignant Tumors, 8th Edition by Union for International Cancer Control (UICC) classifies 'Carcinoma of Skin of the Eyelid' separately from 'Carcinoma of the Skin' under 'Skin tumors' section (Table 1) (7).However, the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition classifies 'Carcinoma of the Eyelid' under 'Ophthalmic Sites' (Table 2) (8).Both classifications classify conjunctival carcinoma in 'Ophthalmic Tumors'/'Ophthalmic Sites' section.Conjunctival SCC is also an important disease but should be discussed separately; this review only touches on it as necessary.

Epidemiology of eyelid cancers
Eyelid cancer accounts for 5-10% of all skin cancers (6), and reports from Europe and the USA have indicated that SCC accounts for 5-10% of all skin cancers that occur on the eyelid (9).Eyelid SCC incidence has been reported to range from 0.09 to 2.42 cases per 100 000 people with a high prevalence in males, lower eyelids, especially medial canthus region, fair skinned individuals and countries with high ultraviolet (UV) light exposure (10).Longitudinal studies conducted in the USA and Canada have shown that the age-adjusted incidence of cutaneous SCC has increased by 50-200% over the past several decades (11).Among eyelid cancers, BCC has relatively low grade histology and is more frequent than SGC and SCC, especially in Europe and the USA (12).Reports from Europe and the USA have indicated that BCC accounts for the majority (83.6-92.2%) of eyelid cancers.SCC is the next most common (7-16.3%),and SGC is less common (0-3%) (10,(13)(14)(15)(16)(17)(18)(19).Although there are no clear statistics on incidence rates of eyelid cancer in Japan, a review of studies from multiple centers from 1976 to 2004 (n = 774) reported 39.5% for BCC, 27.0% for SGC and 21.8% for SCC (20).Subsequent studies from several single centers also revealed higher rates of SGC in Japan than in Western countries, ranging from 16.7 to 43.7% (2,(21)(22)(23).The percentage of SCCs showed a downward trend from 26.7% in the aforementioned review from 1976 to 1994 to 13.0% during 1995-2004 (20).Later studies from several single centers reported similar results, ranging from 8.5 to 16.7% since 1995 (22).In other Asian countries, SGC frequency is as high as that in Japan with BCC being the most frequent, SGC the second most frequent and SCC the third most frequent (Table 3) (24,25,(34)(35)(36)(37)(38)(26)(27)(28)(29)(30)(31)(32)(33).
In Japan, SCC is the second most common form of cutaneous malignancy after BCC.Although statistics on the incidence are unclear, a survey by the Japanese Society for Cutaneous Malignancies reported 2507 cases of cutaneous SCC (28.8% of all cutaneous malignancies) during the 5-year period 1987-1991 with an incidence of ∼2.5 cases per 100 000 people annually (39).SCC accounted for 28% of all 29 170 cases of SCC, BCC and melanoma at ∼100 institutions from 1987 to 2001.In addition, 8975 cases of actinic keratosis, a precancerous lesion, were included, showing an increasing trend of cutaneous SCC and actinic keratosis (40).Skin cancer incidence is high in highly exposed areas, such as the head, neck and dorsum of the hands, because of increased UV light radiation exposure.More than 80% of nonmalignant melanoma skin cancers occur on the head and neck with 4.6-5.4% occurring on the eyelids.In Australia, adults using sunscreen routinely for 4.5 years have a reduced SCC incidence (2).Childhood sunburn has been reported to increase SCC incidence in Asians (3).In a study examining the distribution of facial skin SCC based on modified facial cosmetic units in Japanese people (n = 106), the SCC distribution on the face showed that the cheek (54.2%), frontal region (25.5%) and eyelid (8.5%) were the most common sites of SCC, followed by the lower lip (5.2%), upper lip (3.1%) and nose (3.1%) (41).

Pathogenesis of eyelid SCCs
Eyelid SCCs arise from skin of the eyelid and ocular conjunctiva.The most common sites are lower and medial eyelids, followed by upper eyelids, but they often involve multiple periocular skin zones.Eyelid SCCs may arise de novo or at the site of precancerous lesions such as actinic keratosis and Bowen's disease.The major risk factor for tumor development is exposure to UV light radiation.Fair skin, radiation exposure, immunosuppression, a high fat diet, exposure to chemicals (e.g.hydrocarbons and arsenic), smoking and infection by human papillomavirus are also risk factors.The disease is more common in older individuals in their sixties and seventies, and reports from Western countries have indicated that eyelid SCC is 2-3 times more common in men than in women (42,43,44,45).It is important to note that cutaneous SCC is the most common malignancy to develop after solid organ transplantation with a 5-year incidence rate of 30% in lung transplant patients and up to 26% in heart transplant patients (46,47).
Eyelid SCC typically presents as a mass that does not heal spontaneously with various morphologies from small erythematous plaques to papillomatous, nodular or ulcerative lesions that are often painless and progress slowly.As the tumor enlarges, vision may be obstructed, resulting in decreased visual acuity and diplopia may occur due to compression of the eyeball.Early eyelid SCC can present as chronic anterior blepharitis and is easily misdiagnosed (12,6,42).Symptoms of eyelid SCC vary and include a new growth or mass, skin ulcers, eyelash loss, resistant blepharitis or conjunctivitis, tarsal plate thickening, nonspecific eyelid swelling, eyelid discomfort, bleeding or scarring, excessive tearing, a nonhealing stye, wart, or chalazion, violaceous nodules and a pigmented macule with irregular features.Because these clinical features are common to SCC and BCC, they are easily confused (48).Biopsy should be considered when spots on the eyelid change in size, bleed, do not heal, or are a constant source of irritation (43,49).
Cutaneous SCC is highly invasive and may be complicated by local tissue destruction, orbital invasion, perineural invasion, and lymphatic and hematogenous metastases (43).The frequency of microscopic perineural invasion in facial and periorbital SCCs has been reported to be 8-14% (43,50).Eyelid SCC patients with perineural infiltration may present with dysesthesia of trigeminal nerve distribution, ophthalmoplegia, orbital pain and facial paralysis (51).The frequency of regional lymph node metastasis has been reported to be 24%, most commonly in the preauricular, parotid and submandibular glands (42).The frequency of distant lymph node metastasis is reported to be 6.2% (42).

Examination and diagnosis of eyelid SCCs
On visual examination and slit lamp microscopy, a substantial mass is found on the eyelid.In malignant cases, the mass is often 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 accompanied by malformed protrusions, hair loss and hypervascularization.In most cases, histology can be estimated from clinical findings alone.BCC is often accompanied by pigmentation and ulceration.SGC is yellowish, reflecting fatty deposits, and ridges extend vertically along meibomian glands.SCC is richly vascular with papillary-like structures and is often reddish.Histological diagnosis is usually made by excisional biopsy.SCC appears as nests of squamous cells and is characterized by infiltration by atypical keratinocytes, often with a characteristic keratin pearl.The degree of keratinocyte dysplasia varies from partial thickness keratosis to full thickness intraepidermal carcinoma before invasion of the epidermis (52).The histopathological features of SCC depend on the degree of tumor differentiation.In highly differentiated tumors, cells are polygonal with abundant acidophilic cytoplasm, polychromatic nuclei of varying sizes and staining, dyskeratotic cells and intercellular bridges.In poorly differentiated SCC, there is pleomorphism with undifferentiated cells, an abnormal mitotic picture, little or no keratinization and loss of intercellular bridges (53).The tumor size, presence or absence of invasion into the angle of the eye and the presence or absence of pagetoid spread are important to determine the extent of resection.Tissue samples should be carefully examined for perineural invasion.Biopsy of the supraorbital nerve may be considered, especially when the trigeminal nerve distribution presents with paresthesias, ophthalmoplegia, orbital pain and facial palsy (54).Palpation should be performed to check for swelling of regional lymph nodes (parotid and cervical), and imaging tests such as CT should be considered when metastasis is suspected.

Treatment of eyelid cancers
Eyelid cancers can have a devastating effect on a patient's vision and quality of life, because surgical removal and reconstruction can affect eye functions.Cosmetic considerations are also necessary because the disease and surgical deformity can significantly affect how the patient is viewed by others and themselves, requiring different considerations than other skin cancers of the same histological type (12,52).Treatment of eyelid cancer is considered to save life, sight and the eye, often requiring a multidisciplinary team of ocular oncologists, medical oncologists, radiation oncologists, pediatricians, psychologists and other specialists (1).

Surgery
Surgical resection is the standard treatment for locally advanced eyelid SCCs.The 2020 guidelines for cutaneous malignancies classify patients with eyelid primary SCC as a high-risk group with a recommended safe margin of resection of 6-10 mm or more (55).
The 5-year local recurrence rate after surgical resection has been reported to be 2.4-36.9%(42,50).For complete surgical excision using histology to verify tumor-free margins, options include excision with a frozen section control or Mohs surgery (56).Mohs surgery is an intraoperative pathological examination to verify whether a complete resection has been performed prior to reconstruction.The surgeon performs a tumor resection at what is considered the gross margins of the tumor.The tissue is frozen on a cryostat and sliced horizontally, and sections are prepared from the lowest layer and stained.If tumor cells are found, additional sections are prepared, and the procedure is repeated to remove the minimal amount of tumor tissue.The same procedure can also be used to resect the surrounding margin to minimize the margin.This technique allows a single-stage resection of the tumor with minimal margins (57).The recurrence rate of Mohs surgery has been reported to range from 0 to 3.6% (58).
Although it has the potential to be more beneficial than conventional surgical methods, Mohs surgery is not widely used in Japan because of the complexity of the technique, the need for specialized training and the time and labor required for a series of procedures (55).In a German report, the percentage of R1 resection due to failure to achieve R0 resection in Mohs surgery tended to be higher for eyelid SCC [24.3% (17/70)] compared with 16.1% (208/1084) for skin SCC of all sites (59).In addition, when the orbit is involved, removal of the orbital contents is necessary (12,45).Sentinel node biopsy is considered for eyelid cancers with a risk of regional lymph node metastasis, such as melanoma, SGC and MCC in addition to SCC.It is considered for advanced cancers ≥T2b, because lymph node metastasis has been reported to be present at presentation or during follow-up for eyelid SCCs >18 mm or advanced to AJCC stage T2b (60).In cases with a high risk of lymph node metastasis on sentinel node biopsy, postoperative adjuvant radiotherapy is usually added (12,45).

Definitive radiotherapy
Definitive radiotherapy is indicated for patients for whom surgery is unsafe or who decline surgery.Treatment is usually administered three to five times a week for 1-2 months.A report of 38 eyelid SCC patients (14 had relapsed disease after prior treatment) who underwent radiation therapy between 1964 and 2010 in a Japanese institution showed that the median radiation dose was 60.0 Gy (range, 45.0-70.4Gy) and 5-year local and nodal relapse-free, distant metastasis-free and relapse-free rates were 71.8, 77.5, 90.6 and 58.0%, respectively; and the 5-year overall survival was 79.5%; Nine patients complicated Grade 3 or greater late adverse events, and two patients lost their vision (61).Another report of 159 periocular lesions including 18 SCC in 145 patients who underwent radiation therapy between 2009 and 2014 in a single institute in Switzerland showed a recurrence rate of 11% (62).For preserving function and cosmetics, radiation therapy could be a therapeutic option for eyelid SCC.
In clinical practice, lead or tungsten eye shields are often used to protect the cornea, eye, retina and optic nerve, and electron beams are used to achieve both tumor control and functional preservation.Intensity-modulated radiation therapy has also been often used with irradiation methods tailored to the extent of the eyelid conjunctiva and ocular conjunctiva lesions, but there are no published reports.

Adjuvant radiotherapy
Adjuvant radiotherapy is administered to patients with positive sentinel node biopsies, positive microscopic perineural invasion, positive resection margins or closed margins.The standard radiation dose has not been established, but has been reported to be 26-63 Gy (median: 60 Gy).Known side effects of radiation include local hyperemia, erosion, alopecia, local pain, skin atrophy, pigmentary changes, telangiectasia, dry eye syndrome, conjunctival keratosis, blepharitis, trichiasis, optic neuropathy, retinopathy and keratopathy at the irradiated site (63).

Treatment of eyelid SCC in situ
SCC in situ lesions include actinic keratosis and Bowen's disease.Actinic keratosis is a precancerous lesion or intraepithelial carcinoma of cutaneous SCC that predominantly affects exposed areas of the face, including eyelids and dorsal palms, and 0.025-20% of patients per year progress to SCC when untreated.Bowen's disease is an intraepidermal lesion of cutaneous SCC, and 3-5% of patients progress to SCC (55).Treatments of these in situ cases of eyelid SCC include surgical resection, which is especially recommended for Bowen's disease (64), local chemotherapy, photodynamic therapy and cryotherapy.

Local chemotherapy.
Topical imiquimod, mitomycin C ophthalmic solution, 5-fluorouracil ophthalmic solution and interferon alpha-2b ophthalmic solution may be used as local chemotherapy for eyelid SCC in situ (12,45).
Imiquimod is an agonist of Toll-like receptor 7 that activates production of cytokines (e.g.IFN-α, IL-12 and TNF-α), cellular immunity and apoptosis of tumor cells, and inhibits viral growth.
For actinic keratosis, several clinical trials have reported that topical imiquimod therapy has a lesion resolution rate of 55-85% (65,66).Imiquimod has been approved in Japan for treatment of actinic keratosis limited to the face or bald head area and is recommended in the Japanese guidelines for local treatment of multiple lesions of actinic keratoses.It is also recommended in the Japanese skin malignancy guidelines for local treatment of multiple lesions of actinic keratosis.Studies have demonstrated treatment efficacy of imiquimod for periocular SCC in situ (67,68).However, imiquimod has a known risk of conjunctival irritation, but in a retrospective study of topical imiquimod for periocular lesions, the major ophthalmic side effects were temporary conjunctivitis and ocular stinging pain that resolved after completion of imiquimod treatment (69).
For Bowen's disease, a randomized controlled trial of topical imiquimod reported a 73% resolution rate of lesions after 12 weeks of treatment (70).Therapeutic effects on periocular lesions have also been reported ( 71), but as of April 2023, it is not covered by national insurance in Japan for Bowen's disease.
There is also a report of an elderly patient with locally advanced eyelid SCC who achieved CR after local chemotherapy with imiquimod alone (72), and this may be an option for locally advanced cases for which surgery is not indicated.

5-Fluorouracil.
Topical 5-fluorouracil is recommended in the Japanese guidelines for cutaneous malignancies for multiple thin lesions of actinic keratosis (55).The reported resolution rate of lesions ranges from 26 to 96%, and the incidence of local adverse reactions varies somewhat from 25 to 77%.The most common side effects include skin irritation and hyperemia (73,74,75,65,76).
Mitomycin C. Topical mitomycin C is not mentioned in the Japanese guidelines for cutaneous malignancies.In a retrospective report of patients with ocular surface SCC who received topical 5-fluorouracil (n = 89) or mitomycin C (n = 64) for residual disease after surgical excision, there was one recurrence in the 5-fluorouracil group and zero in the mitomycin C group.Adverse effects occurred in 69% and 41% of patients, respectively, but no sight-threatening complications were noted (77).

Cryotherapy
Cryotherapy destroys the tissue structure of SCC using liquid nitrogen at very low temperatures.Cryotherapy with liquid nitrogen is recommended as a simple and effective treatment for actinic keratosis in the Japanese guidelines for cutaneous malignancies (55).The complete resolution rate is 68-86%, and the local side effect rate is 35-43% (73,74,75,78) (79,80).The main side effects include localized pain, swelling, pigment changes, hair loss in hairy areas, blister formation and scarring (81,73,78,79) (80).

Photodynamic therapy
Photodynamic therapy uses photosensitizers, light and oxygen to induce targeted cell death by apoptosis in cancer and abnormal tissues.It is recommended in the Japanese guidelines for cutaneous malignancies for the treatment of extensive multiple lesions of actinic keratosis (55), but it is not covered by national insurance in Japan.
The local lesion resolution rate is 68-93%, and the incidence of local adverse reactions is 26-100%, including minor reactions such as local erythema, although the incidence of adverse reactions is somewhat high (73,79,80,66).

Treatment of metastatic eyelid SCC
No randomized controlled trials of chemotherapy have been conducted for unresectable advanced or metastatic cutaneous SCC including eyelid SCC, and there is no standard of care.Eyelid SCC is often treated by chemotherapy similar to head and neck SCC.
For chemotherapy of cutaneous SCC, cisplatin is considered the main drug, and it is also used for head and neck SCC (65).In a report of 14 patients treated with fluorouracil (5-FU) and cisplatin, a response was seen in 11 patients (82).The degree of epidermal growth factor receptor (EGFR) overexpression is associated with the aggressiveness of cutaneous SCC and has been reported to be an independent predictor of metastasis in an analysis of 54 cases of head and neck SCC (83).Cetuximab, an anti-EGFR antibody, has been shown to be effective for head and neck SCC in several clinical trials (84,85,86).It is also used in definitive chemoradiotherapy for locally advanced head and neck SCC and in palliative chemotherapy for unresectable advanced or recurrent head and neck SCC.There is no evidence for the efficacy of anti-EGFR antibody drugs in eyelid SCC patients.However, for overall cutaneous SCC, a phase II trial of single-agent cetuximab in 36 cutaneous SCC patients, including five primary head and neck SCC patients, showed disease control in 25 patients (69%) (87).A retrospective study of five conjunctival SCC cases showed moderate to strong expression of EGFR in both the invasive and in situ components in all cases (83).In addition, there was a report of response to the EGFR tyrosine kinase inhibitor erlotinib in two elderly patients with skin SCC with orbital involvement (88).
In head and neck SCC, the anti-programmed death receptor-1 (PD-1) antibody nivolumab has shown efficacy in platinum-resistant patients (89,90), and the anti-PD-1 antibody pembrolizumab has shown efficacy in platinum-sensitive patients (91,92) and palliative chemotherapy for unresectable advanced or recurrent head and neck SCC.Immune checkpoint inhibitors have been used as single agents or in combination with chemotherapy, but there is no evidence for the efficacy of immune checkpoint inhibitors in eyelid cancer patients.A phase 2 trial of cemiplimab, an anti-PD-1 antibody, demonstrated a response in 28 (47%) of 59 cutaneous SCC patients, including 38 head and neck primary cases, and 16 (57%) of the 28 responders had a sustained response for >6 months (93).The US FDA approved cemiplimab for cutaneous SCC in September 2018.In a retrospective study of 31 patients with conjunctival SCC, including conjunctival and primary eyelid SCC, 14 patients (47%) showed PD-L1 expression (≥1% of tumor cells) and the density of CD8-positive T cells was higher in advanced stage tumors and that of HPV-positive T cells was higher in primary SCC tumors and HPV-positive tumors (94).
On the basis of this evidence for head and neck SCC and cutaneous SCC, and considering drug accessibility because of the insurance system in Japan, it appears reasonable to use chemotherapy similar to that for head and neck SCC for unresectable and advanced eyelid SCC.

Prognosis and surveillance of eyelid SCC
Patients with eyelid malignancies require long-term follow-up even when resection margins are negative.The recommended frequency and duration of follow-up is 5 years postoperatively for SCC.The local recurrence rate at 5 years after surgical resection has been reported to be 2.4-36.9%(12,45) In all cases of SCC, they could recur, and patients should be encouraged to participate in lifelong follow-up.
There are no prognostic reports stratified by stage.In a retrospective report from Germany of 117 patients with eyelid SCC, including 12 distant metastases, between January 2009 and March 2020, 88 patients (75.2%) underwent radical resection, and the remaining patients underwent surgery plus individualized adjuvant therapy.Disease-specific survival was 95.7% at 2 years and 94.9% at 5 years.Six patients (5.1%) died from eyelid SCC with nodal metastasis and a high T-category being negative prognostic factors.Recurrence was high in patients with multiple lesions, and mortality was associated with the tumor location on the medial side of the upper eyelid and more lymph node metastases (96).
Perineural invasions are a sign of a poor prognosis.Microscopic perineural invasion is reported to be 8-14% (12,45).Therefore, these patients need to be followed more closely (43).
The frequency of visits depends on many factors, including the cancer stage at the time of the initial visit.At each visit, the surgical site should be examined clinically for signs of recurrence.Patients who have undergone orbital resection for advanced cancer of the eyelid or periocular region should have imaging of the orbit performed during the follow-up period.Most nodal metastases occur within 2-3 years after cancer treatment (12).

Conclusion
Eyelid SCC is a rare cancer that requires a multidisciplinary team of specialists, and oncologist should organize their findings.The standard treatment for locally advanced cases is surgery (with the addition of postoperative radiation for sentinel node-positive cases), but there is a lack of evidence regarding the role of definitive radiation therapy, local treatment of in situ disease and drug therapy for distant metastases and recurrent disease.Constructing evidence for eyelid SCC is warranted.

Table 1 .
Position of eyelid cancer in TNM Classification of Malignant Tumors, 8th Edition by UICC