Clinics in Dermatology (2015) 33, 159–169

Eyelid and ocular surface carcinoma: Diagnosis and management Vivian T. Yin, MD a , Helen A. Merritt, MD a,b , Matt Sniegowski, MD a , Bita Esmaeli, MD a,⁎ a

Orbital Oncology & Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030 b Department of Ophthalmology and Visual Science, University of Texas Medical School at Houston, Houston, Texas

Abstract Eyelid cancers account for 5% to 10% of all cutaneous malignancies. The incidence of eyelid cancer is approximately 15 cases per 100,000 individuals per year. Basal cell carcinoma is by far the most common cutaneous malignancy in the periocular area; other cutaneous malignancies that occur in this area include, in decreasing order of frequency, squamous cell carcinoma, sebaceous carcinoma, melanoma, and Merkel cell carcinoma. The most common treatment for eyelid carcinomas is surgical resection with frozen section examination for margin control, but exenteration may be needed when there is orbital invasion. Adjuvant radiotherapy may be needed in patients at high risk for local recurrence; sentinel lymph node biopsy may be considered in patients at high risk for lymph node metastasis. Primary or residual in situ disease of the conjunctiva can be treated with topical chemotherapy, such as mitomycin C, 5-fluorouracil, or interferon alpha-2 b. For patients with metastatic or locally advanced basal cell or squamous cell carcinoma not amenable to surgical excision or radiotherapy, targeted therapy against the hedgehog pathway (for basal cell carcinoma) or epidermal growth factor receptor (for squamous cell carcinoma) has been shown to be effective in preventing disease progression. Patients with eyelid and ocular surface malignancies need to be monitored with careful clinical examination for at least 5 years after surgical treatment, and additional investigations may be warranted in some cases. © 2015 Published by Elsevier Inc.

Introduction Reported age-adjusted incidences of eyelid malignancies range from 5.1 cases per 100,000 individuals per year in Singapore1 and 6.5 cases per 100,000 individuals per year in Taiwan2 to 15.7 cases per 100,000 individuals per year in the United States.3 Basal cell carcinoma (BCC) is by far the most common of all eyelid malignancies, accounting for 86% to ⁎ Corresponding author. Tel.: +1-713-792-4457; fax: +1-713-563-8041. E-mail address: [email protected] (B. Esmaeli). http://dx.doi.org/10.1016/j.clindermatol.2014.10.008 0738-081X/© 2015 Published by Elsevier Inc.

96% of all cases; squamous cell carcinoma (SCC) accounts for 3.4% to 12.6% of cases, sebaceous carcinoma (SebCa) for 0.6% to 10.2%, and melanoma and Merkel cell carcinoma (MCC) for less than 1% each.1–6 SebCa is more common in Asia than in other parts of the world, and in some regions of Asia, SebCa is actually more common than SCC.2 Eyelid malignancies require different considerations from other cutaneous malignancies of the same cell type due to the unique anatomic considerations in the periocular region and the functional impact of surgical resection and reconstruction on ocular protection and visual function. The management of

160 eyelid malignancies is dependent on histopathologic type and disease stage according to the American Joint Committee on Cancer (AJCC) staging system. The standard treatment is surgical excision with negative margins. In patients at high risk for local recurrence, adjuvant radiotherapy may be needed; and in patients at high risk for lymph node metastasis, sentinel lymph node (SLN) biopsy may be considered. In some instances, topical chemotherapy may be considered. Therapy needs to be tailored in each case.

Basal cell carcinoma The incidence of BCC is approximately 14.35 cases per 100,000 individuals per year, age and gender adjusted, according to an epidemiologic study in Olmsted County, Minnesota, published in 1999.3 BCC typically appears at presentation as a nodule with pearly edges, central ulceration, and telangiectatic vessels (Figure 1). Risk factors for BCC include sun exposure, advanced age, immunosuppression, fair skin, and smoking in women7; the incidence of BCC is also increased in patients with xeroderma pigmentosum and Gorlin-Goltz syndrome.8 Histopathologically, the nodular subtype is the most common subtype of BCC, accounting for 43% to 77% of cases, and is classically described as consisting of nests of basophilic cells with peripheral pallisading.9–11 The infundibulocystic subtype of BCC is more common in patients with Gorlin-Goltz syndrome, basal cell nevus syndrome, or HIV.12,13 The sites of periocular involvement with BCC, from most to least common, are the lower lid, medial canthus, upper lid, and lateral canthus.10,11 The morpheaform subtype and medial canthus location are associated with a higher rate of incomplete resection, which is associated with a higher likelihood of local recurrence.10 Medial canthal

Fig. 1 Large basal cell carcinoma involving the left medial canthus, nasal bridge, and glabella showing extensive ulceration and elevated pearly edges (arrow).

V.T. Yin et al. location is also associated with a higher risk of orbital involvement and, thus, a higher likelihood that orbital exenteration will be needed.11,14,15 After complete resection of BCC with negative margins, the rate of local recurrence is less than 1% at 5 years of follow-up; however, with incomplete excision, the local recurrence rate can be as high as 38% at 5 years.16–18 Recurrence is more common with the morpheaform subtype: The 5-year recurrence rate is reported to be as high as 3.8%, even after resection with negative surgical margins.9 The rate of metastasis of BCC is extremely low, .03%, and the disease most commonly metastasizes to the regional lymph nodes.19 Perineural invasion is found in 19% of patients with orbital invasion by BCC.15

Squamous cell carcinoma SCC arises from abnormal keratinocyte proliferation. SCC most commonly appears in the sixth or seventh decade of life. SCC may often appear at presentation as a raised nodule or plaque with overlying scaling, induration, keratinization, or ulceration (Figure 2, Figure 3B). Men are affected two or three times as often as women. The most common periocular sites of SCC involvement are the lower eyelid and medial canthus; however, tumors often span more than one periocular skin zone.20 Risk factors for SCC include fair skin, exposure to ultraviolet light, immunosuppression, exposure to radiation, a high-fat diet, exposure to chemicals (such as hydrocarbons and arsenic), and infection with human papillomavirus.21,22 SCC may arise de novo or from areas of preexisting actinic or solar keratosis and is characterized by invasion by atypical keratinocytes. The degree of keratinocyte dysplasia can range from partial-thickness keratosis to full-thickness

Fig. 2 Squamous cell carcinoma of the right medial lower eyelid in an 84-year-old Caucasian man that showed slow growth over at least 1 year. The plaque-like tumor is associated with overlying scaling and keratinization.

Eyelid and ocular surface carcinoma intraepidermal carcinoma before invasive epidermal involvement. Early eyelid SCC may masquerade as chronic anterior blepharitis. Clinically, SCC can range from small erythematous keratinized patches to papillomatous or nodular lesions to large ulcerated lesions.23 The clinical behavior of SCC may depend on the level of differentiation and can range from indolent with low metastatic potential to rapidly and aggressively invasive. In large studies, local recurrence rates for SCC range from 2.4% to 36.9% at 5 years.20,24 Since SCC is invasive, there is a significant risk of local tissue destruction, invasion into the orbit, perineural invasion, and lymphatic or hematogenous metastasis.24 Microscopic perineural invasion has been found to be present in approximately 8% to 14% of cases of facial and periorbital SCC,24,25 and patients with perineural invasion may present with trigeminal-distribution sensory deficit, ophthalmoplegia, orbital pain, or facial palsy.26 Histologic examination reveals that the majority of periocular SCCs are well or moderately differentiated; well-differentiated tumors are associated with a lower risk of subclinical tumor extension, recurrence, and orbital invasion.27 Histologic specimens should be carefully examined for evidence of perineural invasion, and in cases of particularly aggressive tumors or in patients with trigeminal pain, paraesthesias or numbness, and biopsy of the supraorbital orbital nerve, which is commonly involved, may be considered.28 Adjuvant radiotherapy may be considered in cases of perineural invasion.29 The incidence of regional lymph node metastasis has been reported to be as high as 24%, with most regional metastases occurring in the parotid, preauricular, and submandibular nodes.20 Distant metastasis is much less common, reported in 6.2% of cases.20 A soon-to-be-published review of 65 patients with periocular SCC seen at The University of Texas MD Anderson Cancer Center found AJCC T2 b or greater disease or tumor diameter larger than 18 mm to be associated with nodal metastases, and the reported 3-year disease-free survival rate was 79% (personal communication, Bita Esmaeli).

Ocular surface squamous neoplasia In addition to involving the periocular skin, squamous cell intraepithelial neoplasia and carcinomatous disease can involve and primarily arise from the conjunctiva and cornea. This entity, referred to as ocular surface squamous neoplasia (OSSN), has histologic manifestations mirroring the histopathological range of cutaneous SCC, including dysplasia, carcinoma in situ, and invasive SCC. OSSN most commonly occurs near the limbus, and like cutaneous SCC, it more commonly occurs in older men with a history of risk factors, such as sun exposure, fair skin, immunosuppression, and smoking.30 Additionally, there may be a relationship between OSSN and concurrent infection with human papillomavirus type 16, HIV, or upregulation of matrix metalloproteinases.31,32

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Fig. 3 A. Squamous cell carcinoma of the left inferior palpebral and bulbar conjunctiva with extension to the caruncle in a 64 yearold woman. The tumor shows increase vascularization and leukoplakia extension onto the inferior cornea. B. A more advanced case of invasive squamous carcinoma of lower eyelid causing tissue destruction and severe ulceration.

OSSN has appearances ranging from flat or gelatinous areas of leukoplakia to nodular or papular lesions and may show significant vascularization and pigmentation (Figure 3A). The most common presenting complaints include eye irritation, conjunctival injection, foreign body sensation, pruritus, photophobia, decreased vision, and diplopia.33 Local invasion of OSSN, most commonly to the cornea and sclera, occurs in about 40% of cases.33,34 Deeper intraocular invasion is reported to occur in up to 13% of cases of conjunctival SCC.34 Topical chemotherapy has been used as both primary and adjuvant therapy for OSSN. Drugs used have included topical

162 mitomycin C, 5-fluorouracil, and interferon alpha-2 b.35–37 While both topical 5-fluorouracil and topical mitomycin C have been found to be very effective in preventing recurrence, these agents are associated with ocular surface and eyelid irritation and toxic effects.38 Topical and subconjunctival administration of interferon alpha-2 b has shown excellent efficacy in preventing recurrence and has a much better side effect profile than mitomycin C, but may require longer treatment than 5fluorouracil or mitomycin C.39 Perilesional subconjunctival injection of bevacizumab has recently been shown to be effective in the treatment of conjunctival lesions in a relatively small case series but the authors observed that this treatment had no significant effect on corneal lesions.40 Overall rates of recurrence after treatment of OSSN vary widely depending on treatment and may be as high as 21% with excision and cryotherapy.30 Recurrence risk has been reported to correlate with factors such as involvement of the tarsal surface, nasal location, presence of positive surgical margins, and high-grade lesions.30 Regional nodal metastasis to preauricular, submandibular, and cervical lymph nodes may occur, but is relatively uncommon with a reported incidence of less than 1%.34

Sebaceous carcinoma SebCa is a rare tumor with an estimated incidence of .11 to .65 cases per 100,000 individuals per year and is seen predominantly in elderly individuals; the reported median age at presentation is 70 to 73 years. 41–43 SebCa is misdiagnosed in up to two-thirds of patients. SebCa of the eyelid is frequently misdiagnosed as blepharoconjunctivitis, recurrent chalazion, BCC, or SCC.44–46 There is typically a median delay in diagnosis of 12 to 24 months (range: 1–300 months).44,45 Asians are 6.21 times as likely as non-Asians to have eyelid SebCa.47 Some studies have suggested that men are 1.35 to 1.4 times as likely as women to have SebCa, 41,46 while other studies have found a higher incidence in women.43–45,48 Due to its abundance of sebaceous glands, the face is the most common site of SebCa in the body, accounting for 63.9% to 65.5% of all cases; of those, 41% to 59% of cases occur in the periocular area.41,42,47 SebCa can present as a nodular lesion or diffuse thickening of the eyelids (Figure 4). There is a predilection for involvement of the upper lid and palpebral conjunctiva, but SebCa can also involve the caruncle (2%-8%) or bulbar conjunctiva (2%-5%), and SebCa is multicentric in a small percentage of patients.43,45,46 When patients present with a history of multiple sebaceous neoplasms, the possibility of Muir-Torre syndrome, now considered a subtype of hereditary nonpolyposis colorectal cancer, needs to be considered. In a series of 51 patients with eyelid SebCas from the United Kingdom, Muir-Torre syndrome was found in 1 of 34 patients evaluated43; however, in a series from Australia, 10 of 31 patients with periocular

V.T. Yin et al.

Fig. 4 Sebaceous carcinoma of the left upper eyelid in a 64-yearold man with a history of seven previous incisions and drainage for presumed chalazion. There is diffuse thickening and a nodular mass in the lateral aspect of the left upper eyelid.

SebCa had Muir-Torre syndrome as indicated by clinical diagnosis of visceral malignancies.49 Muir-Torre syndrome has been associated with defects in mismatch-repair genes hMSH2 and hMSH1, resulting in microsatellite instability.50 Resected SebCa specimens can be stained immunohistochemically for MSH1 and MSH2 expression. A relative lack of expression of MSH1 or MSH2 is observed in SebCa specimens from patients with Muir-Torre syndrome compared with patients with isolated SebCa.49 The most common internal organ malignancies associated with Muir-Torre syndrome are colorectal cancer (occurring in 43% of patients), genitourinary cancer (21%), and breast cancer (14%).51 Not only is eyelid SebCa commonly misdiagnosed clinically, in 35% of cases it is initially misdiagnosed on pathologic evaluation of biopsy or surgical resection specimens.44 Up to 75% of cases of SebCa are misdiagnosed as SCC due to “large ovoid nuclei, eosinophilic nucleoli, abundant eosinophilic cytoplasm, and distinct cell borders.”52 SebCa commonly exhibits a lobular or solid growth pattern, and pagetoid spread (intraepithelial neoplasia) is reported in 40% to 45% of patients.45,52 Lipid and fat staining with Oil-red O and Sudan Black on fresh frozen sections is commonly used to identify intracytoplasmic lipids. More recently, adipophilin antibody stain, which can be used on paraffin-embedded sections, has been shown to have a specific pattern of “strong uptake at the periphery of intracytoplasmic lipid vacuoles” in SebCa that differs significantly from the patterns of expression in BCC or SCC.53 In a series of 60 patients with eyelid SebCa, the local recurrence rate after surgical excision was 18% to 19.4%44; however, in the subset of 26 patients who presented with a delay in diagnosis of at least 6 months, the local recurrence rate was higher than 30% (7 of 26).45 In a series of 42 patients with eyelid SebCa, all three patients with microscopic perineural invasion discovered in the resection specimen developed lymph node or distant metastasis.54

Eyelid and ocular surface carcinoma Rates of pagetoid spread, which refers to intraepithelial (in situ) disease in the conjunctiva in a noncontiguous fashion in SebCa, have been reported to be 26% to 47%.44,45,55 The pagetoid spread can involve as much as 90% of the conjunctival surface.56 Surprisingly, in one study pagetoid spread was reported not to increase the risk of recurrence, which occurred in 1 of 11 patients with pagetoid spread and two in 12 without.57 Reported mean times from initial treatment to diagnosis of recurrence are 21 to 25 months, and reported metastasis rates are 8% to 18% for nodal metastasis and 3% to 8% for distant metastasis44,45,55; however, nodal metastasis as late as 11 years after initial treatment has been described in patients with SebCa of the caruncle after excision with negative surgical margins.58 Patients with AJCC T2 b or a more advanced disease had a significantly higher risk of nodal metastasis, and no tumor smaller than 9 mm was associated with nodal metastasis.55 In addition, disease-specific survival was significantly worse for patients with T category of T2 b or worse at presentation.55 The most common types of distant metastasis were metastasis to the lungs, metastasis to the liver, and widespread metastatic disease.44,59

Merkel cell carcinoma MCC is a rare and aggressive neuroendocrine malignancy of the skin that can present in the eyelids and periocular region. MCC has a notoriously rapid growth rate. MCC typically appears as an asymptomatic, solitary nodule with distinctively “violaceous” coloration (Figure 5) and may have ulceration or overlying telangiectasia.

Fig. 5 Merkel cell carcinoma in a 72-year-old woman with a violaceous nodular tumor of the right upper eyelid for 10 months.

163 MCCs arise most commonly in the eighth decade and are slightly more common in men.60 MCCs often mimic other lesions and are often initially misdiagnosed as cysts, chalazia, keratoacanthomas, or BCCs.61,62 The cell of origin, as first described by Friedrich Merkel in 1875, is of epithelial origin with neuroendocrine differentiation and has been hypothesized to function as a tactile mechanoreceptor.63 More recently, it has been suggested that MCCs may derive from proliferations of dermal pluripotent stem cells.64 While MCC may occur on any area of the skin, half of all tumors appear on the head and neck, and 10% of all tumors involve the eyelids or periocular region.65 MCC has been found to be associated with sun exposure, immunosuppression, and polyomavirus.66,67 It is more commonly identified in the upper eyelid and usually arises near the lid margin, often causing partial or complete eyelash loss. MCC may be associated with concurrent neoplasms, such as SCC, BCC, SebCa, breast and ovarian adenocarcinomas, and lymphomas,68–72 and may share carcinogenic processes with other cells of neural crest origin.73 Microscopic evaluation of MCC reveals poorly defined groupings of small cells in the dermis and subcutaneous tissue with characteristic scant cytoplasm and salt-andpepper, finely dispersed chromatin.74 Electron microscopy can aid in diagnosis, demonstrating characteristic cytoplasmic granules 80 to 150 nm in diameter.75 The immunohistochemical presence of neuron-specific enolase, chromogranin, synaptophysin, CD44, and CK20 and the absence of leukocyte common antigen and S100 protein are helpful for histopathological differentiation of MCC from neuroendocrine tumors with a similar appearance.76,77 MCC of all sites is associated with a poor prognosis because it is often delayed in diagnosis and has a propensity for rapid and aggressive growth, local recurrence, early nodal metastasis, and widespread distant metastasis. While eyelid and periocular MCC may be diagnosed earlier than MCC at other sites due to better visualization of tumors at these locations, eyelid and periocular MCCs still shows predictable spread to preauricular and submandibular lymph nodes: Up to two-thirds of patients have regional lymph node metastasis and one-third of patients have distant metastasis diagnosed within 18 months of initial MCC diagnosis.61,78 Distant metastasis most commonly involves the skin, bone, brain, liver, and lung, and the distant metastasis rate has been found to be as high as 38%.61 Recently, a large retrospective series of 18 patients with MCC of the eyelid revealed a lymph node metastasis rate of 22% at presentation and showed a significant correlation of lymph node metastasis at presentation with shorter disease-free survival and increased risk of distant metastasis.79 Although many clinicians investigate the possibility of lymph node involvement in the case of primary MCCs larger than 2 cm, even MCCs smaller than 1 cm have been reported to be associated with SLN involvement in up to 23% of cases.80 Careful consideration of regional lymph node involvement is, therefore, important before treatment is

164 planned for MCCs of any size. SLN biopsy has been shown to be a sensitive method for early detection of regional lymph node metastasis in MCC.81,82 The role for and implementation of adjuvant radiotherapy in the treatment of MCC remain controversial. While some clinicians advocate nodal bed irradiation only if SLN biopsy reveals nodal disease; other clinicians employ prophylactic irradiation of parotid, submandibular, and cervical nodal basins in every case.79,83 A role for prophylactic irradiation of the tissue between the lesion and lymph node bed after excision has also been suggested.84

Patient evaluation Patients who present with suspected eyelid malignancies should undergo a thorough medical history with specific inquiry about a history of prior skin cancer, sun exposure, radiation exposure, and immune status, and a complete ocular adnexal examination, including eversion of all four eyelids and palpation of the lymph nodes in the preauricular and cervical regions. Baseline external photographs or slit lamp photographs are useful for documentation and for future comparison. Patients with eyelid cancer should also undergo a full-body skin check under the care of a dermatologist. If the diagnosis is unclear, a biopsy should be done to establish the diagnosis. When there is suspicion of orbital invasion, which is more common in the case of large tumors or tumors at certain locations, as discussed above, fine-cut orbital computed tomography or magnetic resonance imaging is needed. Signs of orbital involvement range from no symptoms to strabismus, hypoglobus or hyperglobus, ocular motility deficit, and proptosis. Patients with malignancies associated with a high risk of nodal metastasis should undergo ultrasonography of the parotid, submandibular, and cervical nodes, and fine-needle aspiration biopsy of suspicious lymph nodes. For patients with eyelid tumors associated with a risk for metastasis, baseline chest radiography should be considered, and chest radiography should be performed as needed during the follow-up period.

Surgical resection The standard of care for nonpigmented eyelid malignancies (suspected carcinomas) is surgical excision with frozen section control of margins. The recommended safe margin of excision varies by histologic subtype: A 2- to 3-mm clear clinical margin may be appropriate for BCC, whereas, larger margins may be needed for more aggressive carcinomas, such as SCC, SebCa, and MCC.61,84–86 For BCC, the abnormal cell on a histologic section should be at least 0.2 mm from edge of section to decrease the recurrence rate.86 For any type of eyelid

V.T. Yin et al. malignancy, an orbital exenteration may be needed when there is extensive orbital invasion. Mohs micrographic surgery has been advocated for eyelid malignancies to ensure maximal preservation of normal tissue and to obtain margins free of disease.61,87–89 In one series of BCC, the rate of recurrence was zero among six patients who underwent Mohs micrographic surgery, compared to .71% among 423 patients who underwent en face resection17; however, a series of 385 patients with BCC showed no significant difference in recurrence rates between patients treated with Mohs micrographic surgery and those treated with permanent sections when results were adjusted for patient age.90 For carcinomas involving the conjunctiva, such as OSSN or SebCa, the margin width considered safe is usually smaller than the margin width considered safe for carcinomas involving the skin. Some clinicians advocate a “no touch” technique with application of alcohol to the epithelial corneal edge and cryotherapy of the resection edge.91 The addition of cryotherapy to the margins and scleral bed has been shown to significantly reduce rates of recurrence.30,92–94 Due to the high rate of pagetoid spread in SebCa, conjunctival map biopsies have been advocated.44 Cryotherapy had been tried as a primary treatment. In a report of 100 patients with BCC smaller than 8 mm in diameter treated with cryotherapy, the 5-year recurrence rate was 8%95; however, it is important to note that this study had a high proportion of patients lost to follow-up.

Indications for SLN biopsy for eyelid carcinoma Rates of regional lymph node metastasis in tumors involving the eyelid and conjunctiva are up to 24% for SCC,20 18% for SebCa,55 21% for MCC,61 and 11% for eyelid melanoma.96 Early detection of lymph node micrometastases should theoretically improve survival. Morton et al.97 showed that in 1269 patients with intermediate-thickness melanoma of the skin it was estimated a 5-year disease free survival rate was higher in the patients who had SLNB (78%) compared to observation (73%). In addition, in patients with nodal metastasis, the 5-year survival rate was significantly higher for those who had immediate lymphadenectomy since a positive SLN compared to those who had a delayed lymphadenectomy, ie, patients in whom discovery of nodal metastasis was delayed until obvious on clinical examination (72% vs. 52%; p = 0.004).97 SLN biopsy has been recommended for eyelid malignancies associated with a risk for regional lymph node metastasis, including melanoma, SCC, SebCa, and MCC. For SCC of the eyelid, Nasser et al.98 found that SCC ≥ 18 mm or AJCC stage T2 b or more advanced is associated with nodal metastasis at presentation or during the follow-up. For SebCa of the eyelid, risk factors for nodal metastasis, are AJCC T category of T2 b or greater and a tumor larger than

Eyelid and ocular surface carcinoma 10 mm in the greatest diameter.55 These two studies suggest that for eyelid sebaceous or squamous carcinoma with T category of T2 b or more advanced may be considered for SLN biopsy. Merkel cell carcinoma is known for its propensity for nodal metastasis with an estimated nodal metastasis risk as high as 43%.81 A study of 97 primary MCC showed an association between positive SLN biopsy and increased diameter and tumor thickness, high mitotic rate, and infiltrative growth pattern.79 SLN identification starts with preoperative lymphoscintigraphy 1 to 2 days before a planned surgical biopsy. Filtered 99 m Tc-labeled sulfur colloid from 0.3 to 0.4 mCi in 0.2 mL is injected into the area immediately surrounding the tumor.99 Transmission images are taken every few minutes with low-activity cobalt 57 sheet source in addition to dynamic photos with a gamma camera.99 More recently, SPECT/CT has been used to give better anatomic delineation. 100 Intraoperative identification of the SLN is accomplished using a handheld gamma probe after 99 mTc-labeled sulfur colloid, 0.3 mCi in 0.2 mL, is injected in the same fashion described above 1 to 1.5 hours before surgery. The rate of successful identification of SLNs for ocular and conjunctival lesions on preoperative lymphoscintigraphy is as high as 96.7% and during intraoperative mapping as high as 100%.101 In this report by investigators from MD Anderson Cancer Center, the authors reported a false negative rate of 8% (2 of 25 patients); however, the two false negative cases were both from the authors early experience with SLN biopsy and one of the two cases was due to missing the diagnosis on histologic evaluation of the SLNs.101 Another series of 17 patients with eyelid and conjunctival tumors found 100% identification rate and no false negative findings.102 It is important to note that for false negative event reporting to be meaningful there is a need for meaningful long-term follow-up of the patients to rule out recurrence in the regional lymph nodes that have been deemed negative on SLN biopsy. The management of patients with a positive SLN biopsy result entails completion lymph node dissection and possible parotidectomy, if the positive SLN is in the parotid area; however, the Multicenter Selective Lymphadenectomy Trial II found disease-specific survival to be similar at 73 months in patients who undergo complete lymphadenectomy immediately after positive SLN biopsy compared to patients with a positive SLN biopsy result who did not receive additional completion lymphadenectomy.103 A randomized follow-up study is currently further evaluating the potential survival benefit of immediate lymphadenctomy after a positive SLN biopsy versus observation in melanoma patients with a positive SLN.

Adjuvant radiotherapy and chemotherapy In the management of eyelid malignancies, radiation has historically been used for adjuvant treatment of high-risk

165 tumors, especially those with perineural invasion; primary treatment of advanced disease; or palliative treatment.104,105 In a study of 13 patients with T3 SebCa, the local recurrence rate was lower among those who received adjuvant radiotherapy (2 of 7 patients; 28%) than among those who did not (5 of 6 patients; 83.3%).106 Adjuvant radiotherapy has been recommended for eyelid malignancies with aggressive histologic subtype, perineural invasion, or nodal metastasis at presentation.104 In a series of 13 patients with eyelid SebCa treated with definitive radiotherapy, only one patient had experienced recurrence with a median follow-up time of 55 months, and the calculated 5-year disease-free survival rate was 89%.106 Side effects from radiation include chronic dry eye, conjunctival keratinization, blepharitis, trichiasis, exposure keratopathy, cataract, optic neuropathy, and retinopathy.104,107 Systemic chemotherapy is recommended for patients with distant metastasis and can be considered for patients with extensive nodal disease with Merkel cell carcinoma108 and sebaceous carcinoma.109,110 In 27 patients with Merkel cell carcinoma, 18 of 26 patients responded with 41% complete response, but the response is not lasting unless followed by radiation therapy.108 A variety of chemotherapy agents were used in this study including combination of cyclophosphamide, methotrexate, and 5-FU, cisplatin and cisplatin and etoposide. Two case reports on management of recurrent, locally advanced or metastatic SebCa of the eyelids showed neoadjuvant cisplatin and 5-FU for 1 cycle in one case report and carboplatin and 5-FU for 3 cycles in the other with favorable response and stable residual disease.109,110 Topical treatments for management of eyelid cancers include imiquimod 5% cream (Aldara) mitomycin C eye drops, 5-fluorouracil eye drops, and interferon alpha-2 b eye drops. Imiquimod induces apoptosis of cancer cells through activation of cell-mediated immune response and cytokine production. Although imiquimod is not approved by the US Food and Drug Administration for periocular use due to the risk of conjunctival irritation, this drug has shown promise in the treatment of periocular SCC in situ,111–113 nodular BCC,114,115 and melanoma in situ.116 In a study of 8 patients with 10 BCC lesions, application of imiquimod 1 to 2 times a day 5 times a week for 6 to 16 weeks resulted in complete clinical resolution in 80% of cases.115 Another study of 27 patients compared topical imiquimod (n = 15) to radiotherapy (n = 12) for BCCs smaller than 12 mm and found equivalent results, but better cosmesis in the group treated with imiquimod.117 Intense conjunctival injection occurred in 2 of 15 patients treated with imiquimod.117 Topical chemotherapy has been used as both primary and adjuvant therapy for OSSN and as adjuvant therapy for residual SebCa in situ. For residual SebCa in situ, topical mitomycin C .04% 4 times a day 1 week on, 1 week off has induced clinical tumor regression after 3 cycles in 1 patient and 4 cycles in 2 patients.56 Lower concentrations of mitomycin C (eg, 0.02%) have also been used in clinical practice.118 Topical 5-fluorouracil and mitomycin C have both been found to be very effective in preventing recurrence

166 of OSSN.38 Epiphora as a result of punctual stenosis occurred in 14 of 100 eyes treated with 1 to 3 cycles of mitomycin C 0.04%, and 31 of 91 patients (34%) treated with mitomycin C developed allergic reactions to the drug.119 Topical and subconjunctival administration of interferon alpha-2 b has showed an excellent efficacy in controlling and preventing recurrence of OSSN and has a much better side effect profile than 5-fluorouracil and mitomycin C, but may require longer treatment duration.38,39 Additionally, perilesional subconjunctival injection of bevacizumab for OSSN has recently been described and shown to be effective in treatment of conjunctival lesions, but with no significant effect on corneal lesions.40

Targeted therapies Sonic hedgehog inhibition for periocular BCC Mutations in the hedgehog pathway have been seen in association with BCC. BCC has been associated with lossof-function mutation of the gene encoding the patched 1 transmembrane protein and gain-of-function mutation of smoothened resulting in a constitutively activated hedgehog pathway even in the absence of hedgehog binding, leading to cellular proliferation and angiogenesis. Vismodegib, a small molecule inhibitor of smoothened, at 150 mg daily in tablet form has been shown to be effective against both locally advanced and metastatic BCC.120,121 In addition, significant clinical response to vismodegib has been seen in patients with basal cell nevus syndrome (Gorlin-Golz syndrome). In a randomized trial comparing vismodegib with placebo in patients with basal cell nevus syndrome, patients in the vismodegib group had a significantly higher rate of decrease in the size of existing BCC (65% vs. 11%) and a lower rate of occurrence of new surgically eligible BCCs (2 per year vs. 29 per year), defined as a diameter of 3 mm or greater on the nose or periorbital skin, 5 mm or greater on the rest of the face or 9 mm or great on the rest of body.122 The most common side effects are dyspepsia, dysgeusia, weight loss, leg cramps, alopecia, and lower back pain. Fourteen of 26 patients (54%) with basal cell nevus syndrome treated with vismodegib had to discontinue the medication due to side effects.122

EGFR targeting for advanced periocular SCC The degree of overexpression of EGFR has been associated with the aggressiveness of cutaneous SCC and was an independent predictor of metastasis in an analysis of 54 head and neck SCCs.123 EGFR overexpression was also shown in conjunctival SCC.124 Two small molecule EGFR inhibitors are currently available, erlotinib and gefitinib. Both are tyrosine kinase inhibitors, available as oral drugs, and administered daily. Erlotinib and gefitinib have similar

V.T. Yin et al. side effect profiles and produce rash, diarrhea, mucositis, and trichomegaly. Erlotinib, approved by the US Food and Drug Administration for treatment of locally advance or metastatic non–small-cell lung cancer and pancreatic cancer, produced disease stabilization in 44 of 115 patients (38.3%) for a median duration of 16.1 weeks in a multicenter phase two study.125 Gefitinib was previously approved as monotherapy for non–small-cell lung cancer, but is now approved only for use in patients who had previously displayed benefits from gefitinib. In addition to the small molecule inhibitors, cetuximab, a mouse-human chimeric monoclonal antibody to EGFR, is available. Cetuximab was the first EGFR inhibitor approved by the US Food and Drug Administration for metastatic colorectal cancer. It can be given as a weekly infusion and has produced disease control in 69% to 81% of patients with metastatic or surgically unresectable SCC.126 Positive experience with durable responses to EGFR inhibitors in a few cases of advanced recurrent eyelid and orbital SCC has been reported.127 The authors of this report from MD Anderson found that EGFR inhibitors may offer an alternative nonsurgical treatment for patients who may not be good surgical candidates due to advanced age, or extensive nature of proposed surgery.

Surveillance of patients with eyelid carcinoma Patients with eyelid malignancies require long-term follow-up even after surgical resection with negative margins. The frequency and duration of follow-up is dependent on the type of malignancy. For primary BCC of morpheaform subtype or recurrent BCC, as well for SebCa, MCC, and SCC, a minimum of 5 years of follow-up is recommended.9 The frequency of visits is dependent on many factors including the stage of carcinoma at initial presentation. During each visit the surgical site should be clinically examined for signs of recurrence. Slit lamp biomicroscopy is important in detecting microscopic recurrence on the conjunctival surface or in the tarsal plate. For patients who have undergone an orbital exenteration for their advanced carcinoma of the eyelid or periocular region, imaging of the orbit is indicated during the follow-up surveillance period. In addition to careful clinical examination for local recurrence at each visit, patients with carcinomas associated with an increased risk of nodal metastasis should have a clinical examination for preauricular and cervical adenopathy and neck sonography. Fine-needle aspiration biopsy can be done if a suspicious node is noted on parotid and neck sonography. Most cases of nodal metastasis occur within the first 2 to 3 years after treatment of carcinoma44,61,78; however, unusually late metastasis can occur in rare cases.58 For patients with carcinomas associated with a high risk for distant metastasis. such as Merkel cell carcinoma or advanced cases of sebaceous carcinoma surveillance for lung metastasis with chest X-rays or CT, scans may be appropriate.

Eyelid and ocular surface carcinoma

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