CHAPTER 49 The management of eyelid tumors
Having a comprehensive knowledge of the epidemiology, the clinical features of benign and malignant eyelid tumors, an understanding of the relevant tumor biology, and available diagnostic and therapeutic options is essential for the clinician caring for these patients to be able to deliver an appropriate standard of care1.
Epidemiology
Skin cancer is the most common human malignancy with a corresponding human morbidity, mortality, and health care cost. A variety of benign and malignant primary skin, adnexal and other tumors may involve the eyelids, as well as a range of secondary malignancies2. The four relatively common malignant tumors to involve the eyelids are basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous carcinoma (SC), and malignant melanoma (MM). Additionally almost any other adnexal process can involve the eyelids but these tumors have a very low incidence.
BCC represents about 80% of eyelid malignancies, SCC about 15%, with SC, MM, and other rarer lesions making up the remainder. The age-standardized incidence of BCC ranges from 53 (Germany) to 1041 (Australia) per 100 000 per year3. The age-standardized incidence of SCC is lower, ranging from 11 (Germany) to 499 (Australia) per 100 000 per year. MM incidence in the United States was 24.6 per 100 000 in 20064–6. The Australian incidence is higher; statistics from an Australian cancer registry show an age-standardized incidence rate of 64.4/100 000/year and a mortality rate of 7.1/100 000/year for MM7. The reported incidence in a United States population of SC in whites is 0.11–0.2/100 000/year8, 0.1 in Asian/Pacific Islanders and 0.05/100 000 in blacks9. The incidence in Asians has been reported as much higher, representing 30–40% of all eyelid malignancies in Chinese, Indian, Thai, and Japanese populations10.
The incidence of Merkel cell carcinoma ranges from 0.17 to 0.44/100 000/year in a number of incidence reports, occurring predominately in elderly white males in the head and neck region11–13.
BCC is usually associated with long-term sun exposure14.
Australian studies, where there is a high baseline incidence of BCC, have not shown a strong occupational association, whereas German studies, with a lower baseline incidence, have shown an association with occupational exposure3,15,16. Higher dietary fat intake is associated with a higher incidence of SCC but not BCC17. A population-based study into the association of antioxidant levels and non-melanoma skin cancer (NMSC) incidence, looking at carotenoids, α-tocopherol, and selenium, showed no association with carotenoids or α-tocopherol, but an inverse association between serum selenium levels and the incidence of BCC and SCC18.
Clinical features, diagnosis, and differential diagnosis
BCC typically presents in the fifth to eighth decade of life, most commonly as a well-circumscribed nodular lesion with pearly edges and some telangiectasia, with or without ulceration (Fig. 49.1). These lesions are relatively easy to diagnose clinically but there are many clinical variants which can confound the clinician. Superficial, multifocal BCC may present as flat erythematous plaques; micronodular lesions as multiple small nodules, while the infiltrating, morpheic lesions may have very subtle features and indistinct margins, which make, diagnosis difficult and margins impossible to assess clinically (Fig. 49.2). Less commonly, BCCs may have cystic or pigmented components19.
SCCs may arise de novo, or from a pre-existing actinic keratosis (AK) or areas of squamous intraepidermal carcinoma (IEC, Bowen’s disease, SCC in situ), with appearances that range from erythematous plaques to raised nodular lesions that may be ulcerated, keratotic, or papillomatous (Fig. 49.3)20–22.
Melanomas are generally variably darkly pigmented, but may be amelanotic. They are usually categorized into lentigo maligna melanoma (Fig. 49.4A), superficial spreading melanoma (Fig. 49.8A), nodular melanoma, and acral melanoma. Most melanomas undergo a radial then a vertical growth phase (to be discussed later), such that they present as fairly large flat pigmented macules. The nodular form has a very short or absent radial growth phase and more commonly presents as a dark or reddish-brown nodule. Signs of ulceration clinically usually indicate progression into the vertical growth phase23.
Sebaceous carcinoma is notoriously difficult to diagnose clinically. The lesion may present as a nodule, or as an area of thickening of the tarsal plate associated with a yellow discoloration and ulceration (Fig. 49.5)24–26. Merkel cell carcinoma is also difficult to diagnose clinically, although they usually have a slightly violaceous, purplish hue and grow rapidly.
Probably more important than being able to diagnose each individual lesion correctly at every presentation is the ability to decide whether the lesion is benign or malignant. Further, various clinical features will suggest that a malignant lesion is either low risk or high risk for recurrence27–28.
These include the location and size of the lesion, rate of growth, regular or irregular borders, presence of chronic inflammation, prior irradiation, or neurological symptoms. Clinical diagnosis may need to be confirmed by biopsy. A number of biopsy techniques exist, including shave, punch, incisional, or excisional. Shave biopsies may allow confirmation of diagnosis, but the other techniques give more useful information about the behavior of the tumor in the deeper dermis. Where an attempted excisional biopsy is inadvertently incomplete, identification of the residual disease may be difficult. For these reasons, if biopsy is to be performed prior to definitive treatment, a punch or an incisional biopsy technique is preferred. There are also histological features which are associated with the rate of tumor recurrence. These include degree of differentiation, lymphovascular or perineural invasion, tumor subtype, and depth of invasion27–28. Using these guidelines the National Comprehensive Cancer network has made available guidelines for the management of NMSC. Similarly the Australian Cancer Network, with funding from the Australian Government, and the National Health and Medical Research Council have also published comprehensive multidisciplinary guidelines for the management of NMSC29.
Management
Prevention
Given that sun exposure is one of the main precipitants of NMSC, measures to reduce exposure are very important. Sunscreen has been shown to reduce the incidence of SCC and precursors. Sun exposure should be avoided between 10.00 hours and 14.00 hours, when 60% of the most harmful UV exposure occurs. Application of 30 sun protection factor (SPF) sunscreen should occur prior to sun exposure and be repeated after swimming, or sweating. A broad-brimmed hat and clothing that does not transmit light should be worn outdoors. Additional exposure from solariums increases the incidence of BCCs, SCCs, and MM. Their use should be discouraged. Annually, 281 new melanoma cases, 43 melanoma-related deaths, and 2572 new cases of squamous cell carcinoma were estimated to be attributable to solarium use in Australia30–32.
α-difluoromethylornithine (DFMO) 10% ointment appears to reduce BCC incidence but not SCC incidence, and holds promise as a form of chemoprevention33–35.
Resveratrol
Resveratrol, a polyphenolic phytoalexin, is a chemopreventative agent, present in grapes and red wine, which is currently under investigation in animal studies. SKH-1 hairless mice exposed to UVB and treated with topical application of resveratrol had a statistically significant lower incidence of AK, IEC and SCC development36. Further studies have confirmed this chemoprevention of squamous skin tumor development in SKH-1 hairless mice and suggested that transforming growth factor β2 signaling is targeted37.
Afamelanotide (CUV1647) is an analog of α-MSH which promotes synthesis of melanin in cutaneous keratinocytes and melanocytes and is being evaluated for AK and SCC prevention in organ transplant patients38.
Investigation
The vast majority of periocular tumors need little or no investigation. Diagnosis is usually clinical and treatment can be instituted. There are, however, situations where investigations are necessary. Where a diagnosis is unclear clinically, biopsy can be helpful in order to plan management39. For most NMSC a shave or punch biopsy from the thickest or most representative tumor region can be performed. When radiotherapy is considered as primary treatment for selected cases (too frail for surgical excision, or other specific reasons) biopsy should be performed prior to treatment to confirm diagnosis and plan treatment.
Should a lesion have any clinical sebaceous features, as suggested by location, a diffuse lid margin thickening or yellowish discoloration, generous biopsy to include representative tissue sampling is important and some advocate full-thickness biopsy for this reason. Where a melanoma is suspected, ideally biopsy should be excisional. Shave or punch biopsies may result in incorrect diagnosis or errors in pathological staging, particularly in relation to tumor thickness40–42.
Where a lesion might have invaded the orbit, as suggested by tumor extent, limited eye movements, or enophthalmos, imaging is mandatory to look for the posterior extent of the tumor (Fig. 49.6). Where there might be a possibility of perineural invasion (PNI), imaging is important to obtain preoperatively, if possible. Should PNI be found on histology, imaging should be considered, depending on the size of nerves involved. PNI of small nerves within the excised specimen may be too small to detect with imaging. PNI of larger, named nerves seen on pathology, or patients with clinical evidence of PNI (cranial nerve palsies, altered sensation, pain), may be detected on imaging studies43–47.
Magnetic resonance imaging (MRI) has better resolution for intraorbital structures and should be used for detection of PNI (Fig. 49.7). Larger tumors are also more likely to have PNI and imaging could be considered. Usually PNI will involve either motor or sensory nerve of the face and within the orbit coursing posteriorly to the brainstem. The possibility of PNI should be included on the imaging request form47.
Management of established disease
Once a tumor has developed and a diagnosis has been established, treatment should be undertaken to eradicate the tumor with minimal damage to surrounding ocular and periocular structures and their function. Currently available treatments for periocular tumors include surgery, radiotherapy, cryotherapy, curettage/diathermy, electro-dissection, photodynamic therapy, and topical agents (imiquimod, 5-fluorouracil, diclofenac gel), as well as emerging medical treatments. Traditionally, for most eyelid malignancies, the treatment has been surgical with excision of the tumor and subsequent repair. Less commonly, some lymphoid, metastatic or other lesions have are managed differently with chemotherapy, radiotherapy, or immunotherapy, reflecting their different tumor biology. The tumor should be staged according to the American Joint Committee on Cancer (AJCC) Eyelid Carcinoma staging protocol, which has been recently revised48. Further, if a melanoma, the AJCC specific melanoma staging system should be used49.
The integument consists of three main layers: the epidermis, the dermis, and the subcutis. The vast majority of cells are keratinocytes, involved in a staged maturation from the basal to superficial skin layers. Other cell types (<5%) include Langerhans cells, which have an important immune function, neural crest derived melanocytes, which are essentially protective, Merkel cells, which perform specialized sensory functions, as well as T-cells50.
Skin homeostasis is mediated by two populations of progenitors: renewable stem cells and their offspring, transient amplifying cells, which can give rise to the various cells of the hair follicle, the interfollicular epidermis (IFE), as well as sebocytes and sebaceous glands. The basal cells undergo an orderly, progressive maturation to suprabasal (or spinous cells), then granular cells. They then undergo a terminal differentiation into the stratum corneum, performing a barrier function before being shed as squames. Under the influence of lower levels of β-catenin they may develop into sebocytes and IFE, rather than hair follicles, suggesting that these pathways are closely linked51–52. Melanocytes migrate from the neural crest to the basal layer of the epidermis, uveal, and meningeal tissues, as well as ectodermal mucosa.
There are a number of important embryonic signaling pathways that influence skin development and homeostasis, influenced by a molecular conversation of their various proteins and genes. The most important of these are the hedgehog pathway (Hh), Wnt (wingless related mouse mammary tumor virus integration site), BMP (bone morphogenic protein), and notch53. Hh signaling influences hair follicle bulge stem cells to produce transit amplifying cells. This process is modulated by Wnt, which increases nuclear β-catenin resulting in upregulation of Hh signaling and Patched homolog 1 (Ptch1) in new follicles. Altered Hh function has been implicated in all BCCs following the finding of a mutant Ptch1 gene in the basal cell nevus syndrome (BCNS or Gorlin’s syndrome). Ptch1 functions as a classic tumor suppressor gene and 90% of sporadic BCCs can be shown to have Ptch1 mutations. Smoothened (SMO) is a downstream activator of the Hh pathway which may show an activating mutation in the remaining 10% of BCCs. Smo activates the Gli family of transcription factors. While genetic abnormalities at these levels are the most common seen in BCC development, other genes including those that influence skin color, repair DNA, or are involved with Wnt, PI3K, and FOXM1 have also been implicated.
SCC conforms to the multi-stage model of cancer, with mutations arising in the p53 tumor suppressor gene. Keratinocytes with multiple p53 mutations do not undergo apoptosis but rather proliferate with clonal expansion leading to SCC in situ and with progression to invasive SCC54.
MM progression from normal melanocytes has been linked to mutations in a number of genes involved: signaling RTK, Pl3K, retinoblastoma, p53, Wnt, and NF-kB pathways55. Five main oncogenes have also been implicated: NRAS, BRAF, MITF, NEDD-9, and KIT, and many others may also be involved.
Sebaceous carcinoma may develop via a number of different pathways. Muir–Torre syndrome is an autosomal dominant genodermatosis caused by mis-sense mutations in genes coding for mismatch repair enzymes, which is the best understood56. Loss of the fragile histidine triad protein has been shown to play a role in some periocular sebaceous carcinomas. Lef-1 mutations, as well as overexpression of β-catenin in the cytoplasm of eyelid sebaceous carcinomas have been reported, suggesting the involvement of multiple developmental pathways56–58.
There has been a great deal of recent activity in trying to inhibit the hedgehog pathway to influence the behavior of BCCs. These have largely come about following the linking of cyclopamine, a naturally occurring teratogenic alkaloid derived from the plant species Veratrum californicum, to its effects on the Hh pathway, and the identification of the importance of the Hh pathway in the development of BCC in the BCNS and sporadically59.
Knowledge of these genetic pathways has provided the opportunity to search for drugs which might alter the behavior of BCCs at a molecular level, without having to resort to surgery or other invasive techniques. Drugs targeting the hedgehog pathway can be thought of as SMO inhibitors of the Hh pathway, or other non-SMO inhibitors60. Unfortunately, cyclopamine, as well as being teratogenic, had poor aqueous solubility and did not lend itself to clinical trials61. Curis-61414 showed promise but had poor skin penetration, which precluded it from ongoing study62. GDC-0449 has been studied in Phase I trials with promising results showing 18 of 33 patients with advanced or metastatic disease showing a clinical or imaging response63. Consequently GDC-0449 is now undergoing Phase II trials for BCC and BCNS64–65. A small number of other SMO antagonists and non-SMO antagonist Hh inhibitors are also currently under investigation66–68.
Surgery
Surgery remains the main therapeutic modality for most malignant eyelid tumors. Management of BCC and SCC can be considered together as NMSC. The aim of surgical excision is to obtain cure, with histologically confirmed complete excision in both width and depth. Ideally normal function is retained and cosmesis is as good as possible. The main advantage of surgical excision is that it provides excellent overall cure rates and is currently superior to all other treatment modalities. Surgical excision also allows pathological examination of the excised specimen. Recommended surgical margins for BCC vary from 2 to 5 mm and for the majority of simple nodular lesions a 2–3 mm margin will be adequate. Factors associated with recurrent disease include the tumor size, site, and type. Morpheic, micronodular, or infiltrative lesions, or those with sclerotic or ulcerated histology, have a higher recurrence rate. Where lesions are reported as incompletely excised on routine histology, careful complete re-excision is the prudent recommendation. SCC is potentially more aggressive with the possibility of spread to draining lymph nodes, via perineural infiltration, or to other distant sites. Recommendations for SCC excision margins vary from 2 to10 mm. Realistically, complete tumor clearance should be the goal, with the initial excision margin varied according to the tumor type, location, and biology (if known from prior biopsy). Histological confirmation of excision may be performed subsequently, or at the time of excision with either frozen section control or Mohs’ micrographic surgery (MMS). Histological confirmation at the time offers the great advantage of being able to deal with any residual disease in the same surgical sitting, until clear margins are obtained, giving the highest cure rates. Simple breadloafing techniques will not examine the entire excision margin and ideally patients having intraoperative margin control should undergo MMS under care of a Mohs’ surgeon, with subsequent repair by an oculoplastic surgeon, or en-face examination of the entire excision margin by a dermatopathologist if frozen section is being performed19,69–71. MMS is primarily used in a tertiary referral setting for difficult to treat tumors arising from anatomically sensitive areas (including the periocular region), tumors with poorly defined borders, or poor tumor biology, recurrence, or extensive disease. Frozen section using en-face examination of the entire excision margin can offer similar cure rates in the periocular area. While intraoperative margin control is the ideal, it may not be practical in all health care systems. Some clinicians perform staged excision with overnight paraffin sections to obtain clear margins prior to surgical repair. Currently, surgical techniques that use comprehensive margin control, such as Mohs’ micrographic surgery, or frozen section with en face excision to examine the entire excision surface, give extremely low recurrence rates while minimizing the extent of the excision to facilitate reconstruction19,69–71. Using these techniques, primary BCC recurrence rates are roughly 1%, while previously recurrent lesions were 5.6%19,69–70.
Using combined series, recurrence rates for primary SCC are roughly 3%, whereas previously recurrent lesions had a higher rate of up to 10%21,71.
Wide local excision is the recommended treatment for cutaneous melanoma, including in the periocular region23,72–74. The surgical margin is determined by the Breslow thickness of the tumor74–75. Generally MMS and frozen section are not performed for cutaneous melanoma because of the difficulty in distinguishing atypical melanocytes, melanoma in situ, and invasive melanoma on frozen specimens. Most authors would perform rapid overnight paraffin section and mapped-serial excision (MSE) in order to obtain clear margins prior to reconstruction of the defect76. Most eyelid melanomas are <1 mm thick and a margin of 1 cm is generally recommended for these thin melanomas (pT1). Even with small lesions this results in large defects best managed by specialist clinics. For thicker lesions (pT2-3) margins of 1–2 cm are recommended. A 2 cm margin is recommended for T4 lesions40–42. Using the updated AJCC classification, sentinel lymph node (SLN) status is an important prognostic factor and is recommended for lesion greater than 1 mm thick and for some thinner melanomas with ulceration or other unfavorable features41–42,74,77–78.
Sebaceous carcinoma also occurs in the periocular region and warrants special mention for a number of reasons. First, it may be sporadic or occur as part of a systemic genodermatosis, the Muir–Torre syndrome. For these patients, the eye lesion may be the first manifestation of a systemic disorder associated with gastrointestinal, genitourinary, or other carcinomas. Diagnosis of an ocular sebaceous carcinoma should prompt systemic screening for the syndrome and other carcinomas. Appropriate genetic referral and counseling should be seen as part of the management. Immunohistochemical staining of the ocular specimen can predict the presence or absence of the systemic genodermatosis79,80. Second, the lesion is notoriously difficult to diagnose and is often regarded as a masquerading lesion, thus a high index of suspicion is required to anticipate the diagnosis81. Chronic blepharitis associated with a thickened lid margin, or the so-called ‘recurrent chalazion’, should prompt consideration of sebaceous carcinoma and appropriate biopsy. Traditionally lipid-based stains, such as Oil Red-O, have been used for confirmation of diagnosis but with advances in immunohistochemical profiles these are now complementary rather than essential. Third, it has a relatively high local recurrence rate due to a high incidence of pagetoid or other intraepithelial spread, requiring special management. Recommendations for excision vary, with some using MMS and others wide excision with 4–5 mm margins82. The overarching principle with all of these techniques is the pursuit of histologically confirmed complete excision. Because of the high incidence of pagetoid spread, multiple map biopsies of the conjunctiva are also advocated25. Should there be positive map biopsies topical treatment with adjunctive mitomycin C has been advocated to avoid exenteration in selected cases83.
Certain aspects of surgical management require further comment. Orbital invasion of malignant eyelid tumors should be managed with the principle of trying to obtain tumor clearance. Traditionally this has called for exenteration, and for extensive orbital involvement; this is still appropriate84. For lesser degrees of orbital involvement Madge et al. have advocated retention of the globe in selected cases85. Where orbital invasion has occurred in the setting of PNI, there appears to be a limited role for exenteration, with limited local resection and adjunctive radiotherapy to the antegrade and retrograde distribution of the involved neural structures, posteriorly to Meckel’s cave43.
Surgical reconstruction of the defect should ideally be delayed until histologically clear margins have been obtained. Simple principles should be followed to achieve the goal of restoration of function with a cosmetically satisfactory outcome86–88. The periocular region can be broken down into the upper and lower eyelids, the medial and lateral canthi, and specialized structures such as the lacrimal secretory and drainage apparatus. Loss of the anterior lamella (skin and orbicularis) only can be repaired by laissez-faire, skin grafts, or local flaps. Laissez-faire may have a role for small defects, or in patients unable or unwilling to undergo surgical repair. The results using this technique can be surprisingly good; however, eyelid malposition and canthal dystopia are potential complications89. Full-thickness skin grafts can also give pleasing results but tend to have greater shrinkage and potential for infection than vascularized flaps. This is especially true for skin grafts to the lateral aspect of the lower eyelid, particularly when there is concomitant solar damage. Grafts may be fenestrated to allow for drainage of collections and expansion of the graft surface area. Donor sites should be chosen to match like tissue with like tissue and in general the surgeon will look to the upper eyelid, pre- and postauricular, supraclavicular and upper arm skin in descending order of preference. Flaps also have the advantage of generally transposing tissue that is more similar to the excised tissue.
Where the defect involves the full thickness of the eyelid, consideration must be given to reconstructing both the anterior and posterior lamellae. Smaller defects may be closed directly, or with the assistance of a lateral cantholysis for lower and upper eyelid defects. The lower eyelid is more forgiving in terms of reconstruction than the upper eyelid. Loss of the lower eyelid can be better tolerated than loss of, or inadequate reconstruction of, the upper eyelid. Larger lower eyelid defects generally require a two-stage Wendell–Hughes (or Koellner–Hughes) repair, which may be divided as early as 1–2 weeks post primary repair90–93. Posterior lamella tarso-conjunctival grafting with an overlying transposed upper to lower eyelid myocutaneous flap, based at the lateral canthus, can give very pleasing cosmetic and functional results for larger lower eyelid defects. Many other reconstructive techniques have also been described, including Tenzel myocutaneous semicircular flaps, McGregor flaps, and much larger Mustardé cheek rotation flaps when required. The midline forehead flap is versatile for large upper and lower eyelid defects (see Fig. 49.4). All of these techniques have their place and the skilled oculoplastic surgeon will be facile with each of them.
Larger upper eyelid defects present more challenges. Traditionally a Cutler–Beard two-stage repair has been performed. This is a good technique providing the reconstructed upper lid is stabilized with some form of ‘tarsal’ reconstruction, to prevent late entropion. Alternatives are available and might need to be considered when actinic change to the lower eyelid restricts the mobility necessary for a Cutler–Beard flap. Where any of the superior aspects of the posterior lamella have been retained, this can be recessed to contribute to the new posterior lamella. Should this be absent then a tarsoconjunctival (preferably) or hard palate mucosal graft could be utilized. The anterior lamella can be derived from a fully vascularized sub-brow bipedicle myocutaneous flap, transposed to cover the tarsal remnant or tarso-conjunctival graft, with a full-thickness skin graft placed into the donor site of the bipedicle flap (see Fig. 49.8). Another approach for these large upper eyelid defects is to rotate the lower eyelid into the upper eyelid defect with a so-called Mustardé rotation flap (Fig. 49.9). This requires a second stage, to divide the reconstructed upper eyelid and to secondarily repair the lower eyelid donor site.
Radiotherapy
Radiotherapy is a well-established treatment modality that can be effective in the treatment of primary and recurrent periocular NMSC94.
Cryotherapy
Cryotherapy has utility elsewhere in the body, based on its ability to freeze intracellular water components, but has limited applicability in the periocular region. When used elsewhere, histological confirmation prior to treatment may not be obtained, but this can have significant consequences around the eye95. Deeper lesions may not be completely eradicated, extending deeply toward the orbit with little surface abnormality, risking orbital invasion. Lesions close to the lid margin, particularly intraepidermal SCC (IEC) tend to invade down follicular structures and not be affected by superficial applications of cryotherapy. For these reasons cryotherapy is not generally recommended close to the eye. One series of patients with eyelid BCC treated with cryotherapy have a lower cure rate than surgery, with 97% and 95% success for nodular and infiltrative lesions less than 1 cm in diameter but 85% and 82% respectively when the lesion diameter was greater than 1 cm96.
Laser
Lasers have been used to prevent and treat NMSC. CO2 lasers have been used to prevent the progression of AK’s and to treat IE, or Bowen’s disease. NeodymiumYag lasers have been effectively used in the treatment of BCC and SCC, with low recurrence rates of 2–5%97–99.
Topical agents
The two main topical agents include 5-fluorouracil (5FU) and imiquimod. 5FU acts by depleting thymidine in cells resulting in decreased DNA production, reduced cell growth, and subsequent cell death100. Normal cells are relatively resistant to the effects of 5FU, but rapidly proliferating tumor cells are more susceptible. 5FU has been used in the treatment of actinic keratoses, SCC in situ, SCC, keratoacanthoma, and superficial BCC, elsewhere in the body 101,102. Unfortunately, 5FU has poor penetration of the dermis, so has limited applicability to invasive BCC or SCC. There are also reports of its use in the periocular region. There are anatomical reasons that limit its use in this region, as well as poor dermal penetration. First, there is the risk of extension of squamoproliferative lesions downwards along eyelash follicles, or more deeply into the orbit if treatment is unsuccessful. Also, conjunctival and ocular irritation can occur as a complication of topical 5FU applied close to the eye. Having said this, there may well be situations in selected patients too frail to undergo surgery, or those with tumor predispositions such as ongoing immunosuppression (including organ transplant recipients) or the basal cell nevus syndrome (BCNS), who may benefit from the use of this topical agent.
Imiquimod stimulates toll-like receptors (TLRs) on antigen presenting cells to stimulate innate and acquired immunity. It causes the production of a number of inflammatory cytokines, including interferon α, tumor necrosis factor α, as well as interleukins 12 and 6, to prolong the immune reaction and promote Langerhans cell activity103. There is increased cytotoxic T-cell, natural killer cell, and B-cell activity, resulting in powerful anti-viral and anti-tumor activity104. Imiquimod has a proven role against basal cell carcinoma, in-situ and invasive squamous proliferations as well as lentigo maligna. Recently there have been a number of case reports and small series of the benefits of imiquimod in the treatment of periocular BCC, SCC (and related lesions) as well as lentigo maligna, in selected cases105–106. Resiquimod is another TLR7/8 agonist, currently under trial, with greater potency than imiquimod107. There is little doubt that these medical approaches to periocular malignancy will have an increasingly important role.
Photodynamic therapy
Photodynamic therapy (PDT) has a role in the management of squamoproliferative lesions as well as BCC. PDT works by the accumulation of a photosensitizer, light energy, and oxygen within the target cell. The photosensitizer, usually alpha- or methyl aminolevulinic acid, accumulates light energy of a specific wavelength and generates reactive oxygen species (ROS), which causes tissue damage by the induction of necrosis and apoptosis. The technique has a lower success rate than surgical excision or radiotherapy but, like 5FU and imiquimod, may have some application in the periocular region in patients who are unable to undergo surgical excision, or who have multiple lesions, as seen in immunosuppressed patients and those with the BCNS108–109.
Retinoids
Retinoids have been demonstrated to be useful in the management and prevention of NMSC. Systemic toxicity has been a problem with broad-spectrum retinoic receptor agonists. Tazarotene activates a specific group of retinoid receptors and is useful against BCC but with fewer systemic side effects (mainly skin irritation)110. Currently under study, tazarotene may have application in chemoprevention and of BCCs where there is an underlying predisposition to the development of multiple lesions, as in the BCNS.
Diclofenac gel
Cyclooxegenase 2 is expressed in a range of skin lesions, AK, SCC, BCC, and melanoma. UVB induces COX-2 in humans. Studies have shown benefit from the use of selective COX-2 inhibitors in AK, BCC, and SCC. Diclofenac 3.0% gel is effective against Bowen’s disease111–113.
Interferon
Interferon exerts an anti-proliferative effect on lesional cells and enhances surrounding local tissue immune system activity. This has been used as a gel preparation for AKs with no advantage over placebo, although intralesional injections have been successful for BCC and SCC, but limitations include significant cost and the need for multiple injections114–116.
Ingenol mebutate
Ingenol mebutate, initially used as a home treatment for various skin lesions, is derived from the milkweed plant, and is now being subjected to controlled studies for the treatment of actinic keratoses. It acts by causing plasma membrane disruption, and mitochondrial dysfunction in dysplastic keratinocytes. It also induces an antibody dependant cytotoxicity117,
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