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Periocular Tumours: Green Lights, Orange Warnings and Red Flags

2 CPD in Australia | TBC in New Zealand | 1 February 2019

By Dr Dov Hersh

Two in three Australians will be diagnosed with skin cancer by the time they are 70, and of these, 5–10 per cent will be eyelid malignancies. Eye care professionals have a unique opportunity to identify ‘red flags’ that may indicate malignant transformation of periocular lesions. With timely referral to an oculoplastic surgeon, excellent functional and aesthetic results can be achieved in the treatment of malignant periocular tumours.


1. Understand important basic science concepts relating to the development of periocular tumours

2. Gain an appreciation of the presentation and spectrum of malignant periocular tumours

3. Identify clinical “red flags" that may indicate malignant transformation of periocular lesions and that should serve as a catalyst for specialist review

4. Gain an understanding of treatment options and future trends in treating periocular tumours

5. Appreciate the anatomical constraints and special considerations in periocular reconstruction. 

In his 2011 Pulitzer Prize winning book The Emperor of All Maladies: A Biography of Cancer, Siddhartha Mukherjee wrote “Cell division allows us as organisms to grow, to adapt, to recover, to repair – to live. And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair – to live at the cost of our living”.

Two thirds of Australians will be diagnosed with skin cancer by the time they are 70, and of these cases, 5–10 per cent will consist of eyelid malignancies.2 Due to the anatomical constraints and functional importance of the eyelids in protecting and maintaining a healthy ocular surface, the management of periocular tumours can be challenging. Additionally, in advanced disease, periocular tumours can invade the orbit and intracranial space via perineural or sub periosteal spread. To this end, eyelid tumours warrant particular consideration of the clinical presentation and specific treatment options. Complications from a poorly reconstructed eyelid can include ptosis, lid malposition, lagophthalmos, restriction of eye movements and exposure keratopathy. Oculoplastic surgeons are specifically trained in the diagnosis and treatment of periocular tumours in order to achieve both complete tumour clearance and the maintenance of normal ocular function where possible.

In this article I aim to present a clinically focused overview of periocular skin cancer including important basic science concepts and a practical guide to examination findings suggestive of malignant transformation or ‘red flags’, that should serve as a catalyst for specialist review. I will also provide an overview of current management strategies, including surgical reconstructive considerations relevant to the periocular area, and an update on the emerging field of systemic immunotherapy for advanced disease.

Cancer Basics – Cell Division Gone AwRy

What Goes Wrong?

In order to sustain life, cells replicate via an intricately regulated cell cycle – resulting in duplication of DNA and division of cells to produce two identical daughter cells. Cell cycle checkpoints monitor and regulate the progress of cell replication, allowing for verification of cell integrity and repair of any DNA damage that may occur during duplication. 

If cell cycle regulators detect a cell with unrepairable DNA, checkpoint mechanisms initiate cell apoptosis. Apoptosis is defined as ‘programmed cell death’.  It involves the systematic deconstruction of damaged or redundant cells into constituent components, some of which are recycled for use in new cell division.

In normal cells, specialised genes categorised as tumour suppressor genes (TSG), code for proteins that actively screen for unrepairable DNA during cell division and trigger apoptosis. In cancerous cells, there is malfunctioning of the cell cycle checkpoints leading to uncontrolled growth of abnormal cells with unrepairable DNA damage (Figure 1). Most cancers arise as cells acquire a series of mutations in DNA that allow unlimited cell growth, promote angiogenesis, evade internal and external controls on division, and avoid apoptosis. As a tumour progresses, its cells typically acquire more and more mutations, to the point where advanced stage cancers may have major changes in their genomes, including large scale mutations such as the loss or duplication of entire chromosomes.3

Figure 1.  In normal cells, if unrepairable DNA damage is detected by checkpoint mechanisms, the cell undergoes apoptosis. In cancerous cells a series of mutations in DNA enable evasion of internal and external controls on division, resulting in unregulated abnormal cell growth.


How It Goes Wrong

Broadly speaking, cancer associated gene mutations can affect the normal cell cycle in two ways:

  1. Up regulation of oncogenes promoting uncontrolled cell replication, or
  2. Down regulation of TSGs, resulting in bypassing of the checkpoint mechanisms that trigger apoptosis. Carcinogens including UV radiation, ionising radiation and smoking promote up regulation of proto-oncogenes and down regulation of TSGs. 

Up Regulation of Oncogenes

All cells contain proto-oncogenes, which in normal circumstances promote healthy cell replication providing growth factors are initiated. Certain mutations can transform proto-oncogenes into oncogenes resulting in abnormal and uncontrolled cell replication in the absence of growth factors ie. cancerous cells.

Examples of mutations and up regulation of proto-oncogenes associated with specific cancers include BRAF mutations in melanoma, and herceptin mutations (HRC) in breast cancer. Epidermal growth factor receptor (EGFR) over-activation is present within 78 per cent of cutaneous squamous cell carcinomas (SCC).4

Down Regulation of Tumour Suppressor Genes

In cancer cells, down regulation of TSGs results in malfunctioning of the normal cell cycle checkpoints, disrupting detection and repair of damaged DNA and bypassing the apoptosis regulatory pathway.

A number of different TSGs are associated with cancers. The p53 gene plays a key role in the cellular response to DNA damage while other gene mutations are associated with specific disease presentations. For example, mutation in the RB1 TSG (located on chromosome 13q14) is highly correlated with retinoblastoma whereas mutations in BRCA1 and 2 TSGs increase a female’s chance of developing breast cancer from 12 per cent to 70 per cent, and ovarian cancer from 1.3 per cent to 44 per cent by the age of 80.5 Of particular relevance to periocular tumours is the association of basal cell carcinomas (BCC) to mutations in TSGs controlling sonic hedgehog pathway (SHH).

Understanding these mechanisms has resulted in the development of novel targeted immunotherapy which functions by interfering with up regulation of oncogenes and down regulation of TSGs. Specific immunomodulatory medications used in the treatment of epidermal and periocular cancers will be discussed later in this article.

The Language of Cancer

The language of cancer can seem overwhelming, however a brief outline of the important terminology is useful when discussing the management of patients with cancer.

Periocular Cell Types –

The Precursors and Clinical Spectrum

The Precursor Cells

The most common eyelid malignancies, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM) arise from cells located in the periocular skin (Figure 2). Sebaceous cells of the meibomian glands and conjunctiva, and merkel cells located in the eyelid dermis are the precursors to rare, but highly aggressive sebaceous gland carcinoma (SGC) and merkel cell carcinomas respectively.

Figure 2. Skin cancer progenitor cells


The Spectrum

In clinical practice, a spectrum of disease is encountered. The progression of a normal cell to a cancerous cell is a multi-step process in which several mechanisms fail before a critical mass is reached and the cell becomes wholly cancerous. Eyelid lesions vary from benign, dysplastic and in-situ carcinomas to frankly malignant and metastatic disease. Table 1 summarises cell types and correlated clinical tumour spectrum from benign to malignant.

Table 1: Clinical spectrum of periocular tumours classified by cell type


Periocular Cancer

Basal Cell Carcinoma

Basal cell carcinomas (BCCs) account for 90 per cent of malignant eyelid tumours, and make up the vast majority of periocular malignancies I treat. BCCs most frequently affect the lower eyelid, followed by the medial canthus, upper eyelid, and lateral canthus.6 These lesions tend to grow slowly, ulcerate centrally and may invade adjacent tissue. Invasion is a feature of advanced disease, and initially involves local spread with later involvement of the orbit and intracranial space via perineural or sub periosteal spread. Fortunately BCCs tend not to metastasise.

Two clinically distinct subtypes of BCC are recognised:

  1. Nodular and
  2. Infiltrative/morphaeform.

Nodular BCCs (Figure 3) account for 80 per cent of eyelid BCCs and typically present as distinct nodules with pearly edges, fine telangiectatic surface vessels, central ulceration and may display madarosis (loss of lashes). These tumours are the more indolent compared with the infiltrative subtype of BCC. Infiltrative or morphaeform BCCs present as indistinct plaques, which may cause cicatrisation of surrounding tissue. Infiltrative BCCs represent 15–20 per cent of BCCs and as their name suggests, have a greater tendency to invade deeper dermal structures and into the orbit.7

Figure 3: Periocular basal cell carcinoma displaying ulceration, telangiectatic vessels, pearly edges and madarosis


Risk factors for the development of BCCs include sun exposure, age, fair skin and immunosuppression. Patients with Gorlin-Goltz syndrome have an autosomal dominant mutation PTCH1 gene in the SHH Tumour Suppressor Pathway, resulting in a predisposition to widespread and aggressive BCC6 above.

Squamous Cell Carcinoma

Squamous cell carcinomas (SCCs) account for 5–10 per cent of malignant eyelid tumours. These tumours tend to be locally aggressive, display peri-neural invasion and have a relatively high potential for orbital invasion (Figure 4). Regional lymph node metastasis has been reported to be as high as 24 per cent, with the pre-auricular, parotid, and submandibular nodes most often involved.8

Figure 4. CT scan of a patient demonstrating Intra-orbital (red arrow) invasion along the medial orbital wall originating from a right medial canthus SCC


SCCs can arise de novo or at sites of actinic keratosis or Bowens disease. Actinic keratosis consist of dysplastic squamous cells and appear as erythematous, scaly macules or papules typically in sun exposed skin. Bowens disease (in-situ squamous cell carcinoma), occurs where the entire epidermis is replaced by atypical, disorganised squamous cells without dermal invasion. Bowen's disease presents as full thickness hyper keratotic plaques. SCCs typically present as erythematous nodules or plaques with overlying keratinisation, scaling and local tissue destruction (Figure 5). Histologically, SCC shows atypical squamous cells with varying degrees of differentiation, in nests and strands with invasion beyond the epidermis and into the dermis.

Figure 5. Periocular squamous cell carcinoma displaying hyperkeratosis, erythematous lesion, destruction of brow


Risk Factors for the development of SCCs include fair skin, exposure to UV light, immunosuppression, and infection with human papilloma virus. Inactivation of p53 tumour suppressor gene, and up regulation of EGFR proto-oncogene play a role in the pathogenesis of SCCs. SCCs are increased in hereditary conditions such as xeroderma pigmentosum, in which there is a decreased ability to repair DNA damage caused by ultraviolet light.6

Malignant Melanoma

Malignant melanomas (MMs) account for approximately 1 per cent of malignant eyelid tumours. Despite their low incidence, MMs are locally aggressive and have a propensity for metastatic spread, in particular to the brain followed by liver, bones, abdomen and distant lymph nodes. Mortality rates are high. Patients diagnosed with MM >1.5 mm thickness have a 50 per cent five-year survival rate. Patients with Stage IV MM have a one-year survival rate between 33–62 per cent.8

Most melanomas arise de novo, however they can arise from congenital nevi (lifetime transformation risk 1–5 per cent) and dysplastic nevi (lifetime transformation risk 30 per cent). Lentigo Maligna refers to melanoma in situ and is considered malignant melanoma once it has invaded the dermis. MMs present as macules or nodules with varying pigmentation (Figure 6) ranging in colour from tan/brown to grey/black. Borders are typically irregular and may be scalloped. Diagnosis of amelanotic melanomas, which do not display any pigmentary features, pose a particular challenge.

Figure 6. Periocular malignant melanoma displaying variable pigmentation, madarosis, lid destruction


The American Cancer Society ABCDE mnemonic is useful as a guideline for diagnosis of early melanoma.

A = Lesion asymmetry,

B = Border irregularity,

C = Colour variegation,

D = Diameter >6 mm, and

E = Evolving nature of lesion over time.

Prognosis is highly correlated with depth of invasion (Breslow thickness) quantified via biopsy.9

The most important risk factor is ultraviolet (UV-B) exposure, consequently Australia continues to have the highest incidence of melanoma in the world.2 Mutations in BRAF proto-oncogene  play a significant role in the pathogenesis of MM and are demonstrated in nearly 66 per cent of MM.

Sebaceous Gland Carcinoma

Sebaceous gland carcinomas (SGCs) arise from the sebaceous glands of the eyelids (meibomian glands and glands of Zeiss). SGCs are locally aggressive and display high rates of metastatic disease. SGCs deserve special mention as these tumours often mimic benign conditions such as recurrent chalazion, chronic unilateral blepharitis and benign sebaceous lesions.

SCGs are more common in Asian patients, and most commonly affect the upper lid, given the higher density of meibomian glands. A distinguishing feature is aggressive local extension and pagetoid (intraepithelial) spread, which allows the tumour to affect a significant amount of periocular tissue (Figure 7). SGCs often appear yellow due to lipid found within, and can cause localised destruction of tissue. Due to pagetoid spread, SCGs can be multicentric involving multiple distinct eyelid locations.

Figure 7. Upper lid SCG displaying pagetoid spread and skip lesions


Reported distant metastases range between 15–25 per cent, most commonly to the liver and lung. In patients with metastatic spread the five-year mortality rates range from 30–67 per cent.10

Merkel Cell Carcinoma

Merkel cell carcinomas (MCCs) are rare but aggressive tumours arising from cutaneous neuroendocrine cells, and have a predisposition for affecting the head and neck region. These tumours present as rapidly growing (weeks to months) painless red/purple nodules (Figure 8). Lymphatic spread is to the preauricular and submandibular lymph nodes. Mortality rates are high ranging between 36–44 per cent, and currently there is no effective treatment for metastatic disease.10

Figure 8. Merkel cell carcinoma


Clinical Assessment – The Red Flags

While biopsy is the only definitive way to distinguish between benign, dysplastic, in-situ and malignant lesions, certain clinical features are suggestive of malignant transformation. Suspicious clinical signs or ‘red flags’ indicative of malignant transformation include:

  1. Madarosis (local loss of lashes),
  2. Ulceration,
  3. Telangiectatic vessels,
  4. Disruption of the lid margin anatomy,
  5. Cicatrisation (tissue contraction causing distortion of normal anatomy), and
  6. Variable pigmentation.

Presence of these ‘red flags’ should serve as a catalyst for referral to an ophthalmologist or specialist for review (Table 2).8

Table 2. Clinical ‘red flags’ suggestive of malignant transformation


A clinical history of rapid growth or a change in pigmentation should arouse suspicion. Symptoms of paraesthesia, reduced periorbital sensation or diplopia may indicate perineural or orbital invasion.


Surgical excision with verified histological tumour clearance and reconstruction remains the gold standard of treatment for periocular tumours.11 Surgical excision allows for:

  1. Confirmation of pathology,
  2. Definitive tumour excision with verified negative margins, and
  3. Reduced rates of recurrence compared with alternate treatments.

Surgical cure rates approach 95 per cent for BCCs, and 80 per cent for SCCs. Topical chemotherapeutics, radiotherapy and systemic immunomodulatory medications are generally reserved for locally widespread or advanced disease not amenable to surgical excision and reconstruction. 

Surgical Excision and Reconstruction


Surgical margins for periocular tumours differ from other areas of the body given the functional consequences of removing large amounts of tissue from the periocular area. Controversy still exists regarding the recommended margins for standard excision of periocular malignancy. The accepted margins (for non margin controlled excision) for periocular tumour excision is determined by the nature of the lesion. For a presumed or biopsy proven BCC, 2–3mm is acceptable, 3–4mm for SCCs, and between 5–10mm for melanoma, sebaceous cell carcinoma and merkel cell carcinoma. By contrast, recommended surgical excision of margins for tumours outside of the periocular area are significantly wider: BCC 4–5mm, SCC 5–6mm, MM 15–20mm and merkel cell carcinoma 30mm.12 Due to the propensity for skip lesions, map biopsies should be performed in cases of SGC.

Margin controlled surgery permits real time histological confirmation of tumour clearance at the time of excision. Margin control surgery is extremely useful as this method allows for definitive tumour removal while preserving the greatest amount of normal tissue for reconstruction. The two recognised methods for margin controlled surgery are Moh's micrographic surgery and intraoperative frozen section (IFS) pathology service. I am fortunate enough to operate at centres with the ability to perform intraoperative frozen section, where a specialist pathologist attends surgery for my patients and confirms histological margin clearance prior to my performing the reconstruction. Surgeons without access to margin controlled pathology services will generally use the excision guidelines above, and refer tumours with indistinct clinical boarders or in anatomically complex areas, such as the medial canthus, for margin controlled surgery. An important caveat regarding the use of Moh's or IFS is that these methods are not appropriate for excision of melanoma, where paraffin section with delayed reconstruction should be performed.

Although regional lymph node metastases occur in periocular tumours, sentinel lymph node biopsy (SLNB), a procedure in which the sentinel lymph nodes are identified, removed, and examined to determine whether cancer cells are present, remains controversial. Studies have shown that SNLB does not provide a survival benefit, however it does provide prognostic information to the patient and can guide adjuvant treatment.13 Different centres and clinicians will have a preference as to cost benefit of SLNB for periocular tumours.


When consenting patients for surgical treatment of periocular tumours I explain that the order of priorities are:

  1. Tumour excision with clear histological margins,
  2. Reconstruction of the lids to allow for their function of protecting the globe and maintaining a clear ocular surface, and
  3. An acceptable cosmetic result.

A detailed review of the surgical techniques for treating periocular tumours is beyond the scope of this review, however I will provide a brief outline of the important concepts illustrated with examples of two patients I have recently treated.

The periocular tissue can be considered as comprising of three function units or lamella (Figure 9). The anterior lamella comprising of the skin, lashes and orbicularis muscle, functions to provide the outermost barrier via the skin, and closure of the lids via the orbicularis muscle. The middle lamella functions as the attachment to the muscles that open the eyelids (superior lid – levator palpebrae superioris, and inferior – inferior retractor muscles). The posterior lamella contains the tarsal plate and conjunctiva, providing tensile structure and secretory mucosa for the ocular surface. Potential complications of a poorly reconstructed eyelid include ptosis, lid retraction, lagophthalmos, trichiasis, chronic epiphora, entropion, ectropion, restriction of eye movements, exposure keratitis or corneal ulcer development.

Figure 9. Eyelid lamellae: A – Anterior, M – Middle, P – Posterior


When reconstructing the eyelid post excision it is important to replace the anterior and posterior lamella with the appropriate tissue type in order to preserve the function of the lids. Direct closure of all three lamella is the preferred reconstruction for central lid lesions. If closure is not possible, the anterior lamella can be reconstructed using either vascularised skin/skin muscle flaps from local tissue or full thickness skin grafts (FTSG). In order to allow for lid movement, donor skin should be thin and is commonly harvested from local tissue such as excess upper lid skin or from relatively sun protected distant donor sites with thin skin including clavicle, post auricular or inner arm skin. In order to provide lid structure and a smooth ocular surface, the posterior lamella must contain a firm tissue (collagen) base with a mucosal covering. Typical posterior donor sites include the upper lid tarsoconjunctiva, hard palate grafts or nasal mucosa. The middle lamella can be sutured between the reconstructed anterior and posterior lamella to provide eyelid opening.

Case Studies

Patient One

Patient one presented with an infiltrative left lower lid BCC. Excision involved 90 per cent of the lower lid (Figure 10a). Reconstruction of the posterior lamella was performed using a Hughes Flap, whereby a tarsoconjunctival flap (Figures 10b and c, white arrow) from the upper lid is transposed to the lower lid with a vascular bridge (Figures 10b and c, red arrow) providing blood supply. The anterior lamella was reconstructed using an inferior skin muscle advancement flap, outlined with the surgical marker. The flap is subsequently divided when the tissue has integrated to the host site, approximately three to six weeks. Figure 10d shows the final postoperative result six weeks after division of the posterior lamellar Hughes flap.

Figure 10. a. Defect created post excision BCC from lower lid, b. Posterior lamella reconstruction using Hughes tarsoconjunctiva flap (white arrow) from superior lid transposed to the lower lid with a conjunctival vascular bridge (red arrow) providing blood supply, c. Anterior lamella skin muscle advancement flap, and d. Postoperative result six weeks after division of the posterior lamellar Hughes flap.


Patient Two

Patient two presented with a rapidly growing lesion in his right eyebrow, and a scaly lesion in the pre-auricular area. The lesion displayed features of hyperkeratosis, irregular boarders and ulceration. Biopsy of both the brow and pre-auricular lesions revealed SCC (Figure 11a). Excision of both lesions was performed with intra operative frozen section margin control, with final lesion extent and depth illustrated in Figure 11b. Reconstruction involved an island flap for the brow lesion and direct closure for the smaller pre-auricular lesion (Figure 11c). Figure 11d shows the four month post operative appearance, with a well vascularised and viable flap and a cosmetically acceptable appearance.

Figure 11. a. Left brow and pre-auricular SCC, b. Defects post margin controlled IFS excision, c. Island flap reconstruction of main lesion and direct closure of pre-auricular lesion, and d. Post operative appearance displaying a well vascularised flap and a cosmetically acceptable appearance.


Radiotherapy and Topical Treatment

Radiotherapy is an established treatment for cutaneous malignancies, however periocular radiotherapy is associated with adverse effects including radiation keratopathy, cataract, optic neuropathy and radiation retinopathy. Consequently periocular radiotherapy is reserved for patients with unresectable tumours or patients who are too unwell for surgical resection and reconstruction. An exception to this general rule is in the management of merkel cell carcinoma as these tumours are particularly radiosensitive and given the aggressive nature of this tumour type, adjuvant radiotherapy may be recommended.

Topical treatment creams including Aldara (Imiquimod) an immune response modifier used to treat BCC, and Effudex (5-Fluorouracil) an anti-metabolite used to treat actinic keratosis and Bowens disease may be used in periocular lesions distant from the conjunctiva. The main drawbacks of using topical therapy are there is no definitive confirmation of regression and treatment, and ocular surface toxicity is a side effect.

Topical treatment of periocular tumours is generally reserved for patients with extensive unresectable cutaneous disease.

Systemic Immunotherapy

The advances in our understanding of tumour genetic pathways outlined earlier in this review have led to the development of novel immunotherapy treatments targeting the underlying cellular drivers of tumour genesis. In practice, due to a high side effect profile and disease recurrence once the medication is discontinued, these treatments are generally reserved for advanced and metastatic disease.14 A recent trend has seen immunotherapy used as chemoreduction to shrink tumours prior to surgical excision.

Vismodegib inhibits the SHH signalling and is used in the treatment of advanced and metastatic BCC. Studies have demonstrated a reduction in tumour burden in 43 per cent of patients with locally advanced disease and 30 per cent of patients with metastatic disease. In clinical trials, up to 50 per cent of patients stop the Vismodegib treatment due to side effect. Cetuximab inhibits EGFR, which is over expressed in 78 per cent of SCC and is used in the management of inoperable SCCs. With treatment, mean overall survival of metastatic SCC is still relatively poor at 8.1 months. Vemurafenib inhibits BRAF and is approved for the treatment of BRAF-mutated unresectable or metastatic MM. Although initial response is impressive, resistance to the medication is acquired in nearly all cases after an average of seven months. Furthermore, a side effect of treatment is the development of SCCs. Combination of BRAF inhibitors with MEK inhibitors may reduce the incidence of SCC seen with BRAF inhibitors alone.

While cost, side effect profile and tumour recurrence on cessation of therapy are significant limitations, it is important to note that development of systemic immunotherapy is still in its infancy and likely represents an exciting paradigm shift in our treatment of advanced carcinomas.


Lid lesions are common. Thankfully most eyelid tumours are benign, however early identification of clinical ‘red flags’ that may indicate malignancy is critical in reducing the morbidity associated with large periocular tumour excisions and mortality of advanced metastatic disease.

With timely referral to an oculoplastic surgeon, excellent functional and aesthetic results can be achieved in the treatment of malignant periocular tumours.


Dr Dov Hersh is a Sydney-based ophthalmologist with dual international fellowship qualifications and specialises in complex oculoplastic and cataract surgery. Dr Hersh has extensive experience in minimally invasive oculoplastic and endoscopic lacrimal (DCR) surgery, Asian and redo blepharoplasty, and complex peri-ocular tumour management. He also has a keen interest in premium cataract surgery and offers patients the latest intraocular lens options.

Dr Hersh is a founding partner of Sydney Eye Surgeons, Dr Hersh  (sydneyeyesurgeons.com.au), with practices in Bondi Junction and Miranda. He also consults and sees patients at Northern Sydney Cataract on the lower North Shore, and Metwest Eye Centre in Blacktown, NSW.

Dr Hersh has been appointed to the executive committee of the Australian and New Zealand Society of Ophthalmic Plastic Surgeons (ANZSOPS), and is a member of the Australian Association of Facial Plastic Surgeons (AAFPS).



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' Two thirds of Australians will be diagnosed with skin cancer by the time they are 70, and of these cases, 5–10 per cent will consist of eyelid malignancies '