Cutaneous Squamous Cell Carcinoma in Ireland

Cutaneous Squamous Cell Carcinoma in Ireland: Rising Incidence, Evolving Treatments, and the Need for Proactive Prevention

1. Introduction

Skin cancer is the most common cancer in Ireland with over 13,000 new cases diagnosed every year.1 Primary cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. CSCC is a malignant tumour arising from keratinising cells of the epidermis or its appendages, and as such is considered a keratinocyte or non-melanoma skin cancer (NMSC).

According to the National Cancer Registry Ireland, from 1984-2010, overall incidence of cSCC has increased by 263%. While Basal Cell Carcinoma (BCC) is a more prevalent NMSC, cSCC poses a greater risk due to its potential for local invasion, lymph node involvement and in rare cases, metastasis. While often treatable, cSCC can become aggressive, leading to significant morbidity and mortality if not managed appropriately.

In Ireland, the incidence of cSCC has been steadily rising, in line with global trends. Between 2011 and 2015, nearly 11,000 invasive skin cancers were diagnosed annually in Ireland. Of these, 3,000 cases per year (approximately 27%) were cSCCs. The rise in keratinocyte cancer is attributed to several factors, including greater cumulative sun exposure, an aging demographic and increased awareness leading to higher detection rates.2

2. Pathophysiology

As mentioned cSCC arises from the malignant transformation of keratinocytes in the epidermis. Recent studies have identified key molecular alterations driving cSCC development. Mutations in tumour suppressor genes such as TP53 and CDKN2A disrupt cell cycle regulation leading to uncontrolled cellular proliferation, while aberrant signalling in the P13K/AKT/mTOR pathway has also been implicated in tumour growth and survival. Genetic polymorphisms in the Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene has been associated with keratinocyte skin cancer in a cohort of renal transplant recipients.3 Epigenetic aberrancies are also evident in cSCC in renal transplant recipients.4

UV radiation induces DNA damage due to the formation of cyclobutene pyrimidine dimers which can result in carcinogenesis. The UV Index is a standardized measure of the intensity of UV radiation, which ranges from 0 (low) to 11+ (extreme). The higher the number, the greater the potential for UV skin damage. The UV Index in Ireland typically ranges between 1 and 7. During the winter months (November–February), the UV Index is usually low (0-2).

In the summer months (May–August), the UV Index often reaches 5-7, especially on clear days between 11 AM and 3 PM. Many people in Ireland assume that cloudy weather reduces UV risk, but over 80% of UV rays can penetrate cloud cover. Reflection from surfaces such as water, sand and snow can further increase UV exposure.

The Celtic skin type (Fitzpatrick phototype I-II) predominant in the Irish population places individuals at greater risk of sunburn with increased susceptibility to UV damage. This skin type coupled with prolonged and often unprotected sun exposure (especially in those who work outdoors) results in a population at higher risk of developing cSCC. Another at risk group is immunosuppressed organ transplant recipients. CSCC is the predominant skin cancer type in renal transplant patients, who have a 65-250 fold increased risk of developing cSCC compared to the general population. CSCC in organ transplant patients also has a more aggressive clinical course, a greater tendency to metastasise and a higher mortality compared to the general population. The increasing use of immunosuppressive therapies in additional patient cohorts is also contributing to an overall increasing burden of cSCC.

Certain ocular iris patterns in the general population are associated with keratinocyte cancers such as a blue periphery, blue collarette and an absence of freckles.5 Meanwhile in immunosuppressed renal transplant recipients, blue iris periphery, light brown collarette and iris freckling confer an independent risk for keratinocyte skin cancer.6 In addition, certain medications have been implicated in increasing the risk of developing cSCC such as voriconazole used to treat aspergillosis, and hydrochlorothiazide, a commonly prescribed diuretic.

3. Public Campaigns

During the 1980s and 1990s, dermatologists in Ireland began to observe an increase in cSCC cases in younger individuals and those with occupational and higher cumulative UV exposure, i.e. farmers, fishermen, construction workers and sports coaches. At the same time, improved access to dermatological services led to better diagnosis, documentation, and reporting of skin cancers, contributing to the apparent rise in incidence.

In 2024 the Irish Association of Dermatologists through the EADV Representative for Ireland, Professor Mary Laing, supported a global call to action to protect outdoor workers from skin cancer by solar UVR exposure at the 2023 EADV congress.

Initiatives such as the Irish Cancer Society’s SunSmart campaign emphasized the importance of sunscreen use, protective clothing and regular skin checks, particularly for high-risk groups. Despite these efforts, many Irish people continue to underestimate the impact of UV exposure, leading to sustained increases in cSCC incidence. A 2007 study examining Irish attitudes and perceptions regarding skin cancer and sun protection by Jones et al. found that 90% of participants knew that sun exposure was the major risk factor for skin cancer, and 95% knew that sun beds were not a safe way to tan. Despite this knowledge <20% used regular sunscreen, and 30% had used or were currently using sun beds in order to tan.7

Ireland has the highest per capita use of fake tan globally. Unlike UV-induced tanning, which poses health risks, fake tan offers a

 

safer alternative. The popularity of fake tan in Ireland is attributed to cultural beauty standards favouring tanned skin amid the country’s predominantly fair-skinned population. Patients presenting with fake tan to pigmented lesion clinics, can lead to difficulties in accurate diagnosis which can result in unnecessary appointment rescheduling.8

4. Diagnosis

CSCC diagnosis in Ireland is based on clinical examination and histopathology. CSCC lesions typically present as a firm, erythematous nodule or plaque with a crusted surface. Lesions may ulcerate and are commonly found on sun-exposed sites such as the face, ears, neck and hands. Patients typically complain of a non-healing ulcer which may or may not be tender in a sun-exposed area. Dermoscopy remains a valuable, non- invasive diagnostic tool that enhances the visualisation, early detection, and differentiation of cSCC from other skin conditions.

Common Dermoscopic features of non-pigmented cSCC as outlined by Professor Harald Kittler of the Medical University of Vienna9, include:

• White Circles which appear as well-defined, round structures and are considered a hallmark of cSCC. They correspond to hyper granulosis of the infundibular epidermis
• White Structureless Areas which lack specific patterns, presenting as homogeneous white zones, associated with fibrosis
• Looped or Coiled Vessels
• Central Keratin manifesting as a yellow/ white clump
• Blood Spots which are small, round, dark red to black structures that result from haemorrhage into the keratin mass
• Pink or Red Background often seen in poorly differentiated or rapidly growing tumours

In cases of pigmented cSCC, dermoscopy may show

• Diffuse homogeneous blue pigmentation or blue-grey pigmented granular structures, often irregularly distributed across the lesion

An additional diagnostic tool available in certain centres includes Reflectance Confocal Microscopy (RCM) which can provide real-time, high-resolution images of the epidermis and superficial dermis at near histologic resolution. Studies have shown that cSCC exhibits specific confocal features such as:

• Atypical Keratinocyte Morphology with irregular, pleomorphic cells and increased nuclear-to-cytoplasmic ratios
• Disruption of the Normal Epidermal Architecture with loss of the regular honeycomb pattern in the epidermis
• Increased vascularity and Inflammatory Infiltrates

5. Treatments

Diagnosis is established histologically with CSCC staging following the AJCC 8th Edition TNM system, which classifies tumours based on size, depth, nerve involvement, lymph node spread and distant metastasis.

According to the Scottish Intercollegiate Guidelines Network (SIGN) guidelines, the choice of treatment for cSCC may be discussed in a multidisciplinary team meeting where any of the following high-risk features are present:

• Tumour diameter > 20mm
• Tumour depth > 4mm
• Tumour extending beyond dermis into or through subcutaneous fat
• Perineural invasion
• Poor differentiation
• Desmoplastic subtype
• Immunosuppression

Treatment decisions are tailored to the individual patient, considering staging, the patient’s overall health and their preferences.

In advanced cSCC, further imaging may be required to assess disease extent. CT evaluates bone, soft tissue, and cervical lymph node involvement, while MRI is useful for head and neck spread and perineural invasion. Radioisotope bone scans detect suspected bony metastases.

1. Surgery

For clinically well-defined, low risk tumours < 2cm in diameter, surgical excision with a minimum 4mm margin around the tumour border is appropriate and would be expected to completely remove the primary tumour mass in 95% of cases. For tumours > 2cm in diameter, classified as moderately, poorly, or undifferentiated and extending into the subcutaneous tissue or those on the ear, lip, scalp, eyelids or nose, such tumours should be removed with a wider margin of 6mm or more.

Mohs micrographic surgery is particularly beneficial for high-risk cSCCs, located in areas where preserving cosmetic and functional integrity is important i.e., on the face, ears, or hands and those cSCCs with an indistinct clinical border, that are large or rapidly growing, that recurred after previous treatment and/or exhibit aggressive histological features.

The procedure involves the precise, layer-by-layer removal of cancerous tissue with each layer examined microscopically in real-time to ensure complete cancer eradication while minimizing the loss of surrounding healthy tissue. The immediate microscopic examination of excised tissue ensures that all cancerous cells are removed during the initial procedure, reducing likelihood of recurrence. Mohs surgery offers cure rates up to 99% for primary cSCCs, making it one of the most effective treatments available.

1. Radiotherapy

Radiotherapy uses high-energy radiation to target and destroy cancer cells. It is employed when surgery is not feasible or as an adjunct treatment to reduce risk of recurrence. It may also be considered for patients with large tumours, perineural invasion or when surgical margins are positive.

III. Cryotherapy

Cryotherapy involves freezing cancerous tissue with liquid nitrogen, causing cells to die, and can be used to treat Squamous cell carcinoma in situ (SCCIS)/ Bowen’s disease which is where malignant cells are confined to the epidermis, and are small and superficial.

1. Topical Treatments

Similarly, for SCCIS/ Bowen’s disease, topical treatments may be appropriate:

• Chemotherapy Creams: Include 5 fluorouracil cream (Efudix) and imiquimod 5% cream (Aldara).
• Photodynamic Therapy (PDT):

This involves applying a photosensitizing agent to the skin, which is activated by a specific wavelength of light to produce reactive oxygen species that selectively destroy cancerous or pre-cancerous cells. PDT requires 1-2 treatment sessions at 1–2-week intervals and may be preferred if there are larger lesions covering a wider BSA.

1. Systemic Treatments

The metastatic rate of cSCC is 2-5% in the general population. However cSCC in high risk sites such as the lip or ear has a 10-20% metastatic rate. Where cSCC has metastasized or is not amenable to local treatments, systemic therapies may be considered.

• Immunotherapy: The European Medicines Agency authorized cemiplimab (Libtayo) as monotherapy for adult patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or curative radiation. The HSE approved its reimbursement effective from October 2024. Cemiplimab is a monoclonal antibody that works as an immune checkpoint inhibitor targeting programmed death receptor-1 (PD-1). In December 2024, the FDA approved cosibelimab (Unloxcyt) for similar indications, expanding therapeutic options.
• Chemotherapy: For locally advanced or metastatic cSCC, systemic chemotherapy may be used in combination with surgery, radiotherapy, or immunotherapy. Regimens may be platinum-based (Cisplatin, Carboplatin) which cause DNA crosslinking leading to apoptosis in rapidly dividing tumour cells, or taxanes (Paclitaxel, Docetaxel) which disrupt microtubule function, inhibiting mitosis.

6. Prevention

Skin cancer is largely preventable, with UVR from the sun or sunbeds responsible for 90% of cases. While sunscreen plays a role in photoprotection, it alone is not enough to prevent keratinocyte cancer. Instead, it should be used alongside protective clothing and shade for optimal protection. There are a number of factors which may limit sunscreen use. One Irish observational study highlighted that tinted sunscreen may have poorer cosmetic acceptability for individuals with darker skin tones due to a white caste. Sunscreens with zinc oxide or titanium dioxide can leave a white residue, making them less appealing for people with darker skin tones.10

In Ireland, keratinocyte cancer currently affects 1 in 6 men and 1 in 9 women over their lifetimes. Men are more commonly affected, likely due to greater lifetime head and neck exposure to UV radiation. Older adult males are at higher risk of developing head and neck skin cancers, presenting at later stages and have worse outcomes overall. Hynes et al. examined males attending Dermatology services in the West of Ireland, they identified that most patients reported wearing hats and SPF, however a minority wear SPF on their lips and often Irish men wear a hat type (baseball cap) that would have too small a brim to provide adequate photoprotection to the head and neck.11

When considering photoprotection campaigns, fashion trends regarding hat types should be considered. The World Health Organisation (WHO) advocates for the use of photoprotective clothing including wide-brimmed hats, tightly woven clothing, and wraparound style sunglasses that provide 100% UV-A and UV-B protection to prevent the effects of UVR. In Ireland there is frequently poor availability in shops of hats meeting sun protection standards.12 The photoprotective standard of clothing is measured as the ultraviolet photoprotective factor (UPF), the UPF rating provides information on how much UV will pass through unstretched dry material and measures skin erythema at various UV radiation doses, analogous to the SPF of sunscreen. Hat material with a UPF rating of 30 would allow 1/30th (3.3%) of UV falling on its surface to pass through it, blocking 96.7% of UV. Kearney et al. found that only 35% of the UK’s largest online retailers stock UPF-rated clothing.13

The National Skin Cancer Prevention Plan 2023-2026 has re-emphasized the importance of public education on sun safety and risks associated with UV radiation. Campaigns aim to reduce cSCC incidence by encouraging protective behaviours and regular self-skin-checks.

The integration of immunotherapies like cemiplimab, offer new avenues for patients with metastatic or inoperable tumours. Ongoing research into combination therapies holds promise for improved outcomes.

This January marks the 10th anniversary of the commercial sun bed ban in Australia. Recognizing the risks associated with UV radiation, the Irish government has also taken steps to regulate sunbed use. The Public Health (Sunbeds) Act 2014 prohibits the sale or hire of sunbeds to individuals under 18 and imposes strict regulations on sunbed businesses. In July 2024, Taoiseach Micheál Martin expressed strong support for a complete ban on sunbeds, citing compelling evidence linking their use to increased skin cancer risk.

While the number of cases of cSCC diagnosed annually in Ireland is projected to double by 2040, advancements in treatment and growing awareness offer hope for the future. Proactive prevention measures, such as targeted public education campaigns and enhanced early detection efforts, combined with innovative immunotherapies, are paving the way for improved outcomes. With a unified commitment to sun safety, research, and equitable access to care, Ireland is well-positioned to tackle this growing health challenge and ensure better care for patients nationwide.

References available on request

Dermatoscopic image courtesy of Dr Karen Reidy1

Written by Dr Olwyn Conlon, Dermatology Registrar1, Professor Mary Laing, Consultant Dermatologist1

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