Cutaneous squamous cell carcinoma of the eyelid in northern latitudes, a 25‐year experience in Finland

To evaluate the incidence, clinical features, diagnostic challenges, management and prognosis of cutaneous squamous cell carcinoma of the eyelid (ecSCC) in southern Finland, northern Europe, latitude 62° N.

Potential sequelae of ecSCC include orbital and intracranial invasion, nodal and distant metastasis, and mortality.EcSCCs may spread by local extension into adjacent structures but may also metastasis via lymphatic or perineural routes.Among patients with ecSCC, the rate of regional lymph node metastasis may be as high as 24% (Faustina et al., 2004;Sullivan, 2009).
The mortality rate for ecSCC is 5% (Faustina et al., 2004).Identifying the tumour and referral to treatment are essential.There are only a few studies on the incidence of ecSCC and there are no studies from Northern Europe.The estimated annual incidence of ecSCC per 100 000 was 0.63 in a study from London, England 51° N and 1.4 in a study from Minnesota, USA 46° N, and the incidence is increasing (Cook & Bartley, 1999;Wawrzynski et al., 2018).
The aim of this study was to analyse the incidence, clinical features, diagnostic challenges, management, and prognosis of ecSCC of the eyelids and periocular region in Finland, latitude 62° N.

| M AT ER I A L S A N D M ET HOD S
Patients were identified either from the Finnish Cancer Registry or from the archives of the Helsinki University Hospital during a 25-year period (1998-2022) according to ICD10 codes C44.1, C69.0, C69.6, C69.8, C69.9 and International Classification of Diseases for Oncology 3rd edition (ICD-03) topography codes 8070/2, 8070/3, 8071/3, 8076/3, 8077/2 (WHO, 2018).All patient charts were reviewed and were included in the study if the diagnosis was cSCC and localization of the tumour was periocular (eyelids and adjacent tissues).Premalignant stages of ecSCC; actinic keratosis, and in situ SCC (Bowen's disease) were not included in this study.Cause of death of patients was checked from the Digital and Population Data Services Agency in Finland.
The Hospital District of Helsinki and Uusimaa in Southern Finland is the largest hospital district in Finland, with a catchment population of 1.7 million (31% of the population of Finland, 5.5 million in 2022).The Helsinki University Hospital receives virtually all patients with ecSCC residing in its catchment area and some patients with ecSCC who are referred from other eye hospitals in Finland.Therefore, our core sample is essentially population based.
We found 58 patients with ecSCC from this 25-year period.The male-female ratio in Finland (0.35) taking into account the age and year of diagnosis of each patient was retrieved from the 2022 Revision of the World Population Prospects by the United Nations (United Nations, Department of Economic and Social Affairs, Population Division, 2022).
All patients were diagnosed and treated in the Department of Ophthalmology, Plastic Surgery, or Dermatology at the Helsinki University Hospital.EcSCCs were operated by ophthalmologists in 32 patients, dermatologists in 11 patients, plastic surgeons in 12 patients, and by a multidisciplinary team (ophthalmologists and plastic surgeons) in two patients.Histopathological examinations were originally performed in the Ophthalmic Pathology Laboratory and in the Department of Pathology at the Helsinki University Hospital.Specimens were evaluated by an ophthalmic pathologist.An ophthalmic pathologist (TO) re-examined the histological specimens for this study that were available.Degree of differentiation was graded I to III.
Perineural and perivascular invasion (PNI and PNV, respectively) and the depth of invasion were documented.
In addition to histopathologic data, we reviewed the age, sex, tumour localization, and the initial clinical and histopathological diagnosis.The occurrence of additional cSCCs elsewhere in the body were also noted.Tumours were staged according to the American Joint Committee on Cancer (AJCC) Staging Manual, 8th Edition as follows: T1 (size <10 mm), T2 (size >10-20 mm), T3 (size >20 mm) and T4 (invades the ocular or intraorbital structures) (Esmaeli et al., 2017).
Diagnostic delay, treatment, follow-up and patient outcomes were also documented.A surgical margin of <2 mm was defined as inadequate in histopathological analysis.Diagnostic delay was considered significant when time from symptom onset before final diagnosis of SCC was ≥3 months.
Statistical analysis was performed using spss v.25 (SPSS Inc, Chicago, IL).Descriptive statistics are provided as median with range.Cumulative frequency plot of age at diagnosis was performed.Univariate analysis of survival time data was based on the Kaplan-Meier product-limit method without considering competing risks.This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Hospital District of Helsinki and Uusimaa (3283/2018).

| R E SU LT S
Altogether 58 patients with ecSCC were diagnosed during the study period.The mean age-standardized incidence of ecSCC in our health care district was 1.03 per 100 000.The median age at the time of the diagnosis was 79 years (female 81 vs. male 78) (range, 55-93).More than half (59%, n = 34) of the patients were women (Figure 1).Considering the year of diagnosis of each patient and the ratio of men to women in that age group we get the assumed male-female ratio (0.35).In our study group this is 0.41 meaning that there are more men than expected (binomial test), p value is 0.34 (considering the size of the data).All patients were white Caucasians (Table 1).We cannot exclude the possibility of increase of ecSCC in Finland years 2005-2021, but in such a low number of patients there was no clear statistically significant increase (Figure 2).One or more of the known risk factors for ecSCC include extensive sun exposure (tanning, travelling, hobby or work related), immunosuppression, smoking, previous in situ SCC elsewhere, or SCC elsewhere on the skin were documented in 71% of the patients.37% of patients had in situ SCC elsewhere, and 5% of these patients had more than 10 in situ SCC changes during the study period.One third (31%) of the ecSCC patients had SCC elsewhere on the skin (Table 1).
The median age of immunosuppressed patients was 79 years (range, 62-89) and was not different than that of non-immunosuppressed patients.
Almost 80% of the patients were referred by a general practitioner or by an ophthalmologist (Table 2).The clinical diagnosis in the referral was BCC in 22 patients (38%; 95% confidence interval [CI], 27-51) and ecSCC in only three patients.The clinical differential diagnosis was incorrect in all 18 referrals by an ophthalmologist, although the clinical diagnosis was suspected as malignant lesion in 53% of patients (Table 2).The signs of suspect malignancy were a suspicious appearance and growth.
The median time from first symptoms until correct histopathological diagnosis of ecSCC was 6 months (range, 1-72 months).If there was a diagnostic delay >3 months (57%, n = 33), the most frequent cause was a slight, slow-growing lesion; 26 of these 33 patients ignored the lesion.One patient delayed seeking treatment because of the Covid pandemic.
A preoperative biopsy was performed in 43 (74%) patients.Among these biopsies, the incorrect histopathological diagnosis of the ecSCC was made in four (9%) patients and was most commonly BCC.Preoperative screening of regional lymph nodes (ultrasound [US], computed tomography [CT], or magnetic resonance imaging [MRI]) was performed in 10 patients.One of the patients underwent sentinel node biopsy (Table 3).
Complete local surgical removal of the tumour with reconstruction was the treatment goal for 56 (97%) patients.One patient was inoperable due to weak general health and received primary external beam radiotherapy.One patient died of urosepsis before planned surgery.
The reconstruction method of the eyelid was graft or flap in 38 (66%) patients.Other methods were direct closure of the wound, microvascular graft and Laissezfaire method (Table 3).One of the patients in our study required an exenteration primarily with microvascular graft reconstruction.Frozen section analysis was taken in 10% of cases.Slow Mohs surgery was performed on two patients.Due to incomplete removal or inadequate margins, 13 (22%) patients had to undergo an additional surgical procedure.Two patients received postoperative radiation therapy.
Primarily histopathological grade of differentiation was specified in 42 (74%) surgically treated tumours.Depth of tumour invasion, tumour size, PNI and PVI were re-examined if histological specimens were available (Table 2).
Follow-up data were obtained for 41 patients (71%).Six patients died of other causes before the first postoperative visit.Most patients were followed up every 6 months during the first 2 years and then once a year for the following 3 years.The median follow-up time was two (range, 0.25-17) years.Three patients developed a local recurrence and were re-operated at a median of 21 months after the primary surgery.Four patients developed metastatic disease (median 19 months) (Figure 3).Two of these patients died of metastatic ecSCC at 25 and 42 months after initial diagnosis (Figure 3).The two other patients with metastatic disease survived during the follow-up period of 4 and 17 years.There was no statistically significant difference in the size of the tumour in relation to recurrence or metastatic disease or death of ecSCC.
Postoperative complications were reported in 11 (19%) patients.These were a thick skin flap, lagophthalmos and abrasive hair or eyelashes.Six patients underwent a surgical reconstruction due to postoperative complications.

| DI SC US SION
The estimated annual incidence of ecSCC in previous studies ranged from 0.63 (London, England) to 1.4 (Texas, USA) per 100 000.There are no previous studies from Northern Europe (Cook & Bartley, 1999;Wawrzynski et al., 2018).The mean age-standardized incidence of ecSCC in our sample was 1.03 per 100 000.More than half of Finns belong to skin type III, a third to types I and II, and 10% to class IV and thus are lighter than the average Caucasian (Jansen, 1989, Hannuksela, 2011).We confirmed previous findings of old age at the time of diagnosis (Donaldson et al., 2002;Faustina et al., 2004;Malhotra et al., 2004;Wawrzynski et al., 2018).There was a minor male predominance in ecSSC patients in our study in proportion to the Finnish population corresponding to the study population.This may be due to patterns of sex-specific lifestyles and behaviour.Outdoor activities and sun exposure were considered as an explanation for head and neck tumours in men (Kim et al., 2020).Finland is in Northern Europe (the latitude 62° N) and receives less UV radiation than many other countries, which may explain the lower male dominance than in other studies (Table 4).We confirmed previous findings that the lower eyelid is the most common anatomic location of ecSSC, due to its increased sun exposure (Donaldson et al., 2002;Faustina et al., 2004;Malhotra et al., 2004).
The median diagnostic delay in our study was 6 months.According to our study, clinical diagnosis of ecSCC is challenging even among ophthalmologists.This was observed in several previous studies, which confirms the inaccuracy of preoperative clinical diagnosis.ecSSC was often misdiagnosed as another tumour or a benign lesion (Donaldson et al., 2002;Doxanas et al., 1987;Limawararut et al., 2007;Malhotra et al., 2004;Mehta & Fay, 2009).In our study, the diagnostic delay of one patient was due to the Covid-19 pandemic, as the patient was hesitant to contact healthcare professionals.There are a few studies related to delayed consultation due to the Covid-19 pandemic.In a Chinese study of 4551 people (47% male, 60% aged >45 years), 10% reported a delayed consultation due to this pandemic.This delay was more common among males and increased with age and fear (Lai et al., 2021).cSCC may be induced by some drugs.In our study, 22% of the patients had a history of systemic immunosuppressive treatment.Immunosuppression was present in 11% of patients in the Finnish Patient Cohort study (2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015), which identified 774 patients with a total of 1131 cSCC from the pathology database.Of these, 824 were in the head and neck area (Korhonen et al., 2019).In an American study of 109 patients, 7.3% were chronically immunosuppressed at time of the diagnosis of ecSCC (Xu et al., 2019).In these studies, as in our study, the type and the length of immunosuppression were not described, which may explain the difference.One explanation for this may be the expression of specific human leukocyte antigen class I proteins on SCC cells related to immunosurveillance in the pathogenesis of SCC (Walter et al., 2010).The immunosuppressive therapy often used in organ transplant recipients or in autoimmune diseases and recent biological drugs increases susceptibility to cutaneous infection and skin neoplasms.Different drugs have unequal risk profiles (Anforth et al., 2015;Berg & Otley, 2002;Harvey et al., 2012;Mittal & Colegio, 2017;Mohan et al., 2016;Sufficool et al., 2014) (Table 5).The challenges related to immunosuppressive medication and biological drugs are already known in departments treating organ transplant patients and among dermatologists and oncologists (Cheng et al., 2018;Varra et al., 2018).Nevertheless, it is important to increase the ophthalmologist's knowledge related to these findings and possible alternative treatment options.Ophthalmologists can recommend sunglasses, protective clothing, staying in the shade, and early removal of all new eyelid lesions for immunosuppressed patients and patients with history of previous cSCC.
In our study, 29% of patients had a history of extensive sun exposure (photodamaged skin or work or hobby with UV exposure as described in the patient database).Sun exposure has been suggested as a cause for the increasing global incidence of cSCC (Keim et al., 2023;Wassberg et al., 2001).This is probably due to increased sun tanning, travel to countries with high UV index and increased life expectancy (Wassberg et al., 2001).Our data show that there may also be an increase of ecSCC in Finland in the last 15 years.Almost half (45%) of the patients in our study had at least in situ SCC, SCC or both in addition to the eyelid tumour.Since the patients may have multiple tumours, the risk of developing new SCCs and other skin cancers is considerable (Marcil & Stern, 2000;Stratigos et al., 2015;Terrill et al., 2009).Preventive measures, such as education on sun avoidance and protection and early detection and intervention are required to reduce development of the more invasive cSCCs (Green & Olsen, 2017).In the Finnish Patient Cohort study (2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015), 76%, 15% and 9% of patients had one,   , 1952, -2002, (Faustina et al., 2004) 111 80 20 31° N two and three or more cSCCs, respectively (Korhonen et al., 2019).In our study of ecSCC patients, a higher number of other SCC findings may be due to the abundant light exposure of the facial area, as most of the SCC in other areas were in the facial area.Surgery and reconstruction of the periocular area are challenging and may lead to functional and cosmetic problems.Thus, the balance between sufficient (but not excessive) resection is challenging in eyelid surgery.In our study, 22% of the patients underwent an additional surgical procedure due to incomplete removal of the tumour or inadequate surgical margins.Postoperative complications were reported in every fifth patient in our study.Only two of the reoperated patients had postoperative complications.Local postoperative complications occurred in 8.5% in an Australian study of 485 consecutive cases of BCC and SCC of the eyelid (Nemet et al., 2006).Since this Australian study also included BCC cases (often operated with smaller margins than cSCC), the outcomes were better than in our study.
During our follow-up, three patients (5%) developed a local recurrence and metastasis occurred in four patients (7%).The local recurrence rate was similar (6%) in the previously mentioned retrospective case series of 68 patients with ecSCC from Australia (Nemet et al., 2006).Other previously reported local recurrence rates ranged from 10% to 21% and metastasis occurred 5%-9% in retrospective studies (Faustina et al., 2004;Nasser et al., 2014;Shulman, 1962;Xu et al., 2019).For example, no patients developed lymph nodes or distant metastases in one retrospective study with 50 patients from Australia (Donaldson et al., 2002).The mean follow-up time in this study was only 31 months, which is relatively brief, as in our study one patient developed nodal metastasis 48 months after primary treatment.In a prospective study from Australia with 79 patients undergoing Mohs' micrographic surgery (MMS) for ecSCC, a recurrence rate of 4% was observed during a seven-year period.Lymph node metastasis occurred in 1% and no patients died of ecSCC during the median 73-month follow-up period (Malhotra et al., 2004).Although the benefits of MMS are clear, this procedure is not always available in many ophthalmological units.Direct comparisons between studies are not possible due to different treatment and follow-up protocols.
Our study has several limitations.This study was based on data retrospectively reviewed at our hospital and therefore the data are not uniform.In addition, the schema of the treatment, histopathological examination, and follow-up was not uniform during the study period.No treatment guidelines for ecSSC were available in Finland or globally at the beginning of our study period.Since then, guidelines have been published and will hopefully lead to better treatment standards (Esmaeli et al., 2017;Xu et al., 2019).In the beginning of our study period, 5-year follow-up in our institution was not yet routine procedure.Therefore, the follow-up period of various patients varied notably.A large portion of the patients were considerably old so that they passed away from other causes interrupting the follow-up.In the end the median follow-up period was only 24 months.This can be reflected in the fact that in our study there is quite low recurrence rate and the low number of metastatic cases, this describes the real-life situation of these mainly old patients.
We reviewed 58 Finnish patients with cSSC of the eyelid and periocular region.Our incidence of 1.03 per 100 000 likely describes the Finnish incidence of ecSCC.This study describes Northern Caucasian patient material, as there are few immigrants in Finland, people change residence infrequently, and most patients are operated in the public sector hospitals.The number of patient-elected drop-outs in our study is low, although some patients passed away before the planned control visit.We found that it is rather difficult to diagnose ecSCC clinically at the first consultation.Patients with extensive sun exposure, fair skin, immunosuppression, and previous in situ SCC or SCC should be considered for the possibility of a new ecSCC.The follow-up period for treated ecSCC must be sufficiently long.As this disease is potentially life threatening, raising awareness of ecSCC to clinicians remains necessary.

AC K NO W L E DGE M E N T S
This study was supported by grants from the Helsinki University Hospital Research Funds, The Eye Foundation, and The Eye and Tissue Bank Foundation, Finland.

F
I G U R E 1 Cumulative frequency plot of age at the diagnosis of squamous cell carcinoma of the eyelid by gender (dashed line indicates males and solid line females).
time of the diagnosis of cutaneous squamous cell carcinoma of the eyelid T A B L E 1 Patient demographic and risk factors.Number of diagnosed patients of cutaneous squamous cell carcinoma of the eyelid per year of diagnosis in Helsinki University Hospital.This graphic has excluded the year 2022 (0 patients) because of possible effects to healthcare in Finland of Covid pandemic.
Initial clinical diagnosis and diagnostic delay of 58 patients with eyelid cutaneous squamous cell carcinoma.
T A B L E 2 a Micrograft surgery and Laissez-faire method.