Periocular basal cell carcinoma of the eyelids – review

, ectro-pion, cicatrisation of the lacrimal duct, secondary neovascular glaucoma

North America.[1, 12 -14].UV radiation produces DNA damage (formation of cyclobutane pyrimidine dimers), gene mutations, immunosuppression, oxidative stress and inflammatory responses, all of which have an important role in photoaging of the skin and skin cancer.In addition to this, UV radiation creates mutations to p53 tumor suppressor genes; these are genes which are involved in DNA repair or the apoptosis of cells that have lots of DNA damage.Therefore, if p53 genes are mutated, they will no longer be able to aid in the DNA repair process; as a result, there is "dysregulation of apoptosis, expansion of mutated keratinocytes, and initiation of skin cancer."UVA radiation has an important role in the carcinogenesis of stem cells of the skin.UVB radiation induces DNA damage, which causes inflammatory responses and tumorigenesis.[15].In skin carcinogenesis the mutations play a significant role by activating hedgehog intercellular signaling pathway genes.Patched Ptch-1 mutations promote the development of eyelid BCC.[16,17].Viral oncoprotein E6 from beta HPV has the ability to bind to the p53 protein and inactivate it, which results in limiting the induction of apoptosis of cells damaged by UV radiation through the reduction of the pro-apoptotic protein Bcl-2.Oncoprotein E7 interferes with p16, and these mechanisms lead to an accumulation of mutations and oncogenic transformation of keratinocytes, which are more sensitive to UV-induced carcinogenesis.[18].
Risk factors of multiple BCC are important; the highrisk patients have to be followed up for recurrence or development of new lesions and they have to examine their skin regularly.[19].
There are many factors as risk factors of multiple BCC development.In several studies, a demonstrable dependence between sex, age and the incidence of BCC can be seen.This occurs most often in patients in the sixth to eighth decade of life, with a median age of 62 years (46% were at least 65 years old).A moderate predominance occurs in the male population; i.e. 61% is male.The relationship of the sex of patients to the risk of BCC recurrence is still controversial.In Silverman's studies, no relationship between sex and tumour recurrences was evident.[19 -24].Important are severe actinic damage [25], history of previous radiotherapy [26], increased numbers of identi-fied tumours already present [26 -28], tumour size over 1 cm [29], lesions on trunk [30][31][32], positive family history of other skin tumours [33] low DNA repair capacity [34] detected tumour necrosis factor (TNF), microsatellite polymorphism [35], PTCH gene polymorphism [36] and glutathione S-transferase and cytochrome P450 polymorphism [23,37].

Classification
For determining the stage of advancement of a tumour, the TNM "staging" classification is used, as well as determining the histopathological degree of "grading" differentiation.Grading is based mainly on the cytological characteristics of the tumour, whereby we distinguish 4 grades: differentiated (G1), moderately differentiated (G2), poorly differentiated (G3) and anaplastic (G4).The classification and stages of basal cell carcinoma in the eyelid region are shown in Fig. 2.
Nodular BCC (50-80%) is the most common type of BCC.It manifests as a slowly growing greyish-white, shiny papule to skin-coloured nodule with a thinned epidermis and telangiectasias.Cystic BCC is often a multilobular lesion made up of transparent nodules with telangiectasias.Both are considered to be low-risk forms of BCC.Superficial BCC (10-30%) (multicentric basal cell carcinoma) are easily infiltrated brown-red lesions, with fine peeling or scabs on the surface; the epidermis in the extent of the tumour lesion has an atrophic appearance.Among the high-risk subtypes of basal cell carcinoma is sclerodermiform BCC (6-10%) -morphea-like basal cell carcinoma.It can grow deep into the dermis and spread perineurally.This type of basal cell carcinoma rarely ul- cerates.Infiltrative BCC (5% of cases) is a locally destructive aggressive subtype with a higher risk of local recurrence, and Micronodular BCC (14-15%) is an aggressive and locally destructive subtype with subclinical spread and a higher risk of recurrence.Basal squamous cell carcinoma (so-called metatypical carcinoma) is a tumour that includes mixed regions with typical basaloid differentiation and regions approaching squamous cell carcinoma.[18,43,44] An aggressive, infiltrative type of BCC showed a high expression of an apoptotic gene Bcl-2 and moderate levels of proliferation associated markers -proliferating cell nuclear antigen.[44].It was found that telomere length was shortened and gene expression correlated with cell proliferation (Bcl-2, Ki-67) was increased in BCC [45].

Treatment of periocular BCC
The primary treatment modality for BCC is surgical resection [44].With respect to the tumour's location, tissue-sparing methods are often used, which increase the risk of recurrence [45 -48].Margin control is necessary to achieve clear resection margins to reduce the risk of local recurrence.The recurrence rate after primary surgery is 1%-5% per year [49,50].
Mohs micrographic surgery has been regarded as the best method of removing BCC with minimal recurrence rate, it is expensive and time consuming and not recommended usually for orbital infiltration due to difficulties by obtaining orientation of specimens from orbital soft tissue.The incidence of recurrence in patients treated without using Mohs micrographic surgery or "en-face" frozen sections intraoperatively ranged from 1.8 to 39%, and the proportion of recurrence increased with longer follow-up of patients.[51][52][53].
A multidisciplinary team must collaborate in planning management of BCC with orbital invasion (Fig. 6 -see cover page 3).In many patients orbital exenteration is the approach selected after the failure of previous therapeutic modalities.Given that recurrence after exenteration can be as high as 50-75%, it is very important not to underestimate the timely management of these lesions.Complications can include fistula formations into sinuses, to the nasolacrimal duct, tissue necrosis, chronically exposed bone, cerebrospinal fluid leak, pain or secondary infections.The time interval after exenteration for healing with granulation can occasionally far exceed the usual 3-4 months.Cosmetic defects after exenteration are covered by individual epithesis.

Other treatment modalities
Vismodegib is an available, orally administered specific inhibitor of the Hedgehog pathway with a small molecule.The signalisation of the Hedgehog pathway through the transmembrane protein Smoothened leads to activation and nuclear localisation of Glioma-Associated Oncogene (GLI) transcription factors and the inducing of the Hedgehog target genes.Vismodegib has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for patients with locally advanced and metastatic basal cell carcinoma that cannot be managed with surgery or radiotherapy.The approved oral dose of vismodegib is 150 mg/day.[54][55][56].Vismodegib can be used to treat basal cell nevus syndrome (Gorlin syndrome) in patients not amenable to surgery with multiple cutaneous lesions of the periocular region and head.[54][55][56].The results of a pilot phase 2 clinical trial (ERIVANCE) in 104 patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC) showed a response rate of 48% (laBCC) and 33% (mBCC), respectively, and median duration of response of 9.5 and 7.6 months.Median survival for patients with mBCC was 33.4 months.In laBCC, it is possible to discuss neoadjuvant treatment with an Hh inhibitor with the intention of shrinking the lesions, but there is no randomised data to demonstrate a favourable outcome.In a series of 15 patients treated with vismodegib for 3-6 months before surgery, only 1 patient relapsed after 22 months.[61].
Vismodegib in cream form or per os therapy is generally well tolerated.Side effects like alopecia, muscle spasms, fatigue, nausea, decreased appetite, weight loss, dyssomnia, or diarrhoea are sometimes the reasons to give up the therapy with vismodegib.Necessity of additional long term studies is required to estimate the risks factors to establish the treatment criteria for periocular BCC.[62].
Local pharmacological treatment, including the immunomodulator imiquimod and 5% 5-Fluoruracil, is less successful and is not yet widely used in localisation near the edge of the eyelid or the outer or inner corner.The principle of PDT (photodynamic therapy) is the accumulation of a photosensitizer: δ-aminolevulinic acid (ALA) or its methyl ester (MAL, Metvix® creme).PDT is the method of choice in patients with non-aggressive low risk BCC, for example, the superficial or nodular type not exceeding 2 mm in thickness, when surgery is not possible or is contraindicated.[18].Usually the cream is applied once per day, five times per week at least 8 to 16 weeks depending on the tumour stage.In a study with 19 patients they evaluated the efficacy of topical immunotherapy for the treatment of BCC and the histological clearance rate was about 90% after 3 months and 84% at 40 months.The 3-year interval of histological clearance rate was 100% for lesions up to 10 mm [62].Garcia-Martin et al compared the efficacy, cosmetic results and tolerance of Imiquimod and radiotherapy.In the Imiquimod cream group all patients had complete clinical clearance at 24 months of follow-up.In the radiotherapy group patients received treatment 2 or3 times per week for 5 weeks with a dose of 300 cGy per session (total administered dose was 4,000-7,000 cGy).Aesthetic and functional results were superior in the Imiquimod group, but radiotherapy was better tolerated.[63].
Curettage and electrocoagulation, cryotherapy and laser ablation are methods suitable for small, non-risky basal cell tumours that are not localised on the face and do not have a multifocal character.In the past, chemotherapy was also applied in the treatment of BCC, but unsuccessfully.[64].
With basal cell carcinomas significantly advanced locally, after incomplete excision, in lesions with a high risk of local recurrence or an unacceptable expected cosmetic effect, in elderly patients or with repeatedly recurring lesions, definitive radiotherapy is a suitable solution.[65].Today there are several types of radiotherapy for BCC: external radiotherapy and also interstitial brachytherapy.About 25% of patients undergo radiation therapy alone for invasive orbital BCC.[66].Brachytherapy has a theoretical advantage compared to surgery in that it enables the covering of larger areas of the skin with a high dose (macroscopic disease, microscopic disease, safety margin) without the need for irreversible damage to the surrounding tissues.It can be done by means of the interstitial route (the surgical introduction of brachytherapy applicators directly into the tumour tissue by puncture) or superficially.Surface brachytherapy is done by using standard applicators (e.g.Leipzig Applicator, Brock Applicator, Nucletron BV, Netherlands) or custom-made emulsions.Standard applicators are characterised by ease of use and good treatment reproducibility, but they cannot be used for irregular lesions and in a "curved" irregular terrain such as the periocular area.[67].
The side effects after external radiotherapy but also brachytherapy can be dry eye, secondary cataract, ectropion, cicatrisation of the lacrimal duct, secondary neovascular glaucoma, radiation retinopathy and maculopathy, radiation optic neuropathy which can lead to blindness.

The recurrence of basal cell carcinoma
Data on the recurrence after surgical treatment of basal cell carcinoma depend on the localization, size, infiltration, histological type, previous treatment options the surgical technique used.The risk of recurrence of BCC after surgery is estimated at 5%-15%.The most recurrences appear on the lower eye lid and in the medial canthus and in infiltrative types.Aggressive histological forms of BCC are associated with a higher risk of recurrence.Lesions with perineural invasion are usually regarded as more aggressive and are associated with higher rates of recurrences.[68].
One of important prognostic factors can be Ki-67, assay of Ki-67 expression is simple and repeatable and is recommended for evaluation of proliferative activity of malignant tumours.In most cases of BCC the values of the Ki-67 index are higher in recurrenced tumours than in primary BCC.[69,70].
We can include the apoptotic index as an unexplained prognostic factor of BCC recurrence.In the work of Staibano et al. 60 BCCs were evaluated, 30 of which were BCC1 (non-aggressive type) and 30 BCC2 (aggressive type).BCC1 showed a lower apoptotic index (AI) than BCC2, with the AI of BCC1from 2.03 -10.45% (mean value: 5.98%) and the AI of BCC2 from 21.91 -43.82% (mean value: 39.82%).It is assumed that low AI in BCC1 could indicate a good prognosis.High expression of the Bcl-2 protein is recorded in indolent, slow-growing BCC, while low expression of Bcl-2 occurs in highly aggressive types of BCC [71].

Conclusions
In the scope of onco-ophthalmology, increased attention must be paid to the issue of malignant periocular tumours.Despite a relatively small percentage of invasive diseases today, advanced stages may still occur.Early diagnosis, multidisciplinary cooperation, lifelong dispensary of the patient with early detection of recurrences are all important.Multidisciplinary cooperation and cooperation of the patient in the area of cancer tumours is essential, as it improves the early diagnosis, treatment and survival of patients.

Information about authors and disclosure of information
Corresponding author: Zuzana Prídavková -zuzana.pridavkova@gmail.com.

Fig. 1 .
Fig. 1.Malignant tumours of the skin of the eyelid -age structure of patients in the period 1997-2012 (NCR SR).
Prídavková: Conceptualization, Project administration, Investigation, Writingoriginal draft; A. Furdová: Conceptualization, Project administration, Writing-review & editing; K. Benca Kapitánová: Editing, Investigation; R. Vida: editing; P. Žiak: editing; I. Popov: editing.Disclaimer: The opinions presented in this article are those of the authors and do not necessarily represent those of their institutions.Financial support: no financial support received.Conflict of interest statement: None of the authors has conflict of interest with this submission.Financial/proprietary interest: None of the authors has financial interest related to this study to disclose.Declaration of Helsinki: The manuscript does not report the results of an experimental investigation on human subjects.Informed Consent: This article does not include results of experimental investigations on human subjects.Abbreviations: BCC -Basal cell carcinoma; SCC -Squamous cell carcinoma; NMSC -Non-melanoma skin cancer; NCR -National Cancer Registry; GLI -Glioma-Associated Oncogene; FDA -Food and Drug Administration; EMA -European Medicines Agency.