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Systematic Review

A Systematic Review and Meta-Analysis of Ocular and Periocular Basal Cell Carcinoma with First-Time Description of Dermoscopic and Reflectance Confocal Microscopy Features of Caruncle Basal Cell Carcinoma

by
Martina Caviglia
1,
Shaniko Kaleci
2,
Pasquale Frascione
3,
Miram Teoli
4,
Maria Concetta Fargnoli
5,
Giovanni Pellacani
1 and
Victor Desmond Mandel
3,*
1
Dermatologic Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, La Sapienza University of Rome, 00185 Rome, Italy
2
Dermatology Unit, Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
3
Oncologic and Preventive Dermatology Unit, San Gallicano Dermatological Institute-IRCCS, 00144 Rome, Italy
4
Porphyria and Rare Diseases Unit, San Gallicano Dermatological Institute-IRCCS, 00144 Rome, Italy
5
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
*
Author to whom correspondence should be addressed.
Diagnostics 2025, 15(10), 1244; https://doi.org/10.3390/diagnostics15101244
Submission received: 12 December 2024 / Revised: 4 February 2025 / Accepted: 9 February 2025 / Published: 14 May 2025
(This article belongs to the Special Issue New Developments in the Diagnosis of Skin Tumors)
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Review Reports Versions Notes

Abstract

:
Background: Basal cell carcinoma (BCC) of the ocular and periocular region is characterized by a painless progressive extension. An early diagnosis can limit the extent of facial tissue involvement and subsequent resection resulting in better cosmetic and functional results. Objectives: The aim is to provide the largest and most up-to-date overview of ocular and periocular BCCs. We also reported the first case of caruncle BCC investigated by dermoscopy and reflectance confocal microscopy (RCM). Methods: A systematic review and meta-analysis (Prospero ID CRD583032) were carried out by searching PUBMED–MEDLINE, including all articles with a full-text English version and with BCCs in eyelids, medial and lateral canthus, caruncle, conjunctiva, and orbit. The following data were collected: authors, year, title and type of publication, medical specialization, number, sex, age and comorbidities of the patients, anatomic localization of the disease, clinical and dermoscopic aspect, histological examination, and treatment. Results: We identified 731 articles through a database search, of which 236 articles matched our inclusion criteria. A total of 71.730 patients with ocular and periocular BCCs were included in the present study, and all data collected were reported in a dataset. Most of the articles included were described by ophthalmologists (67.5%), dermatologists (11.2%), or plastic surgeons (5.6%). The proportional meta-analysis revealed varying significance and heterogeneity for each type of study included. Conclusions: BCC more frequently affects the lower eyelid. The most common BCC subtype of ocular and periocular area is the nodular form. Limited data are available concerning the application of dermoscopy and RCM in this area. RCM may be particularly useful for early diagnosis, mapping, and treatment monitoring of ocular and periocular BCCs. Surgery still remains the first-choice treatment.

Graphical Abstract

1. Introduction

Basal cell carcinoma (BCC) is a skin carcinoma that originates from epidermal cells. It is the most common malignant tumor in white populations, accounting for 75% of cases [1]. The incidence varies geographically; it also increases with age and is slightly more common in men. Several risk factors are involved in the pathogenesis, and ultraviolet radiation (UVR) is the most important cause [1]. BCC typically affects sun exposure areas, especially on the head and neck region, of which 20% occurs on the eyelids [2]. BCC is a malignant cancer that exceptionally metastasizes. The risk of recurrence may depend on the location of the tumor (H zone of the face), the histological characteristics, and immunosuppression [3]. The precise and early identification of these tumors can limit the extent of facial tissue involvement and subsequent resection resulting in better cosmetic and functional results. The diagnosis of BCC often requires a biopsy, especially in the case of ambiguous lesions. Dermoscopy usually allows for the early identification of BCC and preoperatively detects its subtype [1]. Additional non-invasive skin-imaging technology that has proven its high diagnostic value is in vivo reflectance confocal microscopy (RCM), which is often only accessible in specialized skin cancer centers [4].
RCM permits the capture of in vivo, cellular-resolution images of lesions, parallel to the skin surface, from the stratum corneum to the superficial dermis [5]. Acquisition of high-quality images with RCM can be impeded by technical difficulties in curved, or relatively inaccessible, surfaces such as ocular and periocular structures. Herein, we describe a rare case of caruncle BCC investigated with dermoscopy and RCM, after performing a systematic review and meta-analysis of all the available literature concerning ocular and periocular BCC. Currently, this is the first report on the application of non-invasive imaging tools in this anatomical location.

2. Materials and Methods

2.1. Search Strategy

A systematic review and meta-analysis of ocular and periocular BCCs reported in the literature were carried out by searching PUBMED–MEDLINE. Keywords used were “ocular basal cell carcinoma”, “periocular basal cell carcinoma”, “caruncle basal cell carcinoma”, “lacrimal caruncle basal cell carcinoma”, “ocular basal cell carcinoma AND confocal microscopy”, and “ocular basal cell carcinoma AND reflectance confocal microscopy”. PUBMED–MEDLINE was searched for studies published up to 31 December 2023.

2.2. Study Registration

This systematic review with meta-analysis was registered in PROSPERO (Prospero ID CRD583032) and conducted following PRISMA guidelines (Figure 1).

2.3. Data Collection

Data were independently extracted by two authors (MC and MT) and disagreement was resolved by a consensus or a third author (VDM) who acted as a referee. We included published articles with a full-text English version available and with specific BCCs’ localization in eyelids, medial and lateral canthus, caruncle, conjunctiva, and orbit. The search was restricted to studies on humans, while systematic and literature reviews were excluded. The following data were collected: authors, year, title and type of publication, medical specialization, number, sex, age and comorbidities of the patients, anatomic localization of the disease, clinical and dermoscopic aspect, histological examination, and treatment. Moreover, we reported the first case of caruncle BCC investigated with dermoscopy (VivaCam®: Mavig GmbH, Munich, Germany) and RCM (VivaScope® 3000: Mavig GmbH, Munich, Germany). Instruments and the acquisition procedure have been described elsewhere [5,6].

2.4. Statistical Analysis

We performed a proportional meta-analysis using MedCalc 14.8.1 software (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2014, accessed on 1 September 2024) applying the Freeman–Tukey transformation (arcsine square root transformation) to calculate the weighted overall proportion (DerSimonian and Laird, 1986). Symptom proportions (expressed in percentage), within the 95% confidence interval (CI), from each study were included in the meta-analysis. The overall proportion within the 95% CI was calculated using both the random-effects model and the fixed-effects model. The fixed-effects model assumes that all included studies have a similar effect, so the summary effect is an estimate of the weight of similar effects in the studies. The random-effects model assumes that effects vary among studies, and the summary analysis is a weighted average reported in different studies.
A Forest plot was performed for each study included in the meta-analysis; values related to the effect size and CI were presented. The Forest plot also included the weighted effect of the prevalence of BCC by study type, with a 95% CI. The size of the marker (square) represents the weight of each study; studies with a smaller patient sample will have less weight. The overall effect is represented in the plot by a diamond: Its width represents precision, and its position represents the estimate of effects.
Heterogeneity among studies was estimated using Cochran’s Q statistic test and the I2 index. Heterogeneity, defined as whether observed variance exceeded expected variance, was considered significant when p < 0.01 for the Q statistic. The I2 index of given heterogeneity [I2 = 100% × (Q − df)/Q] was defined as I2 = 0–25%, homogeneous; I2 = 25–50%, moderate heterogeneity; I2 = 50–75%, large heterogeneity; I2 = 75–100%, extreme heterogeneity.

3. Results

3.1. Study Selection and Characteristics

We identified 731 articles through database search. Duplicates were omitted and 428 records were excluded (Table S1) because they did not meet the inclusion criteria as mentioned above. A total of 236 articles were considered in our study (235 papers matched our criteria, while one was added after screening references of all selected studies) [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242]. All data collected are reported in a dataset (Table 1), while the characteristics of the studies are summarized in Table 2. The articles selected were mainly retrospective (32.6%), case series (32.6%), and reports (22.8%). Most of the articles included were described by ophthalmologists (67.5%), dermatologists (11.2%), and plastic surgeons (5.6%) but also less frequently by other specialists. A total of 71.730 patients with ocular and periocular BCCs are included in the present systematic review with meta-analysis and their characteristics are described in Table 3. Different anatomical locations are summarized in Table 4. “Eyelid and periocular area” (48.7%) and “eyelid” (29.9%) were the two more commonly involved sites, while “periocular”, “ocular”, and “caruncle” areas were only rarely interested. Clinic, dermoscopy, RCM, and histopathology data are included in Table 5, while treatments are given in Table 6.

3.2. Case

In September 2022, a 38-year-old lady was referred to San Gallicano Dermatological Institute-IRCCS, for evaluation of a caruncle pigmented lesion on the left eye. Her family and medical history were unremarkable. The lesion, which appeared approximately 7 months ago, was indolent. Clinical examination revealed a millimetric flat lesion, with faded and irregular margins, black-blue in color (Figure 2a). After applying oil immersion fluid, dermoscopic examination with VivaCam® showed the presence of blue–black structureless areas (Figure 2b,c). Sharply demarcated lobular nests, outlined by dark peritumoral clefting, were detected with the RCM handheld probe and corresponded to basaloid islands (Figure 2). Polarized elongated keratinocytes (streaming) characterized the overlying skin (Figure 2d). Hyper-refractile thin dendrites and bright oval structures were observed within and around the tumor island (Figure 2e,f), corresponding to melanophages, while peripheral palisading of nuclei can also be detected at higher magnification. The adjacent dermal stroma contained small bright dots compatible with smaller inflammatory cells. Convoluted and dilated blood vessels coursing in the horizontal plane of imaging were seen in real-time or video-mode RCM imaging, juxtaposed to the tumor islands (Video S1). Based on RCM findings, a diagnosis of pigmented BCC was made, and the lesion was subsequently surgically removed by an ophthalmologist. Histopathologic examination confirmed the diagnostic suspicion and the tumor was completely excised with a 2 mm of free margins. The patient did not complain of any discomfort or functional impairment. At a two-year follow-up, no signs of local recurrence were observed.

3.3. Results of Meta-Analysis

The results of the proportional meta-analysis, including the combined proportion (95% CI), are summarized in Table 7, with estimates of the overall proportion shown in the Forest Plot (Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 and Figure 8). The overall proportion for “clinical trial” was 97.6% (91.6–99.9), demonstrating significant and extreme heterogeneity (Q = 122.7, df = 3, I2 = 75.6%, p = 0.006). For “prospective study” and “prospective case series”, the overall proportion was 93.0% (79.2–99.6), indicating significant and extreme heterogeneity (Q = 40.6, df = 20, I2 = 99.5%, p < 0.001). “Retrospective study” showed an overall proportion of 61.1% (48.8–72.8), with significant and extreme heterogeneity (Q = 346.3, df = 75, I2 = 99.8%, p < 0.001). “Case reports” and “case report with review of the literature” studies showed an overall proportion of 85.3% (77.7–91.0), with non-significant and homogeneous (Q = 77.8, df = 53, I2 = 0.0%, p = 1.000). “Case series” studies showed an overall proportion of 73.3% (62.1–83.3), with significant and extreme heterogeneity (Q = 199.1, df = 66, I2 = 99.6%, p < 0.001) and “letter” showed an overall proportion of 89.9% (72.8 to 99.0), with significant and moderate heterogeneity (Q = 233.3, df = 8, I2 = 65.7%, p = 0.003).

4. Discussion

4.1. Epidemiology and Localization

In the development of BCC, the main risk factors include UV radiation exposure, fair pigmentary characteristics, older age, genodermatoses, a family and personal history of BCC, and immunosuppression [1]. UVB radiation (290–320 nm) is believed to play a greater role than UVA radiation (320–400 nm). Different carcinogens can target different stem cell compartments and subsequently give rise to BCCs. Several hypotheses have been formulated regarding the origin of BCCs. Most BCCs seem to derive from hair follicle stem cells, while some authors claim that BCC stem cells are in the interfollicular epidermis. There is generally a latency period of several years between sun damage and the onset of BCC. Thereby, BCC develops in chronically photo-exposed areas most commonly in the head and neck [243] and accounts for 90% of malignant eyelid tumors [2]. Due to changes in sun exposure behavior and the general aging of the population, an increase in the incidence of BCC has been observed in many countries around the world. Wide regional variations in the reported incidence rates of BCC have been found, due to the latitude of the population, the study period, and the methods of recording BCC [244]. Generally, BCC arises in the elderly population. We observed an age range of 9 to 105 years for all cases examined. In 45 reports, the age range is not available. However, some patients can develop this skin cancer at an earlier age (<40 years), and patients with genetic syndromes such as Xeroderma Pigmentosum (XP) or Basal Cell Naevus Syndrome (BCNS or Gorlin–Goltz) can develop BCC earlier, even before 20 years of age [3]. In our study, 21 patients were affected by BCNS with a median age of 43 years and 27 patients suffered from XP with a mean age of 21 years. An increasing trend has been observed for patients aged ≥ 50 years over the next 10 years, and the incidence of BCC is expected to increase by 30–40% (males) and 25–30% (females) [244]. BCC is a tumor that affects both sexes, and no sex predilection has been observed [245]. In the literature, some authors, such as Saleh GM et al. in 2017 [246] in an article on eyelid basal cell carcinoma in England, reported a slight preponderance in males. Dessinioti C et al., in 2010 [247], reported a female-to-male ratio of 2:1. Our analysis showed a mild prevalence of the female sex (53.4%). However, in 91 articles, there were no data regarding the sex of patients. In the case we described, BCC occurred in a woman, who was younger than the average age reported in the literature even with a negative medical history.
The site most frequently affected by BCC is the lower eyelid, followed by the medial canthus, upper eyelid, and lateral canthus [49,63,248]. The involvement of the lower eyelid could be the consequence of light reflection by the cornea, and other irritant chemical or physical insults could be considered [109,249,250,251,252]. The uncommon envelopment of the upper eyelid could be due to the protection of the eyebrow [251].
Our analysis showed that in 193 (81.8%) articles, there was eyelid involvement; in 138 (58.5%), the upper/lower eyelid location was specified; among these, the involvement of both was reported in 89 papers (37.7%); in 38 (16.1%), just the lower eyelid was involved and in 11 (4.7%), just the upper eyelid. In the ocular and periocular regions, the growth of the tumors is characterized by a painless progressive extension; therefore, we often have the involvement of contiguous ocular structures [249].
On the eyelids, the BCC rapidly invades the dermis, followed by the infraorbital extension. On the medial canthus, the tumor can spread on the orbit and then can destroy the globe. Primary BCCs of the mucocutaneous transition region or the conjunctiva are extremely rare [252]. These sites are more frequently affected secondarily by infiltration from the tumor of the eyelid or canthus region [52]. Malignancies of the caruncle are generally very rare with a frequency of 5% among all the caruncle tumors [253,254,255]. In addition to our case of primary caruncle BCC, we identified 11 articles in the literature describing caruncle BCCs in a total of 15 patients with a median age of 61.1 years (range 24–84 years) [12,25,30,51,59,61,62,76,101,113,153].

4.2. Diagnosis

BCCs show polymorphic clinical aspects and different dermoscopical features due to their anatomical location [256,257,258]. The nodular BCC subtype occurs predominantly on the head–neck region and accounts for 60% of all BCCs. The superficial subtype represents 20% of BCCs and mainly involves the trunk, while other subtypes are less frequent. The clinical aspect of BCCs was reported in only 68 articles (28.8%). Palpable lesions resulted in the most common form (73.5%) and were described as “tumors”, “masses”, “papular”, “nodular”, or “exophytic lesions”, followed by ulcerated (36.8%) and pigmented (17.6%) lesions. Instead, sclerosing morphic-like lesions were reported in only two articles. Regarding primary caruncle BCCs, most of the papers (72.7%) mentioned the clinical aspect and described the nodular (33.3%) and pigmented (20%) lesions as the more common type. Dermatoscopic features were reported in only three articles (none regarding caruncle) of our systematic review with meta-analysis. The cause may be associated with the difficulty of exploring this anatomical area with dermatoscopy instruments. However, it is noted that only 11% of the papers were published by dermatologists, while the majority concerned ophthalmologists (67.5%). Non-dermatological assessment is probably the other main reason for the scarcity of dermatoscopic data in literature. Clinical diagnosis confirmed on dermatoscopy without histopathological examination is considered acceptable only for the small nodular form on typical locations such as the head/neck or trunk, and for the superficial BCC located on the trunk and extremities [257]. Classification of BCCs into low and high risks is based on the probability of recurrence. This risk is related to the localization on the H area of the face, aggressive histological features (perineural and/or vascular involvement), and/or immunosuppression. In case of doubtful lesions as well as high-risk BCCs, histological correlation is mandatory [256,257]. In low-risk BCCs, imaging techniques may be sufficient to confirm the diagnostic suspicion [257]. RCM has been arousing great interest in recent years in the diagnosis of skin tumors and particularly, the diagnosis of eyelid margin lesions to minimize the number of unnecessary surgical excisions [123]. Identification of RCM criteria is particularly important in identifying BCC whose clinical and dermoscopical appearance may mimic other malignant or benign lesions [259]. The RCM handheld probe can be applied directly to the skin, and it allows imaging of lesions in less accessible sites, such as the structure of the eye and oral and genital mucosa [260,261,262,263]. Currently, there is only one study published regarding the application of RCM in the eyelid area [123]. Among 47 eyelid margin lesions, the diagnosis of BCC was made in 14 cases and based on the recognition of at least 2 of the following criteria: dark silhouette, lobular nests or trabecular structures of tightly packed cells, peripheral palisading of elongated cells, peritumoral clefts, convoluted and dilated blood vessels, and polarized elongated keratinocytes (streaming) of the overlying skin. RCM sensitivity and specificity in this study resulted in 100% and 60%, respectively. In our caruncle BCC, we observed with RCM the presence of streaming, lobular nests with peripheral palisading, peritumoral clefts, and dilated blood vessels juxtaposed to the tumor islands, confirming the utility of the criteria identified by Cinotti et al. [123]. In our study, histological diagnosis was reported in 234 articles, and among them, the subtype was specified in 40.7% (nodular in 71% of the papers).
Multiple recurrences are linked to aggressive subtype, male gender, large lesion size, perineural invasion, medial canthal localization, and advanced patient age [90,264,265]. A study on 63 patients revealed that medial canthus lesions appear to have a higher risk of orbital invasion in comparison to the other ocular and periocular areas [47]. The cause may be associated with the difficulty of performing a complete surgical excision in this anatomical zone [266,267].

4.3. Treatment

BCCs belong to a special class of tumors characterized by a slow, persistent, and locally invasive growth pattern. If inadequately treated, it may progress into a large and deeply infiltrating locally advanced tumor (laBCC) or rarely (from 0.0028% to 0.55%) in a metastatic BCC (mBCC) [268].
A recent EADO classification introduced the concept of “easy to treat” and “difficult to treat” BCCs [257]. “Difficult to treat” BCCs included mBCC, laBCCs, and other types which, for any reason, pose specific management difficulties. For the treatment of BCC, different modalities can be used, but only surgical excision provides histological confirmation of successful treatment [269]. Moreover, surgeries still have the lowest recurrence rates, but they can cause functional loss or cosmetic disfigurement and have a risk of bleeding and infections [270]. Topical therapy and destructive approaches may be considered in patients with superficial BCC, while photodynamic therapy (PDT) can be an option for superficial and low-risk nodular BCCs [257]. Moreover, combined modalities such as laser CO2 and PDT could be used for selected patients with problematic reconstruction after surgery, aesthetic reasons, for patients with numerous and frequently occurring BCCs like patients affected by Gorlin–Goltz syndrome or patients who have undergone transplantation, for patients for whom anesthesia may be problematic, for patients receiving oral anticoagulants, and finally for patients who refused other treatments [269,270]. Regarding laBCCs and mBCC, treatments included hedgehog inhibitors, immunotherapy with anti-PD1, radiotherapy, and electrochemotherapy [257].
In our study, the only use of surgical techniques is reported in most of the articles (65.3%), confirming to be the first-choice treatment. Combined modality (surgery plus other treatments) found their application in 27.1% of papers, followed by non-surgical therapies in 6.8%. Only two articles did not mention the therapeutic approach. In our case of caruncle BCC, the therapeutic choice was standard surgical excision with 2 mm of free margins. We highlight the importance of RCM for the diagnosis and treatment monitoring of BCC because it allows to control histologic clearance and detect early recurrences [269,270]. Furthermore, RCM facilitates the presurgical and intrasurgical lateral and deep margin assessment of poorly defined BCCs, especially on aesthetically relevant sites such as ocular and periocular areas [271].

5. Conclusions

Our systematic review and meta-analysis collected the largest and most up-to-date collection of ocular and periocular BCCs. The site most frequently affected by BCC is the lower eyelid, followed by medial canthus which has a higher risk of orbital invasion, while primary caruncle BCC is extremely rare. Nodular BCC is the most common subtype of ocular and periocular areas. Dermoscopic and RCM studies concerning these areas are few in the literature. RCM may be very useful for early diagnosis, mapping, and treatment monitoring, especially in aesthetically relevant sites. Surgery still remains the first-choice treatment for ocular and periocular BCC, even if studies regarding the use of combined modality are increasing over time.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/diagnostics15101244/s1, Table S1: List of excluded studies; Video S1: Real-time or video-mode RCM imaging of the caruncle basal cell carcinoma.

Author Contributions

Study conception and design: M.C., and V.D.M.; collection and interpretation of data: M.C., M.T., V.D.M.; manuscript drafting: M.C., and V.D.M.; manuscript editing: V.D.M.; preparation of figures: V.D.M.; preparation of tables and dataset: M.C.; statistical analysis: S.K.; review & editing of the text: P.F., M.C.F., G.P. All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, took responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Italian Ministry of Health (Ricerca Corrente). All authors had full access to all the data used in this study and took complete responsibility for the integrity of the data and the accuracy of the data analysis.

Institutional Review Board Statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1964 Declaration of Helsinki, as revised in 2013. Ethical review and approval have been waived for this study, as they are not required by our Institutional Ethics Committee for reports on individual cases.

Informed Consent Statement

Patients provided informed written consent to the treatment. Informed consent was also obtained from the patient for publication of this manuscript and accompanying images.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors have no conflicts of interest relevant to this article to disclose. Honorarium, grant, or other forms of payment were not given to any of the authors to produce the manuscript.

AI Disclosure

We hereby disclose that no artificial intelligence or assisted technologies were used in the production of this study, including the creation of any figures or illustrations.

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Figure 1. Flow diagram of the study selection process.
Figure 1. Flow diagram of the study selection process.
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Figure 2. Caruncle basal cell carcinoma. (a) Clinically appeared as a millimetric flat lesion, with faded and irregular margins, blue–black in color. (b,c) Dermoscopic assessment revealed black–blue structureless areas. (d–f) Reflectance confocal microscopy (RCM) showed the presence of sharply demarcated lobular nests, outlined by dark peritumoral clefting. Streaming, peripheral palisading, hyper-refractile thin dendrites and bright oval structures, and convoluted and dilated blood vessels are other RCM criteria detected.
Figure 2. Caruncle basal cell carcinoma. (a) Clinically appeared as a millimetric flat lesion, with faded and irregular margins, blue–black in color. (b,c) Dermoscopic assessment revealed black–blue structureless areas. (d–f) Reflectance confocal microscopy (RCM) showed the presence of sharply demarcated lobular nests, outlined by dark peritumoral clefting. Streaming, peripheral palisading, hyper-refractile thin dendrites and bright oval structures, and convoluted and dilated blood vessels are other RCM criteria detected.
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Figure 3. Proportional meta-analysis of the included “clinical trial” studies.
Figure 3. Proportional meta-analysis of the included “clinical trial” studies.
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Figure 4. Proportional meta-analysis of the included “prospective study” and “prospective case series”.
Figure 4. Proportional meta-analysis of the included “prospective study” and “prospective case series”.
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Figure 5. Proportional meta-analysis of the included “retrospective study”.
Figure 5. Proportional meta-analysis of the included “retrospective study”.
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Figure 6. Proportional meta-analysis of the included “case reports” and “case report with review of the literature”.
Figure 6. Proportional meta-analysis of the included “case reports” and “case report with review of the literature”.
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Figure 7. Proportional meta-analysis of the included “case series”.
Figure 7. Proportional meta-analysis of the included “case series”.
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Figure 8. Proportional meta-analysis of the included “letter”.
Figure 8. Proportional meta-analysis of the included “letter”.
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Table 1. Dataset.
Table 1. Dataset.
Authors (Year)
[Reference]		TitleType of ArticleSpecializationCasesGender (n° pz)Age (Mean/
Median Age)		Comorbidities (n° pz)Anatomic SiteAnatomic AreaClinical AspectDermoscopyHistological Examination (n° pz)Treatment
Chadfield HW and Kanagasundaram CR (1962) [7]Carcinoma in benign mucous membrane pemphigoid (ocular pemphigus)LetterDermatology1M (1)56Ocular pemphigus (1) Eyelid
Medial canthus		Eyelid
Periocular area		Ulcerated noduleNPSolid BCC (1)Surgery
+
RT
Callahan A et al. (1975) [8]Massive orbital invasion by small malignant lesionsCase seriesOphthalmology8 (among 11 cases)M (6)
F (2)		Range 43–71 (55.8/55)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Caruncle
Periocular area		Ulcerated lesionNPNodular BCC (1)
Morpheaform BCC (3)
Ulcerative and invasive BCC (4)		Surgery
±
RT
Fraunfelder FT et al. (1977) [9]Cryosurgery for ocular and periocular lesionsCase seriesOphthalmology101 (among 270 cases)NANANAEyelid
Medial canthus
Lateral canthus
Lacrimal outflow		Eyelid
Ocular area
Periocular area		NANPBCC (101)Cryosurgery
Gaasterland DE et al. (1982) [10]Ocular involvement in xeroderma pigmentosumCase reportsOphthalmology1F (1)36Xeroderma pigmentosum (1)Lower eyelidEyelidNoduleNPBCC (1)Cryotherapy
+
Surgery
Callahan A et al. (1982) [11]Cancer excision from eyelids and ocular adnexa: the Mohs fresh tissue technique and reconstructionLetterOphthalmology3M (3)Range 48–80 (63/61)NALower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (3)Surgery
±
RT
Shields CL et al. (1986) [12]Types and frequency of lesions of the caruncleRetrospective studyPathology 1 (among 57 cases)F (1)61NACaruncleCaruncleNANPBCC (1) Surgery
Nerad JA and Whitaker DC (1988) [13]Periocular basal cell carcinoma in adults 35 years of age and youngerCase seriesOphthalmology13 (among 409 cases)M (6)
F (7)		Range 21–35 (28.9/29)Basal cell nevus syndrome (3)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Erythematous, flat or slightly raised lesionNPMorpheaform BCC (7)
Nodular BCC (6)		Surgery
+
Cryotherapy
Rodriguez-Sains RS et al. (1988) [14]Radiotherapy of periocular basal cell carcinomas: recurrence rates and treatment with special attention to the medical canthusRetrospective studyOphthalmology631NANANAEyelidEyelidNANPBCC (631)Surgery
±
RT or other therapy
Hoppenreijs VP and Cruysberg JR (1989) [15]Spontaneous repair of lower eyelid after tumour excisionRetrospective studyOphthalmology11 (among 12 cases)M (5)
F (6)		Range 48–77 (66.1/69)NALower eyelidEyelidNANPBCC (11)Surgery
De Keizer RJ and Scheffer E (1989) [16] Masquerade of eyelid tumoursCase seriesOphthalmology15 (among 830 cases)NANANAEyelidEyelidNANPBCC (15)Surgery
Downes RN et al. (1990) [17]Micrographic (MOHS’) surgery in the management of periocular basal cell epitheliomasProspective case seriesOphthalmology22M (8)
F (14)		Range 27–85 (67/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (22)Surgery
+
RT
Morley M et al. (1991) [18] Cis-platinum chemotherapy for ocular basal cell carcinomaCase reportsOphthalmology3M (2)
F (1)		Range 66–80 (71.3/68)Mental confusion (1)Lower eyelidEyelidNoduleNPBCC (2)
Infiltrating morpheaform BCC (1)		Surgery
+
Cis-platinum chemotherapy
+
Surgery or EBRT
Rodriguez JM and Deutsch GP (1992) [19]The treatment of periocular basal cell carcinomas by radiotherapyRetrospective studyRadiotherapy127NARange 40–94 (62/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (127)RT
+
Surgery
Amdur R.J et al. (1992) [20] Radiation therapy for skin cancer near the eye:
kilovoltage X-rays versus electrons		Case reportsRadiotherapy1NANANALower eyelidEyelidNANPBCC (1)RT
Mansour AM (1993) [21]Adnexal findings in AIDSCase seriesOphthalmology1 (among 21 cases)M (1)31AIDS and
pneumocystis carinii pneumonia (PCP) (1)		Lower eyelidEyelidNANPBCC (1) Surgery
Tuppurainen K (1995) [22]Cryotherapy for eyelid and periocular basal cell carcinomas: outcome in 166 cases over an 8-year periodCase seriesOphthalmology 146 (among 166 cases)NARange 30–89 (67.9/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (142)
Morpheaform BCC (4)		Surgery
+
Cryotherapy
Naugle TC et al. (1995) [23]Free graft enhancement using orbicularis muscle mobilizationCase seriesOphthalmology 4 (among 7 cases)M (1)
F (3)		Range 48–83 (67.5/69)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (4)Surgery
Behmand RA and Guyuron B (1996) [24] Resection of bilateral orbital and cranial base basal cell carcinoma with preservation of visionCase reports Plastic surgery1F (1)68NABoth orbitsOcular areaUlcerated noduleNPBCC (1) Surgery
Poon A et al. (1997) [25]Primary basal cell carcinoma of the caruncleCase reportsOphthalmology 1M (1)74SCC, BCC, and glaucoma (1)Caruncle Caruncle Vascular, pink noduleNPSolid-microcystic BCC (1)Surgery
Günalp I and Gündüz K (1997) [26] Secondary orbital tumorsRetrospective studyOphthalmology129 (among 524 cases)NARange 37–84 (58.4/NA) NAEyelidEyelidNANPBCC (129)Surgery
Fosko SW et al. (1997) [27]Basal cell carcinoma involving the lacrimal canaliculus. A documented mechanism of tumor spreadCase reportsDermatology2M (1)
F (1)		30, 62NALacrimal canaliculusPeriocular areaPapuleNPBCC (2)Surgery
Lowry JC et al. (1997) [28]The role of second-intention healing in periocular reconstructionCase seriesOphthalmology52 (among 65 cases)M (26)
F (26)		Range 44–85 (68.7/71)NAUpper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (52)Surgery
Kersten RC et al. (1997) [29]Accuracy of clinical diagnosis of cutaneous eyelid lesionsProspective studyOphthalmology139 (among 864 cases)NARange 31–96 (72/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (139)Surgery
Meier P et al. (1998) [30]Primary basal cell carcinoma of the caruncleCase reportsOphthalmology 1M (1)24NACaruncle Caruncle Whitish nodule with a reddish center and fine vesselsNPSolid-cystic BCC (1)Surgery
Mantovani E et al. (1998) [31]Recurrent eyelid basal cell carcinoma with sclerochoroidal infiltration: echographic findingsCase reportsOphthalmology1F (1)82NAUpper eyelidEyelidNANPBCC (1) Surgery
Arlette JP et al. (1998) [32]Basal cell carcinoma of the periocular regionCase seriesDermatology233M (106)
F (127)		Range 17–102 (58.8/59)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (233)Surgery
±
Electrodesiccation and curettage or cryotherapy or RT
der Plessis PJ et al. (1998) [33]Mohs’ surgery of periocular basal cell carcinoma using formalin-fixed sections and delayed closureProspective studyDermatology120M (61)
F (59)		Range 25–94 (NA/68)NAUpper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (120)Surgery
±
RT
±
Curettage and cautery or cryotherapy
Inkster C et al. (1998) [34]Oculoplastic reconstruction following Mohs surgeryRetrospective studyOphthalmology57 (among 60 cases)NARange 34–91 (68/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (57)Surgery
Garcia GH et al. (1999) [35]Periocular deep cutaneous basal cell carcinomaCase reportsOphthalmology 1 (among 2 cases)F (1)36NAMedial canthusPeriocular areaNoduleNPBCC (1)Surgery
Wlodarkiewicz A et al. (1999) [36]Extensive periocular defect reconstruction with local flaps and conchal cartilage graftCase reportsDermatology1F (1)77NALateral canthusPeriocular areaUlcerated noduleNPInfiltrative BCC (1)Surgery
Carter KD et al. (1999) [37]Clinical factors influencing periocular surgical defects after Mohs micrographic surgeryComparative studyOphthalmology 250 (among 281 cases)NARange 14–100 (67.5/71)Bazek syndrome (1);
Basal cell nevus syndrome (3)		Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular/nodular ulcerative BCC (230)
Morpheaform BCC (18)
Multicentric BCC (2)		Surgery
Wang I et al. (1999) [38]Photodynamic therapy utilising topical delta-aminolevulinic acid in non-melanoma skin malignancies of the eyelid and the periocular skinCase seriesOncology14M (6)
F (8)		Range 38–89 (77/79.5)Basal cell nevus syndrome (1)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NoduleNPNodular cystic BCC (6)
Nodular/morpheaform BCC (2)
Nodular ulcerative (6)		PDT
Lindgren G et al. (2000) [39]Mohs’ micrographic surgery for basal cell carcinomas on the eyelids and medial canthal area. II. Reconstruction and follow-upProspective case seriesOphthalmology 61M (19)
F (42)		Range 31–92 (73/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPSuperficial BCC (NA)
Micronodular (NA)
Morpheaform BCC (NA)		Surgery
Honavar SG et al. (2001) [40]Basal cell carcinoma of the eyelid associated with Gorlin-Goltz syndromeRetrospective studyOphthalmology 4M (1)
F (3)		Range 67–86 (72.8/69)Basal cell nevus syndrome (4)Upper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		Ulcerated noduleNPBCC (4)Surgery
+
EBRT
Rohrbach JM (2001) [41]Immunology and growth characteristics of ocular basal cell carcinoma Comparative studyOphthalmology 20M (10)
F (10)		Range 41–90 (NA/77)NAEyelid
Medial canthus 		Eyelid
Periocular area		NANPNodular BCC (17)
Fibrosing BCC (3)		Surgery
Assegid A (2001) [42]Pattern of ophthalmic lesions at two histopathology centres in EthiopiaRetrospective studyOphthalmology2 (among 231 cases)NARange 15–>60 (NA/NA)NAEyelidEyelidNANPBCC (2)Surgery
Shankar J et al. (2002) [43] Management of peri-ocular skin tumours by laissez-faire technique: analysis of functional and cosmetic resultsCase seriesOphthalmology18 (among 24 cases)NARange 32–94 (66/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (18)Surgery
Wong VA et al. (2002) [44]Management of periocular basal cell carcinoma with modified en face frozen section controlled excisionCase seriesOphthalmology633 (among 653 cases)NARange NA (64/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPSolid BCC (450)
Infiltrating BCC (123)
Superficial/multifocal BCC (80)
Micronodular BCC (47)
Morpheic BCC (35)
Adenoid BCC (15)
Pigmented BCC (6)
Unspecified/unavailable (57)		Surgery
Selva D et al. (2003) [45]Recurrent morphoeic basal cell carcinoma at the lateral canthus with orbitocranial invasionCase reportsOphthalmology1F (1)85No comorbiditiesLateral canthusPeriocular areaPlaqueNPNodulocystic/morpheic BCC (1)Surgery
+
RT
Hsuan J and Selva D (2004) [46]Early division of a modified Cutler-Beard flap with a free tarsal graftCase seriesOphthalmology2 (among 4 cases)M (1)
F (1)		69, 78NAUpper eyelidEyelidNANPBCC (2)Surgery
Malhotra R et al. (2004) [47]The Australian Mohs database, part I: periocular basal cell carcinoma experience over 7 yearsProspective case seriesOphthalmology 1.275 (among 1.295 cases)NARange 15–92 (60/61)NAUpper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		NANPInfiltrating BCC (431)
Micronodular BCC (63)
Nodulocystic BCC (489)
Morpheaform BCC (51)
Superficial BCC (188)		Surgery
Hsuan JD et al. (2004) [48]Small margin excision of periocular basal cell carcinoma: 5 year resultsCase seriesOphthalmology 52 (among 55 cases)NARange 34–91 (66/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (52)Surgery
Malhotra R et al. (2004) [49]The Australian Mohs database, part II: periocular basal cell carcinoma outcome at 5-year follow-upProspective case seriesOphthalmology801 (among 819 cases)NANANAUpper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		NANPInfiltrating BCC (234)
Micronodular BCC (41)
Nodulocystic BCC (338)
Morpheaform BCC (35)
Superficial BCC (107)
Combined nodular and superficial BCC (1)
Combined superficial and micronodular (1)		Surgery
Boboridis KG et al. (2005) [50]Combination of periocular myocutaneous flaps for one-stage reconstruction of extensive defects of the eyelidCase reportsOphthalmology1M (1)76Renal failure, hypertension, and glaucoma (1)Lower eyelidEyelidEroded noduleNPNodular BCC (1)Surgery
Ostergaard J et al. (2005) [51] Primary basal cell carcinoma of the caruncle with seeding to the conjunctivaCase reports Ophthalmology1F (1)60No comorbiditiesCaruncle Caruncle Pale cyst-like papuleNPSolid BCC (1)Surgery
Leibovitch I et al. (2005) [52]Orbital invasion by periocular basal cell carcinomaCase series Ophthalmology64M (49)
F (15)		Range 35–93 (70/72)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NoduleNPInfiltrative (33)
Morpheaform/sclerosing (20)
Nodular (2)
Micronodular (2)
Superficial (2)		Surgery
±
RT
RT alone
Ben Simon G.J et al. (2005) [53]Orbital exenteration: one size does not fit allCase series Ophthalmology6 (among 34 cases)NARange 37–93 (67/NA)NAOrbitOcular areaNANPBCC (6)Surgery
Cameron M et al. (2005) [54]Synchronous reconstruction of the exenterated orbit with a pericranial flap, skin graft and osseointegrated implantsCase reportsMaxillofacial surgery1M (1)74NAMedial canthusPeriocular areaNANPMorpheaform BCC (1)Surgery
Moretti E et al. (2005) [55]Complete mobilization of the cheek zone for orbit exenterationCase seriesPlastic surgery7 (among 10 cases)M (5)
F (2)		Range 62–85 (73.1/73)NAEyelid
Canthus
Cornea		Eyelid
Ocular area
Periocular area		NANPBCC (7)Surgery
Khandwala MA et al. (2005) [56]Outcome of periocular basal cell carcinoma managed by overnight paraffin sectionRetrospective studyOphthalmology93NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (82)
Morpheaform BCC (8)
Multifocal BCC (3)		Surgery
Papadopoulos O et al. (2005) [57]Orbitopalpebral repair after 835 excisions of malignant tumoursRetrospective studyPlastic surgery714 (among 835 cases)NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (714)Surgery
Leibovitch I et al. (2005) [58]Incidence of host site complications in periocular full thickness skin graftsProspective case seriesOphthalmology 368 (among 397 cases)NARange 20–91 (60/NA)NAUpper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (368)Surgery
Mencía-Gutiérrez E et al. (2005) [59]Lacrimal caruncle primary basal cell carcinoma: case report and reviewCase reports + reviewOphthalmology1M (1)80Hypertension and heart attack (1)CaruncleCarunclePigmented lesion with fine, superficial vascularizationNPNodular BCC (1) Surgery
Mavrikakis I et al. (2006) [60]Linear basal cell carcinoma: a distinct clinical entity in the periocular regionCase seriesOculoplastic surgery4M (2)
F (2)		Range 68–79 (74/74.5)NALower eyelidEyelidNANPPigmented nodular/infiltrative BCC (2)
Nodular BCC (2)		Surgery
Rossman D et al. (2006) [61]Basal cell carcinoma of the caruncleCase reportsOphthalmology1M (1)84Skin cancer (1)CaruncleCaruncleWhitish-yellow noduleNPNodular BCC (1)Surgery
+
RT
Kaeser PF et al. (2006) [62]Tumors of the caruncle: a clinicopathologic correlationCase seriesOphthalmology 2 (among 191 cases)M (1)
F (1)		Range 53–72 (62.5/62.5)NACaruncleCaruncleNANPBCC (1)
Pigmented, macronodular BCC (1)		Surgery
Nemet AY et al. (2006) [63]Management of periocular basal and squamous cell carcinoma: a series of 485 casesCase seriesOphthalmology417 (among 485 cases)NARange 14–95 (68.3/NA) BCC (NA) and
SCC (NA)		Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (378)
Morpheaform BCC (39)		Surgery
±
RT
Taherian K et al. (2007) [64]Surgical excision of periocular basal cell carcinomasCase seriesOphthalmology 25M (15)
F (10)		Range 42–94 (76/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NoduleNPBCC (25)Surgery
Gericke A and Pitz S (2008) [65]Maggot therapy for periocular skin graft failure in the immunocompromised patientLetterOphthalmology1 (among 2 cases)M (1)62Heart transplant (1)Medial canthusPeriocular areaNANPBCC (1)Surgery
+
Maggots therapy
Croce A et al. (2008) [66]Orbital exenteration in elderly patients: personal experienceCase series Otorhinolaryngology4 (among 8 cases)M (3)
F (1)		Range 70–85 (77/76.5)BCC (NA)Eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (4)Surgery
Kovacevic PT et al. (2009) [67]Extended orbital exenteration in the treatment of advanced periocular skin cancer with primary reconstruction with a galeacutaneous flapRetrospective studyPlastic surgery14 (among 21 cases)NARange 57–83 (68/NA)NAEyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Ulcerated lesionNPBCC (14)Surgery
Lawrence CM et al. (2009) [68]Formalin-fixed tissue Mohs surgery (slow Mohs) for basal cell carcinoma: 5-year follow-up dataProspective studyDermatology248 (among 1.336 cases)NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (248)Surgery
Gayre GS et al. (2009) [69]Outcomes of excision of 1750 eyelid and periocular skin basal cell and squamous cell carcinomas by modified en face frozen section margin-controlled techniqueCase seriesOphthalmology 1.638 (among 12.862 cases)NARange 15–96 (65/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (1.638)Surgery
Lavaju P et al. (2009) [70]Pattern of ocular tumors in the eastern region of NepalRetrospective study Ophthalmology15 (among 115 cases)NANANAEyelidEyelidNANPBCC (15)Surgery
Haefliger IO et al. (2009) [71]Large upper eyelid full-thickness defects reconstructed only with an anterior lamellaCase reportsOphthalmology1 (among 3 cases)M (1)51NAUpper eyelidEyelidNANPBCC (1)Surgery
Morris DS et al. (2009) [72]Periocular basal cell carcinoma: 5-year outcome following Slow Mohs surgery with formalin-fixed paraffin-embedded sections and delayed closureProspective case seriesOphthalmology278M (137)
F (141)		Range 25–89 (65.5/NA)NAEyelid
Periocular area		Eyelid
Periocular area		NANPSolid BCC (211)
Morpheaform BCC (11)
Superficial BCC (8)
BCC (47)		Surgery
Levin F et al. (2009) [73]Excision of periocular basal cell carcinoma with stereoscopic microdissection of surgical margins for frozen-section control: report of 200 casesCase seriesOphthalmology190 (among 200 cases)NARange 31–95 (77/NA)BCC (NA)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Nodule
Sclerosing lesion
Superficial lesion		NPBCC (190)Surgery
Chadha V and Wright M (2009) [74]Small margin excision of periocular basal cell carcinomasRetrospective studyOphthalmology 90M (41)
F (49)		Range 35–97 (73.9/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (87)
Morpheaform BCC (3)		Surgery
Ong LY and Lane CM (2009) [75]Eyelid contracture may indicate recurrent basal cell carcinoma, even after Mohs’ micrographic surgeryCase reportsOphthalmology3M (2)
F (1)		Range 53–92 (71.3/69)Chronic obstructive airways disease and rectal carcinoma (1)Upper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		NoduleNPInfiltrative BCC (NA)
Morpheaform BCC (NA)		Surgery
+
RT
Lee C et al. (2010) [76]Primary ocular caruncolar basal cell carcinoma in a Chinese patientCase reportsOphthalmology1M (1)73Hypertension and
coronary artery disease (1) 		Caruncle Caruncle Pigmented noduleNPPigmented BCC (1)Surgery
+
MTX
+
Fluorouracil
Maheshwari R (2010) [77]Review of orbital exenteration from an eye care centre in Western IndiaRetrospective studyOphthalmology3 (among 15 cases)M (3)Range 62–75 (66.7/63) NAEyelidEyelidNANPBCC (3)Surgery
Carneiro RC et al. (2010) [78]Imiquimod 5% cream for the treatment of periocular basal cell carcinomaRetrospective studyOphthalmology8M (7)
F (1)		Range 47–72 (63/65)NALower eyelid
Medial canthus		Eyelid
Periocular area		NANPNodular BCC (8)Surgery
+
Imiquimod 5%
Garcia-Martin E et al. (2010) [79]Efficacy and tolerability of imiquimod 5% cream to treat periocular basal cell carcinomasCase seriesOphthalmology 15M (10)
F (5)		Range 53–84 (71.2/76) Basal cell nevus syndrome (1);
Aortic valve stenosis (1);
Retinal detachment (1);
Pituitary microadenoma (1);
Atrial fibrillation (1)		Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Growing massSuperficial telangiectatic vessels
Central umbilication		Nodular BCC (15)Surgery
+
Imiquimod 5%
+
Cryotherapy or PDT
Madge SN et al. (2010) [80]Globe-sparing surgery for medial canthal Basal cell carcinoma with anterior orbital invasionRetrospective studyOphthalmology20M (7)
F (13)		Range 48–90 (72.6/78)NAMedial canthusPeriocular areaPalpable massNPInfiltrative BCC (9)
Nodular BCC (4)
Micronodular BCC (2)
Mixed BCC (4)
Multifocal BCC (1)		Surgery
+
RT
Ross AH et al. (2010) [81]The use of imiquimod in the treatment of periocular tumoursCase seriesOphthalmology 2 (among 5 cases)F (2)47, 75NALower eyelidEyelidErythematous plaque
Nodule		NPBCC (2)Imiquimod 5%
Cannon PS et al. (2011) [82]The ophthalmic side-effects of imiquimod therapy in the management of periocular skin lesionsRetrospective studyOphthalmology3 (among 47 cases)NARange 42–95 (74/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (3)Surgery
+
Imiquimod 5%
Alves L.F et al. (2011) [83]Incidence of epithelial lesions of the conjunctiva in a review of 12,102 specimens in Canada Retrospective studyPathology1 (among 12.102 cases) NARange NA (59.9/NA)NAConjunctivaOcular areaNANPBCC (1)NA
Shinder R et al. (2011) [84]Survey of orbital tumors at a comprehensive cancer center in the United StatesRetrospective studyOphthalmology7 (among 268 cases)M (4)
F (3)		Range 35–80 (NA/59) NAOrbitOcular areaNANPBCC (7)Surgery
Alfawaz AM and Al-Hussain HM (2011) [85]Ocular manifestations of xeroderma pigmentosum at a tertiary eye care center in Saudi Arabia Retrospective studyOphthalmology4 (among 27 cases)NARange 5–67 (NA/19)Xeroderma pigmentosum (4)EyelidEyelidNANPBCC (4)Surgery
Gautam P et al. (2011) [86]A profile of eye-lid conditions requiring reconstruction among the patients attending an oculoplasty clinic in mid-western region of NepalRetrospective studyOphthalmology5 (among 43 cases)NARange NA (52/NA)NAEyelidEyelidNANPBCC (5)Surgery
Moesen I et al. (2011) [87]Nitrous oxide cryotherapy for primary periocular basal cell carcinoma: outcome at 5 years follow-upProspective case seriesOphthalmology95M (37)
F (58)		Range 44–92 (NA/71)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (95)Surgery
+
Nitrous oxide cryotherapy
Ichinokawa Y et al. (2011) [88]Linear basal cell carcinoma: a case reportCase reportsDermatology1F (1)79NALower eyelidEyelidPigmented noduleArborizing vessels, multiple blue-grey globules, and large, blue-grey ovoid nests Nodular and infiltrative BCC (1)Surgery
Garcia-Martin E et al. (2011) [89]Comparison of imiquimod 5% cream versus radiotherapy as treatment for eyelid basal cell carcinomaClinical trialOphthalmology27M (16)
F (11)		Range 53–84 (73.8/NA)NAEyelidEyelidNodule with telangiectatic vessels NPNodular BCC (27)Imiquimod 5% or RT
Gaitanis G et al. (2011) [90]Imiquimod can be combined with cryosurgery (immunocryosurgery) for locally advanced periocular basal cell carcinomasLetterDermatology3M (2)
F (1)		Range 68–75 (70.7/69)Hypertension, hyperlipidemia, chronic hepatitis B infection (1);
Skin cancers (1)		Lower eyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (3)Immunocryosurgery
Kadyan A et al. (2011) [91]High rate of incomplete resection after primary excision of eyelid BCC: multi-staged resection rarely needs more than two proceduresCase seriesOphthalmology90M (36)
F (54)		Range 47–98 (77/NA)No comorbiditiesUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (90)Surgery
Kvannli L et al. (2012) [92]The method of en face frozen section in clearing periocular basal cell carcinoma and squamous cell carcinomaRetrospective studyOphthalmology204 (among 262 cases)M (100)
F (104)		Range 21–94 (65/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodulocystic BCC (NA)
Infiltrative BCC (NA)
Morpheaform BCC (NA)
Multifocal BCC (NA)
Mixed pattern (NA)		Surgery
Ben Simon GJ et al. (2012) [93]Histological and clinical features of primary and recurrent periocular basal cell carcinomaCase seriesOphthalmology87M (52)
F (35)		Range 33–96 (70/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPSolid, nodular or nodular ulcerative BCC (NA)
Morpheaform or infiltrative BCC (NA)
Cystic or nodulocystic BCC (NA)		Surgery
Bertelmann E and Rieck P (2012) [94]Relapses after surgical treatment of ocular adnexal basal cell carcinomas: 5-year follow-up at the same university centre Prospective studyOphthalmology366M (167)
F (199)		Range NA (69/NA)Parkinson disease (1)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (NA)
Ulcerative BCC (NA)
Morpheaform BCC (NA)		Surgery
Hata M et al. (2012) [95]Radiation therapy for primary carcinoma of the eyelid: tumor control and visual functionRetrospective studyRadiology1 (among 23 cases)NARange 60–91 (NA/79)Gastric cancer (1)EyelidEyelidNANPBCC (1)Surgery
+
RT
Meena M (2012) [96]Triple-Flaps for lateral canthus reconstruction: a novel techniqueCase reportsOphthalmology1F (1)45NAEyelid
Lateral canthus		Eyelid
Periocular area		Pigmented nodule NPNodular–ulcerative BCC (1)Surgery
Attili SK et al. (2012) [97]Role of non-surgical therapies in the management of periocular basal
cell carcinoma and squamous intra-epidermal carcinoma: a case series
and review of the literature		Case series + review Dermatology13 (among 22 cases)M (9)
F (4)		Range 59–79 (68.2/69)Renal transplant (1)Lower eyelid
Medial canthus
Lateral canthus 		Eyelid
Periocular area		NANPMorpheic BCC (3)
Nodulocystic BCC (7)
Superficial BCC (3)		PDT or Imiquimod 5%
Iuliano A et al. (2012) [98]Risk factors for orbital exenteration in periocular basal cell carcinomaCase seriesOphthalmology502 (among 506 cases)NARange 47–84 (67.2/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NoduleNPInfiltrative BCC (NA)
Morpheaform BCC (NA)
Nodular BCC (NA)		Surgery
±
RT
Zeitouni NC et al. (2012) [99]Orbital invasion by periocular infiltrating basal cell carcinomaCase reportsDermatology1M (1)82Hyperlipidemia, coronary artery disease, myocardial infarction (1) EyelidEyelidNANPBCC (1)Surgery
Sirianni D et al. (2013) [100]A 12-year retrospective survey of management of patients with malignant neoplasms in the orbital cavity in a Brazilian Cancer Hospital Case seriesDentistry156 (among 269 cases)NANANAOcularOcular areaNANPBCC (156)Surgery
Fino P et al. (2013) [101]First reported case of primary basal cell carcinoma of the right caruncle: a case report and review of the literatureCase reports + reviewPlastic surgery1F (1)24No comorbiditiesCaruncleCarunclePigmented lesionNPSolid BCC (1)Surgery
Krema H et al. (2013) [102]Orthovoltage radiotherapy in the management of medial canthal basal cell carcinomaRetrospective studyOphthalmology90M (39)
F (51)		Range 48–97 (NA/73)NAMedial canthusPeriocular areaNANPBCC (90)RT or Surgery
+
RT
Bonavolontà G et al. (2013) [103]An analysis of 2480 space-occupying lesions of the orbit from 1976 to 2011Case seriesOphthalmology87 (among 2.480)NARange 42–75 (71/NA)NAOrbitOcular areaNANPBCC (87)Surgery
Yin VT et al. (2013) [104]Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinomaCase reports + reviewOphthalmology1M (1)30Basal cell nevus syndrome (1) Upper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		Nodule with telangiectasia NPBCC (1)Surgery
+
Vismodegib
Sun MT et al. (2013) [105]Periocular basal cell carcinoma pathological reportingLetterOphthalmology1618NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (1.618)Surgery
Tullett M et al. (2013) [106]Excision of periocular basal cell carcinoma guided by en face frozen sectionCase seriesOculoplastic surgery72 (among 78 cases)NARange 35–97 (74.5/NA)NAUpper eyelid
Lower eyelid
Medial canthus 		Eyelid
Periocular area		NANPNodular BCC (NA)
Micronodular BCC (NA)
Superficial BCC (NA)
Infiltrative BCC (NA)		Surgery
Gill HS et al. (2013) [107]Vismodegib for periocular and orbital basal cell carcinomaProspective case seriesOphthalmology7M (5)
F (2)		Range 43–101 (71/75)SCC (2)Upper eyelid
Lower eyelid
Lateral canthus		Eyelid
Periocular area		Ulcerated lesionNPBCC (7)Surgery
+
Vismodegib
Litwin AS et al. (2013) [108]Management of periocular basal cell carcinoma by Mohs micrographic surgeryRetrospective studyOphthalmology 104M (57)
F (47)		Range 35–98 (66/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (67)
Nodular/infiltrative or nodular/superficial BCC (13)
Infiltrative BCC (15)
Superficial BCC (9)		Surgery
±
5-fluorouracil or cryotherapy
Ho SF et al. (2013) [109]5 Years review of periocular basal cell carcinoma and proposed follow-up protocolRetrospective studyOphthalmology311 (among 412 cases)NARange 28–99 (73.7/77)No comorbiditiesUpper eyelid
Lower eyelid
Medial canthus 		Eyelid
Periocular area		NANPBCC (311)Surgery
Pelosini L et al. (2013) [110]In vivo optical coherence tomography (OCT) in
periocular basal cell carcinoma: correlations between
in vivo OCT images and postoperative histology		Prospective studyOphthalmology 15 (among 16 cases)NARange 49–91 (74/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (15) Surgery
Avanaki MR et al. (2013) [111]Investigation of basal cell carcinoma using dynamic focus optical coherence tomographyCase reportsElectrical engineering3M (3)Range 75–78 (76.7/77) NAEyelidEyelidNANPBCC (3)Surgery
Woolley SD and Hughes C (2013) [112]A young military pilot presents with a periocular basal cell carcinoma: a case reportCase reportsOphthalmology 1M (1)32No comorbiditiesLower eyelidEyelidPapule with telangiectasiaNPNodular BCC (1)Surgery
Ugurlu S et al. (2014) [113]Primary basal cell carcinoma of the caruncle: case report and review of the literatureCase reports + reviewOphthalmology1M (1)67No comorbiditiesCaruncleCaruncleNoduleNPNodular BCC (1)Surgery
Sardesai VR et al. (2014) [114]Ocular myiasis with basal cell carcinomaCase reportsDermatology1M (1)83Hypertension, diabetes, ophthalmomyiasis (1)Lateral canthusPeriocular areaUlcerated lesionNPBCC (1)Surgery
Salwa SP et al. (2014) [115]Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management Case reportsOculoplastic surgery3F (3)Range 84–98 (91/90)Multiple (NA)EyelidEyelidNANPBCC (3)Electrochemotherapy with Bleomycin
Halkud R et al. (2014) [116]Xeroderma pigmentosum: clinicopathological review of the multiple oculocutaneous malignancies and complicationsCase seriesSurgery8 (among 11 cases)M (3)
F (5)		NAXeroderma pigmentosum (8)EyelidEyelidNANPBCC (8)Surgery
Das D et al. (2014) [117]Profile of ocular and adnexal tumours at a Tertiary Institute of Northeast IndiaRetrospective studyPathology33 (among 1.003 cases)NANANAEyelidEyelidNANPBCC (33)Surgery
Qassemyar A et al. (2014) [118]Orbital exenteration and periorbital skin cancersRetrospective studyPlastic surgery8 (among 26 cases)M (5)
F (3)		Range 19–89 (68/NA)NAUpper eyelid
Lower eyelid
Lateral canthus		Eyelid
Periocular area		NANPBCC (8)Surgery
Berenji F et al. (2014) [119]A case of secondary ophthalmomyiasis caused by chrysomya bezziana (Diptera: Calliphorid)Case reportsParasitology1F (1)55Ophthalmomyiasis (1)Upper eyelidEyelidEroded lesionNPBCC (1)Surgery
Wu A et al. (2014) [120]Histological subtypes of periocular basal cell carcinomaRetrospective studyOphthalmology1713M (966)
F (747)		Range 21–101 (68.8/71)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (NA)
Infiltrative BCC (NA)
Superficial BCC (NA)
Micronodular BCC (NA)		Surgery
Goyal S et al. (2014) [121]Nonhealing trauma masking periocular basal cell carcinoma in a young black maleLetterOphthalmology 1M (1)39No comorbiditiesMedial canthusPeriocular areaUlcerated papuleNPBCC (1)Surgery
Ebrahimi A et al. (2014) [122]Superpulsed CO2 laser with intraoperative pathologic assessment for treatment of periorbital basal cell carcinoma involving eyelash lineCase seriesDermatology20M (13)
F (7)		Range 42–80 (61.4/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Nodule
Pigmented lesion
Superficial lesion		NPSolid BCC (15)
Cystic BCC (2)
Infiltrative BCC (1)
Micronodular BCC (1)		CO2 laser
Cinotti E et al. (2014) [123]The role of in vivo confocal microscopy in the diagnosis of eyelid margin tumors: 47 casesCase seriesDermatology14 (among 45 cases)M (7)
F (7)		Range 13–86 (70/75.5)NAEyelidEyelidNodule
Papule
Macule		NPBCC (14)Surgery
De Macedo EM et al. (2015) [124]Imiquimod cream efficacy in the treatment of periocular nodular basal cell carcinoma: a non-randomized trialProspective case seriesOphthalmology19M (13)
F (6)		Range 60–>70 (NA/NA)NALower eyelid
Medial canthus		Eyelid
Periocular area		Erythematous lesionNPBCC (19)Surgery
+
Imiquimod 5%
Eftekhari K et al. (2015) [125]Local recurrence and ocular adnexal complications following electronic surface brachytherapy
for basal cell carcinoma of the lower eyelid		Case reportsOculoplastic surgery1M (1)60NALower eyelidEyelidPearly lesionNPBCC (1)Surgery
Sen S et al. (2015) [126]Impression cytology diagnosis of ulcerative eyelid malignancy Prospective case seriesPathology13 (among 32 cases)NARange 22–87 (60.7/NA)NAEyelidEyelidNANPBCC (13)Surgery
Suarez MJ et al. (2015) [127]Clinicopathological features of ophthalmic neoplasms arising in the setting of xeroderma pigmentosumCase seriesPathology1 (among 6 cases)M (1)25Xeroderma pigmentosum (1)Lower eyelidEyelidNoduleNPNodular BCC (1)Surgery
Meyer D and Gooding C (2015) [128]Intralesional bleomycin as an adjunct therapeutic modality in eyelid and extraocular malignancies and tumorsCase seriesOphthalmology3 (among 4 cases)M (2)
F (1)		Range 80–92 (84.3/81)Angina (1)Lower eyelidEyelidNANPBCC (3)Intralesional bleomycin
Chen JJ et al. (2015) [129]Review of ocular manifestations of nevoid basal cell carcinoma syndrome: what an ophthalmologist needs to knowCase reports + reviewOphthalmology1M (1)31Basal cell nevus syndrome (1)Lower eyelidEyelidUlcerated lesionsNPNodular BCC (1)Surgery
Domingo RE et al. (2015) [130]Tumors of the eye and ocular adnexa at the Philippine Eye Research Institute: a 10-year reviewRetrospective studyOphthalmology60 (among 1.551 cases)M (25)
F (35)		NANAEyelid
Conjunctiva
Orbit		Ocular area
Periocular area		NANPBCC (60)Surgery
Demirci H et al. (2015) [131]Efficacy of Vismodegib (ErivedgeTM) for basal cell carcinoma involving the orbit and periocular areaCase seriesOphthalmology8M (6)
F (2)		Range 60–86 (71/69)Basal cell nevus syndrome (1); BCC (NA)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus
Orbit		Eyelid
Ocular area
Periocular area		NANPBCC (8)Vismodegib
±
Surgery
Ozgur OK et al. (2015) [132]Hedgehog pathway inhibition for locally advanced periocular basal cell carcinoma and basal cell nevus syndromeCase seriesOphthalmology8 (among 12 cases)M (7)
F (1)		Range 33–86 (65/66.5) Basal cell nevus syndrome (1)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus
Orbit		Eyelid
Ocular area
Periocular area		NANPBCC (8)Vismodegib
±
Another Hedgehog pathway inhibitor
Sun MT et al. (2015) [133]Accuracy of biopsy in subtyping periocular basal cell carcinomaRetrospective studyOphthalmology167NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (NA)
Superficial BCC (NA)
Mixed BCC (NA)		Biopsy
Tan E et al. (2015) [134]Growth of periocular basal cell carcinomasObservational studyDermatology113 (among 115 cases)NARange 61–79 (69/NA)Skin cancer; immunosuppression (NA)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (30)
Infiltrative BCC (19)
Superficial BCC (19)
Micronodular BCC (19)
Other types of BCC		Surgery
Pelosini L et al. (2015) [135]A novel imaging approach to periocular basal cell carcinoma: in vivo optical coherence tomography and histological correlatesProspective studyOphthalmology15M (12)
F (3)		Range 49–91 (74/79)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (15)Surgery
Nikose A et al. (2016) [136]Periocular basal cell carcinoma in a young school teacherCase reportsOphthalmology1F (1)34No comorbiditiesLateral canthusPeriocular areaPigmented noduleNPAdenoid BCC (1)Surgery
Hamroush A and Cheung D (2016) [137] Irregularly luscious lashes: difficult to say but a sinister sign to missCase reportsOphthalmology1M (1)84Glaucoma,
pseudophakia,
dry age-related macular degeneration (AMD),
macular atrophy, hypertension and hypercholesterolemia (1)		Lower eyelidEyelidNANPMicronodular BCC (1)Surgery
Szewczyk M et al. (2016) [138] Basal cell carcinoma in farmers: an occupation group at high riskRetrospective studySurgery36 (among 312 cases) M (22)
F (14)		Range 25–>80 (NA/NA)NAEyelidEyelidNANPBCC (36)Surgery
Pandey TR et al. (2016) [139]A case of orbital myiasis in recurrent eyelid basal cell carcinoma invasive into the orbitCase reportsOphthalmology1F (1)73Myiasis (1)OrbitOcular areaUlcerated noduleNPBCC (1)Surgery
Bălăşoiu AT et al. (2016) [140]Assessment of VEGF and EGFR in the study of angiogenesis of eyelid carcinomas Retrospective studyPathology23 (among 43 cases)NANANAEyelidEyelidNANPBCC (23)Surgery
Treacy MP et al. (2016) [141]Mohs micrographic surgery for periocular skin tumours in IrelandRetrospective studyOphthalmology107 (among 127 cases)NARange 28–91 (68/NA)NAUpper eyelid
Lower eyelid
Medial canthus 		Eyelid
Periocular area		NANPNodular BCC (68)
Infiltrative BCC (26)
Nodulocystic BCC (8)
Adenoid BCC (5)
Multifocal BCC (3)
Superficial BCC (2)		Surgery
Wilson ME et al. (2016) [142]Acute Charles Bonnet syndrome following Hughes procedureCase reportsOphthalmology 1M (1)69Hypertension (1)Lower eyelidEyelidErythematous lesionNPMorpheaform BCC (1)Surgery
Sin CW et al. (2016) [143]Recurrence rates of periocular basal cell carcinoma following Mohs micrographic surgery: a retrospective studyCase seriesOculoplastic surgery390M (170)
F (220)		Range 24–96 (67/68)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (178)
Morpheaform BCC (105)
Infiltrative BCC (16)
Micronodular BCC (5)
Pigmented BCC (4)
Superficial BCC (4)
Combined subtypes (2)
BCC (76)		Surgery
+
Curettage or cryotherapy or RT
Gaitanis G et al. (2016) [144]Cryosurgery during imiquimod (Immunocryosurgery) for periocular basal cell carcinomas: an efficacious minimally invasive treatment alternativeRetrospective studyDermatology14 (among 16 cases)M (6)
F (8)		Range 52–85 (74.9/79)NALower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (14)Immunocryosurgery
Celebi AR et al. (2016) [145]Evaluation of the “Hedgehog” signalling pathways in squamous and basal cell carcinomas of the eyelids and conjunctivaRetrospective studyOphthalmology 41 (among 75 cases)M (23)
F (18)		Range 29–78 (60.7/NA)NAEyelidEyelidNANPBCC (41)Surgery
Lin SY et al. (2016) [146]TERT promoter mutations in periocular carcinomas: implications of ultraviolet light in pathogenesisRetrospective studyPathology20NANANAEyelid
Medial canthus		Eyelid
Periocular area		NANPNodular BCC (17)
Infiltrative BCC (1)
Micronodular BCC (1)
Morpheaform BCC (1)		Surgery
Yordanov YP and Shef A (2016) [147]Synchronous basal cell carcinoma of the inferior eyelid-combined surgical approach for single-stage ablationCase reportsPlastic surgery1F (1)67NALower eyelidEyelidExophytic pigmented tumor
Pigmented plaque		NPPigmented BCC (2)Surgery
Zlatarova ZI et al. (2016) [148]Eyelid reconstruction with full thickness skin grafts after carcinoma excisionRetrospective studyOphthalmology 35 (among 39 cases)NARange 26–95 (71/NA)NAUpper eyelid
Lower eyelid
Medial canthus 		Eyelid
Periocular area		NANPBCC (35)Surgery
Gerring RC et al. (2017) [149]Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survivalCase seriesOtorhinolaryngology20 (among 49 cases)NARange 39–85 (70.3/NA)Skin cancer (NA)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (20)Surgery
Shafi F et al. (2017) [150]Medial canthal defects following tumour excision: To reconstruct or not to reconstruct?Retrospective studyOculoplastic surgery63 (among 68 cases)NARange 38–94 (70.5/NA)NAMedial canthus Periocular areaNANPBCC (63)Surgery
Agarwal R et al. (2017) [151]Bilateral ocular surface squamous neoplasia with bilateral periocular basal cell carcinoma in a case of xeroderma pigmentosumCase reportsOphthalmology 1M (1)9Xeroderma pigmentosum (1)Medial canthusPeriocular areaEroded papule-noduleNPBCC (1)Surgery
+
Imiquimod 5%
Khan L. et al. (2017) [152]Conjunctival lesions: when should we perform biopsy?Retrospective studyOphthalmology1 (among 129 cases)NARange 25–75 (NA/NA)NAEyelidEyelidNANPBCC (1)Surgery
Shields CL et al. (2017) [153]Conjunctival tumors in 5002 cases. Comparative analysis of benign versus malignant counterparts Case seriesOphthalmology6 (among 5002 cases)M (3)
F (3)		Range 21–>60 (NA/NA)NAEyelid
Caruncle		Eyelid
Caruncle 		NANPBCC (6)Surgery
Mutaf M and Temel M (2017) [154]A new technique for total reconstruction of the lower lidCase seriesPlastic surgery22 (among 24 cases)NARange 45–72 (56.8/NA)NAEyelid
Canthus		Eyelid
Periocular area		NANPBCC (22)Surgery
Kiratli H and Koç I (2017) [155]Orbital exenteration: Institutional review of evolving trends in indications and rehabilitation techniques Retrospective studyOphthalmology 10 (among 100 cases)M (7)
F (3)		Range NA (56.9/NA)NAEyelid
Conjunctiva		Eyelid
Ocular area		NANPBCC (10)Surgery
Furdova A and Lukacko P (2017) [156]Periocular basal cell carcinoma
predictors for recurrence and
infiltration of the orbit		Case seriesOphthalmology7 (among 256 cases)NARange 52–82 (58/NA)NALower eyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (7)Surgery
±
Brachytherapy
Wong KY et al. (2017) [157]Vismodegib for locally advanced periocular and orbital basal cell carcinoma: a review of 15 consecutive casesCase seriesPlastic surgery15M (9)
F (6)		Range 44–90 (74/78) Basal cell nevus syndrome (1)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (15)Surgery
+
Vismodegib
+
RT
Tan E et al. (2017) [158]A practical decision-tree model to predict complexity of reconstructive surgery after periocular basal cell carcinoma excisionProspective studyDermatology150 (among 162 cases)NARange NA (NA/72)Skin cancer; immunosuppression (NA)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (NA)
Infiltrative BCC (NA)
Superficial BCC (NA)
Micronodular BCC (NA)
Adenoid cystic BCC (NA)
BCC (NA)		Surgery
Papastefanou VP and René C (2017) [159]Secondary resistance to Vismodegib after initial successful treatment of extensive recurrent periocular basal cell carcinoma with orbital invasionCase reportsOphthalmology1M (1)84NAUpper eyelidEyelidUlcerated lesionNPBCC (1)Vismodegib
+
Surgery
Karabulut GO et al. (2017) [160]Imiquimod 5% cream for the treatment of large nodular basal cell carcinoma at the medial canthal areaCase reportsOphthalmology3NARange 45–73 (55.7/49)NAMedial canthusPeriocular areaNANPNodular BCC (3)Surgery
+
Imiquimod 5%
Fatigato G et al. (2017) [161]Risk factors associated with relapse of eyelid basal cell carcinoma: results from a retrospective study of 142 patientsRetrospective studyPlastic surgery142 (among 205 cases)NARange 34–96 (70/NA) NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (142) Surgery
O’Halloran L et al. (2017) [162]Periocular Mohs micrographic surgery in Western Australia 2009–2012: A single centre retrospective review and proposal for practice benchmarksRetrospective studyDermatology589 (among 690 cases)NARange 23–93 (65/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (589)Surgery
Bladen JC et al. (2018) [163]Analysis of hedgehog signalling in periocular sebaceous carcinomaObservational studyOphthalmology15 (among 30 cases)NARange NA (73/NA)NAEyelidEyelidNANPNodular BCC (15)Surgery
Tchernev G et al. (2018) [164]Locally advanced basal cell carcinoma with intraocular invasionCase reportsDermatology1M (1)103NAUpper eyelidEyelidUlcerated papuleNPBCC (1)Surgery
Kaiser U (2018) [165]Polarization and distribution of tumor-associated macrophages and COX-2 expression in basal cell carcinoma of the ocular adnexae Retrospective studyOphthalmology30M (11)
F (19)		Range 49–97 (75/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (15)
Fibrosing BCC (15)		Surgery
Khardenavis SJ et al. (2018) [166]Ophthalmomyiasis in a case of basal cell carcinoma of eyelid Case reportsOphthalmology 1F (1)74Ophthalmomyiasis (1)Lower eyelidEyelidUlcerated lesionNPInfiltrating BCC (1)Ampicillin–Sulbactam
+
Surgery
+
Ivermectin
Yunoki T et al. (2018) [167]Gene networks in basal cell carcinoma of the eyelid, analysed using gene expression profiling Case reportsOphthalmology 2F (2)78, 83NAEyelidEyelidNANPBCC (2)Surgery
Al Wohaib M et al. (2018) [168]Characteristics and factors related to eyelid basal cell carcinoma in Saudi ArabiaRetrospective studyOphthalmology 129M (76)
F (53)		Range 16–105 (NA/71.0)Xeroderma pigmentosum (1)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Ulcerated lesion
Pigmented lesion
Nodular lesion
Mixed		NPNodular BCC (65)
Ulcerative BCC (17)
Morpheaform BCC (14)
Sclerosing BCC (5)
Mixed BCC (4)		Surgery
Hogarty DT et al. (2018) [169]Vismodegib and orbital excision for treating locally advanced basal cell carcinomaCase reportsOphthalmology1F (1)51NAMedial canthusPeriocular areaNANPNodular BCC (1)Surgery
+
RT
+
Vismodegib
Espi P et al. (2018) [170]Clinical and genetic characteristics of xeroderma pigmentosum in NepalRetrospective studyDermatology1 (among 17 cases)M (1)24Xeroderma pigmentosum (1)OcularOcular areaNANPBCC (1)Surgery
Damasceno JC et al. (2018) [171]Largest case series of Latin American eyelid tumors over 13 years from a single center in Sao Paulo, BrazilRetrospective studyOphthalmology226 (among 1.113 cases)NARange NA (NA/65)NAEyelidEyelidNANPBCC (226)Surgery
Lemaître S et al. (2018) [172]Outcomes after surgical resection of lower eyelid tumors and reconstruction using a nasal chondromucosal graft and an upper eyelid myocutaneous flapRetrospective studyOphthalmology17 (among 25 cases)NARange 21–91 (72/NA)Xeroderma Pigmentosum (1);
Conjunctival mucosa-associated lymphoid tissue lymphoma (1)		EyelidEyelidNANPSuperficial BCC (2)
Nodular BCC (3)
Morpheic and nodular BCC (1)
Morpheic and infiltrating BCC (2)
Morpheic BCC (1)
Infiltrating BCC (4)
Infiltrating and nodular BCC (4)		Surgery
Costan VV et al. (2018) [173]Mixed (nodular and morpheic) upper eyelid basal cell carcinoma with orbital invasion–histological and clinical featuresCase reportsMaxillofacial surgery1M (1)63Dermatomyositis
Hypertension (1)		Upper eyelidEyelidUlcerated lesion NPNodular/morpheic BCC (1)Surgery
Martell K et al. (2018) [174]Radiation therapy for deep periocular cancer treatments when protons are unavailable: is combining electrons and orthovoltage therapy beneficial?Case seriesOncology3 (among 4 cases)NANANAOrbit
Medial canthus		Ocular area
Periocular area		NANPBCC (3)Electrons and orthovoltage therapy
Li X et al. (2019) [175]Ocular preservation through limited tumor excision combined with ALA-PDT in patients with periocular basal cell carcinomaCase seriesPlastic surgery8M (6)
F (2)		Range 54–81 (NA/NA)NAEyelidEyelidNANPBCC (8)Surgery
+
PDT
Sagiv O et al. (2019) [176]Ocular preservation with neoadjuvant Vismodegib
in patients with locally advanced periocular basal
cell carcinoma		Case seriesOculoplastic surgery8M (8)Range 55–84 (69/69)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (1)
Nodular and infiltrative BCC pattern (7)		Vismodegib
+
Surgery
McGrath L.A et al. (2019) [177]Staged excision of primary periocular basal
cell carcinoma: absence of residual tumour in re-
excised specimens: a 10-year series		Retrospective studyOphthalmology120M (56)
F (64)		Range 38–94 (75/77)Cancers or autoimmune diseases (6);
History of other skin cancers (34)		Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (29)
Superficial BCC (12)
Micronodular (66)
Infiltrative/ Morpheic (13)		Surgery
Klyuchareva SV et al. (2019) [178]Treatment of basal cell cancer with a pulsed copper vapor laser: a case seriesCase seriesDermatology8M (2)
F (6)		Range 34–77 (53.1/50.5)NAUpper eyelid
Lower eyelid
Medial canthus 		Eyelid
Periocular area		NANPNodular BCC (7)
Infiltrative BCC (1)		Surgery
+
Dual-wavelength copper vapor laser
Kaliki S et al. (2019) [179]Ocular and periocular tumors in xeroderma pigmentosum: a study of 120 Asian Indian patients Case seriesOphthalmology8 (among 120 cases)NARange 1–53 (19/18)Xeroderma pigmentosum (8)Lower eyelid
Lateral canthus		Eyelid
Periocular area		NANPBCC (8)Surgery
Cohen S et al. (2019) [180]The Amazon Ocular Oncology Center: the first three yearsRetrospective studyOphthalmology 4 (among 221 cases)NANANAEyelidEyelidNANPBCC (4)NA
Vavassori A et al. (2019) [181]Mould-based surface high-dose-rate brachytherapy for eyelid carcinomaRetrospective studyRadiotherapy5 (among 9 cases)M (3)
F (2)		Range 61–88 (74.4/77)NALower eyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (5)Contact high-dose-rate brachytherapy
Melzer C et al. (2019) [182]Basal cell carcinomas developing independently from BAP1-tumor predisposition syndrome in a patient with bilateral uveal melanoma: diagnostic challenges to identify patients with BAP1-TPDSCase reportsOphthalmology1F (1)69BAP1-tumor predisposition syndrome (BAP1-TBDS), uveal melanoma, BCC,
actinic keratosis and thyroid cancer (1)		Upper eyelid
Medial canthus 		Eyelid
Periocular area		Telangiectatic lesion
Ulcerated lesion		NPBCC (69)Surgery
Alam MS et al. (2019) [183]Sensitivity and specificity of frozen section diagnosis in orbital and adnexal malignanciesRetrospective studyOculoplastic surgery6 (among 55 cases)NARange 0.3–81 (51.5/NA)NAEyelidEyelidNANPBCC (6)Surgery
Bergeron S et al. (2019) [184]Novel application of anterior segment optical coherence tomography for periocular imaging Prospective studyOphthalmology38 (among 50 cases)M (18)
F (20)		Range 27–92 (70/75)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Telangiectatic nodule
Telangiectatic plaque		Scar-like depigmentation and vessels with a crown distribution or irregularly branchedBCC (38)Surgery
Mathis J et al. (2019) [185]Oral hedgehog pathway inhibition as a means for ocular salvage in locally advanced intraorbital basal cell carcinomaCase reports + reviewDermatology1M (1)60NAMedial canthusPeriocular areaNANPBCC (1)Vismodegib
Costea CF et al. (2019) [186]Periocular basal cell carcinoma: demographic, clinical, histological and immunohistochemical evaluation of a series of 39 casesRetrospective studyOphthalmology36 (among 39 cases)NARange 26–87 (66/NA)NAUpper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		Ulcerated noduleNPBCC (36)Surgery
Weesie F et al. (2019) [187]Recurrence of periocular basal cell carcinoma and
squamous cell carcinoma after Mohs micrographic surgery:
a retrospective cohort study		Retrospective studyDermatology683 (among 729 cases)M (293)
F (390)		Range 58–77 (NA/69)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPSuperficial BCC (14)
Nodular BCC (367)
Micronodular BCC (43)
Infiltrative BCC (256
BCC (3)		Surgery
González AR et al. (2019) [188]Neoadjuvant Vismodegib and Mohs micrographic surgery for locally advanced periocular basal cell carcinomaRetrospective studySurgery8M (2)
F (6)		Range 60–90 (76/74.5)NALower eyelid
Medial canthus		Eyelid
Periocular area		NANPNodular BCC (6)
Infiltrative BCC (2)		Vismodegib
±
Surgery
Khoo ABS et al. (2019) [189]Comparative analyses of tumour volume doubling times for periocular and non-periocular head and neck basal cell carcinomasCase seriesDermatology47 (among 126 cases)NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (47)Surgery
Kis EG et al. (2019) [190]Electrochemotherapy in the treatment of locally advanced or recurrent eyelid-periocular basal cell carcinomasCase seriesDermatology12M (7)
F (5)		Range 11–86 (66.6/71)Basal cell nevus syndrome (1);
Xeroderma pigmentosum (1) 		Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (12)Surgery
+
Electrochemotherapy
+
Vismodegib
Sagiv O et al. (2019) [191]Impact of Food and Drug Administration approval of Vismodegib on prevalence of orbital exenteration as a necessary surgical treatment for locally advanced periocular basal cell carcinomaRetrospective studyPlastic surgery42M (31)
F (11)		Range 43–90 (NA/66)NAEyelidEyelidNANPBCC (42)Surgery or RT or Vismodegib or palliative care
Eiger-Moscovich M et al. (2019) [192]Efficacy of Vismodegib for the treatment of orbital and advanced periocular basal cell carcinomaRetrospective studyOphthalmology21M (16)
F (5)		Range 59–91 (74/76)Basal cell nevus syndrome (1);
Melanoma (1);
Paget disease (1)		Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (21)Vismodegib
+
RT or Surgery + RT
Monheit G and Hrynewycz K (2019) [193]Mohs surgery for periocular tumorsCase seriesDermatology240 (among 289 cases)NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (182)
Infiltrative BCC (58)		Surgery
Scofield-Kaplan SM et al. (2019) [194]Predictive value of preoperative periocular skin cancer measurements for final Mohs defect sizeRetrospective studyOphthalmology 34 (among 42 cases)NARange NA (68.5/NA) NALower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (34)Surgery
Brodowski R et al. (2019) [195]Clinical-pathological characteristics of patients treated for cancers of the eyelid skin and periocular areasRetrospective studyMaxillofacial surgery213 (among 262 cases)NARange <30–>81 (NA/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Ulcerated noduleNPNodular BCC (90)
Ulcerative BCC (21)
Cystic BCC (81)
Cicatricial BCC (13)
Pigmented (8)		Surgery
Mercuţ IM et al. (2020) [196]The immunoexpression of MMP-1 and MMP-13 in eyelid basal cell carcinomaRetrospective studyOphthalmology50NANANAEyelidEyelidNANPNodular BCC (41)
Infiltrative BCC (9)		Surgery
Galindo-Ferreiro A et al. (2020) [197]Characteristics and recurrence of primary eyelid basal cell carcinoma in Central SpainRetrospective studyOphthalmology325 (among 337 cases)NARange NA (69.4/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (215)
Infiltrative BCC (48)
Mixed BCC (39)
Micronodular BCC (9)
Superficial multifocal BCC (8)
Sclerosing BCC (6)		Surgery
Hou X et al. (2020) [198]Effective treatment of locally advanced periocular basal cell carcinoma with oral hedgehog pathway inhibitor?Case reportsOphthalmology1M (1)73BCC (1)Lower eyelidEyelidMorphoea-like lesionNPBCC (1) Surgery
+
Sonidegib
Vijay V et al. (2020) [199]Periocular basal cell carcinoma: 20-years experience at a tertiary Eye Care Center in South IndiaCase seriesOphthalmology37 (among 185 cases)M (19)
F (18)		Range 37–90 (63.3/65)Basal cell nevus syndrome (2)Upper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Pigmented and non-pigmented ulcerative lesion
Pigmented and non-pigmented nodular mass
Scar-like lesion		NPNodular BCC (1)
Infiltrating BCC (1)
Pigmented BCC (1)		Surgery
Ben Ishai M et al. (2020) [200]Outcomes of Vismodegib for periocular locally advanced basal cell carcinoma from an open-label trialClinical trialOphthalmology244M (143)
F (101)		Range NA (NA/72.0)Multiple (NA)Eyelid
Canthus
Lacrimal sac
Orbit		Eyelid
Ocular area
Periocular area		NANPBCC (244)Vismodegib
±
Surgery or RT
Fazil K et al. (2020) [201]Evaluation of demographic features of eyelid lesionsRetrospective studyOphthalmology 67 (among 86 cases)NARange 7–88 (62.7/NA)NAEyelidEyelidNANPBCC (67)Surgery
Gupta R et al. (2020) [202] Malignant tumors of the eyelid in India: a multicenter, multizone study on clinicopathologic features and outcomesRetrospective study Ophthalmology47 (among 129 cases)NARange 5–92 (62.7/NA)NAEyelidEyelidNANPBCC (47)Surgery
Boal NS et al. (2020) [203]A black-pigmented eyelid nodule in an African American womanLetterOphthalmology1F (1)73Hypertension,
type 2 diabetes mellitus, hyperlipidemia (1)		Upper eyelidEyelidPigmented noduleNPPigmented nodular BCC (1)Surgery
Gąsiorowski K et al. (2020) [204]Periocular basal cell carcinoma: recurrence risk factors/when to reoperate?Retrospective studyMaxillofacial surgery158M (80)
F (78)		Range 20–95 (68/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (158)Surgery
Finskas O et al. (2020) [205]Cryosurgery of periocular moderately aggressive basal cell carcinomaCase seriesOphthalmology53M (14)
F (39)		Range 49–97 (73/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (53)Biopsy
+
Cryosurgery
Su MG et al. (2020) [206]Treatment of periocular basal cell carcinoma with neoadjuvant VismodegibCase reportsOphthalmology1F (1)63Cerebral aneurysm (1)Medial canthus Periocular areaNoduleNPBCC (1)Vismodegib
+
Surgery
Oliphant H et al. (2020) [207]Vismodegib for periocular basal cell carcinoma: an international multicentre case seriesCase seriesOphthalmology11 (among 13 cases)M (6)
F (5)		Range 43–91 (75.5/84) NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Superficial lesionNPNodular BCC (3)
Infiltrative/nodular BCC (1)
infiltrative BCC (3)
Infiltrative-micronodular BCC (1)
Superficial BCC (1)
BCC (1)
Cystic BCC (1)		Vismodegib
±
Surgery
±
RT
Herwig-Carl MC and Loeffler KU (2020) [208]Regression of periocular basal cell carcinoma: a report of four cases with clinicopathologic correlationCase seriesOphthalmology4M (2)
F (2)		Range 74–87 (78.8/77) Arterial hypertension (4);
Cardiac arrhythmia (2);
Hyperlipidemia (3); Diabetes mellitus type 2
Hypothyroidism (2);
Gout (1); BCC (1)		Lower eyelid
Medial canthus		Eyelid
Periocular area		Telangiectatic ulcerated noduleNPBCC (4)Surgery
MercuȚ IM et al. (2020) [209]Histopathological features of the eyelid basal cell carcinomasRetrospective studyOphthalmology92NANANAEyelidEyelidNANPNodular BCC (53)
Infiltrative BCC (9)
Superficial BCC (2)
Micronodular BCC (8)		Surgery
Peden R et al. (2020) [210]Small margin (up to 2 mm) excision of periocular basal cell carcinomas in the setting of a one-stop clinic-long-term outcomes at a minimum of 11 years’ follow-upCase seriesOphthalmology69M (34)
F (35)		Range 46–99 (74.9/77)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPMorpheic BCC (8)
Multifocal BCC (1)
Nodulocystic BCC (1)
Nodular BCC (2)
BCC (57)		Surgery
Furdova A et al. (2020) [211]Subtotal exenteration of the orbit for benign orbital diseaseCase seriesOphthalmology 12 (among 14 cases)NARange 67–80 (NA/73)NAEyelid
Medial canthus		Eyelid
Periocular area		NANPBCC (12)Surgery
Ben Artsi E et al. (2020) [212]Submental and anterior neck originated full-thickness skin grafts for periocular proceduresCase seriesOculoplastic surgery3 (among 5 cases)F (3)Range 75–90 (83.3/85)NALower eyelidEyelidNANPBCC (3)Surgery
Lin Z et al. (2021) [213]A multicentre review of the histology of 1012 periocular basal cell carcinomasRetrospective studyOphthalmology 745 (among 1.012 cases) NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (NA)
Infiltrative BCC (NA)
Superficial BCC (NA)		Surgery
Stridh MT et al. (2021) [214]Photoacoustic imaging of periorbital skin cancer ex vivo: unique spectral signatures of malignant melanoma, basal, and squamous cell carcinomaProspective studyOphthalmology 8 (among 11 cases)M (4)
F (4)		Range 47–76 (65/69.5)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPNodular BCC (2)
Infiltrative BCC (4)
Morpheaform BCC (1)
BCC (1)		Surgery
Adamski WZ et al. (2021) [215]The prevalence of various eyelid skin lesions in a single-centre observation studyRetrospective studyOphthalmology110 (among 544 cases)NARange 18–92 (60.5/NA)NAUpper eyelid
Lower eyelid
Medial canthus 		Eyelid
Periocular area		NANPNodular BCC (46)
Ulcerative BCC (12)
Superficial BCC (10)
BCC (42)		Surgery
De Giorgi V et al. (2021) [216]Treatment of periocular advanced basal cell carcinoma with Hedgehog pathway inhibitors: a single-center study and a new dedicated therapeutic protocol Prospective studyDermatology15M (7)
F (8)		Range 63–94 (83/87)NALower eyelid
Medial canthus
Lateral canthus 		Eyelid
Periocular area		NANPBCC (15)Vismodegib or Sonidegib
±
Surgery
Bergeron S et al. (2021) [217]Optical coherence tomography of peri-ocular skin cancers: an optical biopsyProspective studyOphthalmology46 (among 58 cases)NANANAPeriocular Periocular areaNANPBCC (46)Surgery
Kaliki S and Das AV (2021) [218]Ocular and periocular tumors in 855 Asian Indian geriatric patientsRetrospective studyOphthalmology25 (among 855 cases)NARange 60–91 (68/67)NAEyelid
Orbit		Eyelid
Periocular area		NANPBCC (25)Surgery
Shimizu N et al. (2021) [219]Ten-year epidemiological study of ocular and orbital tumors in Chiba University HospitalRetrospective studyOphthalmology15 (among 372 cases)M (6)
F (9)		Range NA (76.4/NA)NAEyelid
Conjunctiva 		Eyelid
Ocular area 		NANPBCC (15)Surgery
Battista RA et al. (2021) [220]Combination of Mustardè cheek advancement flap and paramedian forehead flap as a reconstructive option in orbital exenteration Case reportsOtorhinolaryngology1NA67Chronic hepatopathy, severe obesity, kidney transplant under immunosuppressive therapy, arterial hypertension, cerebral ischemic events and
conjunctival SCC (1)		Upper eyelidEyelidNANPBCC (1)Surgery
Prídavková Z et al. (2021) [221]Recurrent periocular basal cell carcinoma. Case ReportCase reportsOphthalmology1M (1)84Cataract (1)Upper eyelidEyelidUlcerated lesion NPBCC (1)Surgery
+
EBRT
Rokohl AC and Heindl LM (2021) [222]Effective systemic treatment of advanced periocular basal cell carcinoma with SonidegibLetterOphthalmology1M (1)NAMultiple BCC (1)Lower eyelidEyelidNANPMorpheaform BCC (1)Sonidegib
Almousa R (2021) [223]Predictors for margin of resection >4 mm in the management of periocular basal cell carcinomaRetrospective studyOphthalmology129 (among 142 cases)NANANAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (129)Surgery
Kahana A et al. (2021) [224]Vismodegib for preservation of visual function in patients with advanced periocular basal cell carcinoma: the VISORB trialClinical trialOphthalmology32 (among 34 cases)NARange 48–95 (NA/68.5)NALower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (32)Vismodegib
±
Surgery
Curragh DS et al. (2021) [225]Neoadjuvant Vismodegib in the management of locally advanced periocular basal cell carcinomaCase seriesOphthalmology8M (5)
F (3)		Range 24–81 (57.6/57)NALower eyelid
Medial canthus
Lateral canthus 		Eyelid
Periocular area		NANPNodular BCC (4)
Infiltrative BCC (3)
Superficial/Nodular BCC (1)		Vismodegib
+
Surgery
Yazici B et al. (2021) [226]Transnasal or transglabellar semicircular flap for medial canthal reconstructionCase seriesOphthalmology36 (among 38 cases)NARange 41–87 (66/NA)NAMedial canthusPeriocular areaNANPBCC (36)Surgery
Weerdt G et al. (2021) [227]Reconstruction of an extensive periocular and bilamellar defect of the lower and upper eyelid using local, regional and free chondral graft techniques: a case reportCase reportsPlastic surgery1F (1)65No comorbiditiesLower eyelidEyelidNANPBCC (1)Surgery
Low KL et al. (2022) [228]Primary basal cell carcinoma of the conjunctivaCase reportsOphthalmology 1M (1)67No comorbiditiesConjunctivaOcular areaPigmented noduleNPBCC (1)Surgery
+
Topical mitomycin-C 0.02%
Ul Kadir SM et al. (2022) [229]Clinicopathological analysis and surgical outcome of eyelid malignancies: a study of 332 cases Case seriesOphthalmology126 (among 332 cases)NARange NA (64.6/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (126)Surgery
Lemaıtre S et al. (2022) [230]Total orbital exenteration with temporalis muscle transfer and secondary healingRetrospective studyOphthalmology1 (among 29 cases)NA87NAEyelidEyelidNANPSclerodermiform BCC (1)Surgery
+
RT
Baş Z et al. (2022) [231]Prevalence of and associated factors for eyelid cancer in the American Academy of Ophthalmology intelligent research in sight registryRetrospective studyOphthalmology49.730 (among 56.610.374 cases)M (22.898)
F (26.832)		Range <20–>65 (NA/NA)NAEyelidEyelidNANPBCC (49.730)NA
Banerjee P et al. (2022) [232]The spectrum and clinicopathological correlation of eyelid lesions: twenty years’ experience at a tertiary eye care center in South IndiaRetrospective studyOculoplastic surgery39 (among 992 cases)NARange 21–>60 (NA/NA)NAEyelidEyelidNANPBCC (39)Surgery
Balchev G et al. (2022) [233]Glabellar flap technique in oculoplastic surgeryCase seriesOphthalmology 13NARange 49–72 (NA/67.2)NAEyelidEyelidNANPBCC (13)Surgery
Luo Y et al. (2022) [234]Deep learning-based fully automated differential diagnosis of eyelid basal cell and sebaceous carcinoma using whole slide imagesRetrospective studyOphthalmology116 (among 245 cases)NANANAEyelidEyelidNANPBCC (116)Surgery
Karlsdóttir SB et al. (2022) [235]Periocular basal cell carcinoma results and surgical outcome during a 5-year period
in a larger Danish population		Case seriesOphthalmology239 (among 242 cases)NARange NA (70/NA)NAUpper eyelid
Lower eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		NANPBCC (239)Surgery
Villani A et al. (2022) [236]The effectiveness of Vismodegib in patients with advanced periocular basal cell carcinoma: a case series of 13 patientsLetterDermatology11 (among 13 cases)NARange NA (76.5/NA)NAUpper eyelid
Lower eyelid
Lateral canthus 		Eyelid
Periocular area		NANPBCC (11)Vismodegib
+
Topical treatments or Surgery or RT
Küronya Z et al. (2022) [237]Atezolizumab for the treatment of advanced recurrent basal cell carcinoma and urothelial carcinoma of bladder: a case reportCase reportsUrologist1F (1)72Urothelial carcinoma (1)Medial canthusPeriocular areaUlcerated lesion NPFollicular BCC (1)Surgery
+
RT
+
Vismodegib
+
Atezolizumab
Unsworth SP et al. (2022) [238]Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: follow up to the VISORB trialClinical trialOphthalmology32 (among 34 cases)NARange 48–95 (NA/68.5)NALower eyelid
Medial canthus
Lateral canthus 		Eyelid
Periocular area		NANPBCC (32)Vismodegib
±
Surgery
Singh M et al. (2022) [239]Long-term efficacy and safety of imiquimod 5% and fluorouracil 1% creams in medical monotherapy of complex eyelid basal cell carcinomasRetrospective studyOphthalmology 27NARange NA (70.5/NA)Coronary disease (19); Diabetes mellitus (12); Hypertension (6); Asthma (3); Pulmonary diseases (2) Eyelid
Medial canthus
Lateral canthus		Eyelid
Periocular area		Pigmented lesionNPNoduloulcerative BCC (16)
Superficial BCC (11)		Surgery
+
Fluorouracil 1% or Imiquimod 5%
Chan R et al. (2023) [240]Mohs surgery for periocular basal cell carcinoma without a Mohs surgeon: the first series in Hong KongCase seriesOphthalmology20M (10)
F (10)		Range 55–91 (78.5/NA)Pemphigoid (1); BCC (1)Upper eyelid
Lower eyelid
Medial canthus		Eyelid
Periocular area		Ulcerated noduleNPBCC (20)Surgery
Lin Y et al. (2023) [241]The clinicopathological analysis of ocular and orbit tumors in southeast of ChinaRetrospective studyOphthalmology59 (among 3.468 cases)M (29)
F (30)		Range NA (54/NA)NAEyelid
Conjunctiva
Cornea		Eyelid
Ocular area		NANPBCC (59)Surgery
Bagheri A et al. (2023) [242]A survey on orbital space-occupying lesions during a twelve-year period from a referral center in IranRetrospective studyOphthalmology11 (among 375 cases)NARange 19–>60 (NA/NA)NAEyelidEyelidNANPBCC (11)Surgery
Table 2. Characteristics of the 236 studies included.
Table 2. Characteristics of the 236 studies included.
Study TypeNumber of Articles (%)
Clinical trial4 (1.7)
Prospective study11 (4.7)
Prospective case series10 (4.2)
Case series (>3 patients)66 (28.0)
Case series with a review of the literature1 (0.4)
Retrospective study77 (32.6)
Comparative study2 (0.8)
Observational study2 (0.8)
Case reports (max 3 patients)48 (20.3)
Case report with a review of the literature6 (2.5)
Letter9 (3.8)
SpecializationNumber of articles (%)
Ophthalmology159 (67.5)
Dermatology27 (11.1)
Plastic surgery13 (5.6)
Oculoplastic surgery10 (4.3)
Pathology7 (3)
Maxillofacial4 (1.7)
Otorhinolaryngology3 (1.3)
Surgery3 (1.3)
Radiotherapy3 (1.3)
Oncology2 (0.9)
Radiology1 (0.4)
Dentistry1 (0.4)
Urologist1 (0.4)
Parasitology1 (0.4)
Electrical engineering1 (0.4)
Table 3. Characteristics of the 71.730 patients.
Table 3. Characteristics of the 71.730 patients.
CharacteristicsData
Female29.782 patients (53.4%)
Male25.956 patients (46.6%)
Gender not reported91 studies (38.9%)
Age range9–105 years
Range not reported36 studies (15.4%)
Table 4. Different anatomic localization described in the 236 articles included.
Table 4. Different anatomic localization described in the 236 articles included.
Anatomic AreaNumber of Articles (%)
Eyelid and periocular area115 (48.7)
Eyelid70 (29.9)
Periocular area20 (8.5)
Ocular area9 (3.8)
Caruncle10 (3.8)
Eyelid, ocular area, and periocular area5 (2.1)
Eyelid and ocular area3 (1.3)
Ocular area and periocular area2 (0.8)
Caruncle and eyelid1 (0.4)
Table 5. Assessment performed in the 236 studies included.
Table 5. Assessment performed in the 236 studies included.
ExaminationNumber of Articles (%)
Clinic68 (28.8)
Dermoscopy3 (1.3)
Reflectance confocal microscopy1 (0.4)
Histopathology234 (99.2)
Histological subtypes specified96 (40.7)
Table 6. Treatment selected in the 236 studies included.
Table 6. Treatment selected in the 236 studies included.
Treatment Number of Articles (%)
Surgery 154 (65.3)
Surgery plus other treatments64 (27.1)
Non-surgical therapies16 (6.8)
Treatment not reported2 (0.8)
Table 7. Meta-analysis of the aggregated proportion of included studies for the prevalence of BCC.
Table 7. Meta-analysis of the aggregated proportion of included studies for the prevalence of BCC.
Type of StudiesSample SizeNumber of EventsProportion (%)95% CI
Clinical trial33933597.691.6 to 99.9
Prospective study/Prospective case series5313409993.079.2 to 99.6
Retrospective study33,882930261.148.8 to 72.8
Case reports/Case report with review of the literature696685.377.7 to 91.0
Case series27,597616073.362.1 to 83.3
Letter1643164089.972.8 to 99.0
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Caviglia, M.; Kaleci, S.; Frascione, P.; Teoli, M.; Fargnoli, M.C.; Pellacani, G.; Mandel, V.D. A Systematic Review and Meta-Analysis of Ocular and Periocular Basal Cell Carcinoma with First-Time Description of Dermoscopic and Reflectance Confocal Microscopy Features of Caruncle Basal Cell Carcinoma. Diagnostics 2025, 15, 1244. https://doi.org/10.3390/diagnostics15101244

AMA Style

Caviglia M, Kaleci S, Frascione P, Teoli M, Fargnoli MC, Pellacani G, Mandel VD. A Systematic Review and Meta-Analysis of Ocular and Periocular Basal Cell Carcinoma with First-Time Description of Dermoscopic and Reflectance Confocal Microscopy Features of Caruncle Basal Cell Carcinoma. Diagnostics. 2025; 15(10):1244. https://doi.org/10.3390/diagnostics15101244

Chicago/Turabian Style

Caviglia, Martina, Shaniko Kaleci, Pasquale Frascione, Miram Teoli, Maria Concetta Fargnoli, Giovanni Pellacani, and Victor Desmond Mandel. 2025. "A Systematic Review and Meta-Analysis of Ocular and Periocular Basal Cell Carcinoma with First-Time Description of Dermoscopic and Reflectance Confocal Microscopy Features of Caruncle Basal Cell Carcinoma" Diagnostics 15, no. 10: 1244. https://doi.org/10.3390/diagnostics15101244

APA Style

Caviglia, M., Kaleci, S., Frascione, P., Teoli, M., Fargnoli, M. C., Pellacani, G., & Mandel, V. D. (2025). A Systematic Review and Meta-Analysis of Ocular and Periocular Basal Cell Carcinoma with First-Time Description of Dermoscopic and Reflectance Confocal Microscopy Features of Caruncle Basal Cell Carcinoma. Diagnostics, 15(10), 1244. https://doi.org/10.3390/diagnostics15101244

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