==== Front J Cancer Res Clin Oncol J Cancer Res Clin Oncol Journal of Cancer Research and Clinical Oncology 0171-5216 1432-1335 Springer Berlin Heidelberg Berlin/Heidelberg 35870014 4207 10.1007/s00432-022-04207-7 Research Epidemiological and clinicopathological analysis of basal cell carcinoma in Egyptian population: a 5-year retrospective multicenter study http://orcid.org/0000-0002-5835-6160 El-Khalawany Mohamed makhalawany@gmail.com 12 Hassab-El-Naby Hussein M. M. 12 Mousa Ahmed Mustafa 1 Sameh Ahmed 2 http://orcid.org/0000-0001-6212-9748 Rageh Mahmoud A. 1 Genedy Rasha Mahmoud 3 Hosny Aya Magdy 3 Aboelmagd Marwa A. 4 Aboeldahab Soha 4 1 grid.411303.4 0000 0001 2155 6022 Department of Dermatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt 2 grid.511523.1 0000 0004 7532 2290 Department of Dermatology, Egyptian Armed Forces College of Medicine (AFCM), Cairo, Egypt 3 grid.7155.6 0000 0001 2260 6941 Department of Dermatology, Faculty of Medicine, Alexandria University, Alexandria, Egypt 4 grid.412659.d 0000 0004 0621 726X Department of Dermatology, Faculty of Medicine, Sohag University, Sohag, Egypt 23 7 2022 23 7 2022 2023 149 7 31213129 17 5 2022 12 7 2022 © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Purpose Basal cell carcinoma (BCC) is the most diagnosed type of cancer accounting for 80% of all keratinocyte malignancies. However, the exact demographic properties and clinicopathological criteria for BCC in Egyptians are not clearly reported. Our aim is to report and analyze the epidemiological and clinicopathological features of BCC in Egyptians. Methods We retrospectively reviewed the medical records for patients diagnosed pathologically with BCC during the period from January 2017 to December 2021. Data were recruited from four dermatology centers with different geographical distributions. Results We registered 544 patients. Their age ranged between 22–91 years with a mean of 61.6 ± 13.2 years. Females showed younger age of onset. The mean duration of the tumor was 3.9 ± 3.8 years. The most common involved region was the head (79.4%), and about one third of patients (32.2%) had a giant lesion (> 5 cm). The most common clinical presentation was ulcerative lesions (44.9%). Pathologically, the nodular type represented the most common variant (50.4%). Conclusion Our results proposed that the annual incidence of BCC is increasing among Egyptians. Ultraviolet radiation is considered a high-risk factor of BCC leading to a higher affection of the head region and more prevalence in men. This study also highlights some criteria of BCC in Egyptians such as the long duration of the tumor, the early onset in females, the higher percentage of giant types, and the predominance of nodular type. To our knowledge, this is the first report describing the characteristic features of BCC among Egyptians. Keywords Basal cell carcinoma BCC Keratinocyte carcinoma Epidemiology Skin cancer Non-melanoma skin cancer Clinical dermatology Dermatopathology Al-Azhar UniversityOpen access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction Basal cell carcinoma (BCC) is the most frequently diagnosed malignancy with increasing annual incidence. Also, it is the most common malignant epithelial tumor worldwide that statistically constituting 80% of keratinocyte cancers. This malignant epithelial neoplasm arises from the interfollicular basal cell layer of the epidermis, and it is mainly caused by chronic exposure to ultraviolet (UV) radiation of sunlight. Therefore, BCCs occur mostly in those areas of the body which are exposed to sun rays, particularly on the head and neck. Although BCC is a locally aggressive tumor with low metastatic activity, it is associated with comorbidity and increasing cost burden (Kim et al. 2019; Schreuder et al. 2022; Cameron et al. 2019; Tan et al. 2015, 2018). BCCs are diagnosed by direct inspection and histopathological examination is necessary to ascertain the diagnosis and determine the risk of recurrence (Cameron et al. 2019; Roewert-Huber et al. 2007). BCCs are often histopathologically described as a proliferation of homogeneous, basaloid cells with a hyperchromatic nucleus and minimal, poorly defined cytoplasm that resemble the epidermal basal cells morphologically (Tan et al. 2018; Altamura et al. 2010). Clinical types of BCC include nodular, superficial spreading, pigmented, morpheaform, and fibroepithelioma of Pinkus. Histopathological variants are nodular, micronodular, superficial, pigmented, infiltrative, morpheaform, metatypical, and fibroepithelioma. Less common types are keratotic, adenoid, clear cell, granular type, and BCC with sebaceous and eccrine differentiation. Basosquamous cell carcinoma is a rare subtype of BCC with areas of both basaloid and squamoid differentiation. Some consider basosquamous cell carcinoma and metatypical BCC as synonyms, whereas others are of the view that they are separate entities (Nedved et al. 2014). The exact demographic properties and clinicopathological criteria for BCC in Egypt are not reported in the literature, so this work aims to report the recorded data for patients diagnosed pathologically with BCC during the last five years. Patients and methods Study design A retrospective cross-sectional multicenter study. Inclusion criteria Egyptian patients diagnosed pathologically with BCC in the period from January 2017 to December 2021. Exclusion criteria Patients originating from geographical areas other than Egypt. Data collection A collaboration of 4 dermatology centers of university hospitals with different geographical distributions [2 in Cairo (Al-Azhar, AFCM), 1 in North Egypt (Alexandria), and 1 in Upper Egypt (Sohag)]. The study was conducted in accordance with the Declaration of Helsinki and its amendments, and it was also approved by the Institutional Review Boards of all participating centers in the study. Written informed consents from the patients were obtained at the time of the biopsy. We retrospectively reviewed the medical records and the pathology archives to obtain the baseline clinical and histopathological data needed for the study. Demographic data such as age, sex, occupation, sun exposure (the average number of hours spent outdoors every week), number of lesions, and Fitzpatrick skin type were collected for each patient and correlated to the studied parameters. The clinical classification of BCC subtypes was done using Rook's Textbook of Dermatology classification system (Madan and Lear 2016). Histologic subtyping was performed according to the classification mentioned by Weedon including nodular, micronodular, cystic, superficial, pigmented, adenoid, infiltrating, sclerosing, keratotic, infundibulocystic, metatypical, basosquamous, fibroepitheliomatous, and mixed patterns (Weedon and Patterson 2015). Statistical analysis The collected data were revised for completeness and accuracy, coded, entered, and analyzed using Statistical Program for Social Science (SPSS) version 26 (IBM, USA). Quantitative data were expressed as mean ± standard deviation (SD). Qualitative data were expressed as frequency and percentage. The suitable statistical tests were used according to the type of data. Results A total of 544 patients with histopathologically proven BCCs were registered through the collaborated centers in this 5-year study. There was a slight male predominance with 326 patients (59.9%), while female patients were 218 (40.1%). Male to female ratio was about 1.5 to 1. The mean age of presentation was 61.6 ± 13.2 years with female patients showing younger age of onset. Patients who reported a history of daily sun exposure (≥ 40 h spent outdoors per week) formed 71.3% (388 patients). The most common skin type affected was skin type III in 316 patients (182 males and 134 females) as shown in Table 1. The results showed an increased incidence of BCC from 2017 to 2021 with a peak of incidence in 2021 as shown in Fig. 1.Table 1 Epidemiological criteria of the studied patients Male (N = 326) (59.9%) Female (N = 218) (40.1%) Statistical test and P value The whole studied patients (N = 544) Mean age of presentation 63.9 ± 12.1 58.02 ± 14.1 T = 5.11 P < 0.001 61.6 ± 13.2 Skin type II 16 (4.9%) 182 (55.8%) 128 (39.3%) 8 (3.7%) 134 (61.5%) 76 (34.9%) χ2 = 1.84 P = 0.398 24 (4.4%) 316 (58.1%) 204 (37.5%) III IV T, independent sample t-test; χ2, chi-square test; P value < 0.001 is considered highly significant; P value > 0.05 is considered non-significant Fig. 1 Number of annually diagnosed cases of BCC Regarding the clinical criteria, most of the cases (93.8%) presented with solitary BCC, contrary to 34 patients who presented with multiple BCCs. It was observed that multiple BCCs were more prevalent in males. The head was the most commonly involved region (79.4%) where most of the lesions were located on the nose in 116 (21.3%) patients. Other sites of BCCs on the head were as follows: scalp in 96 (17.6%) patients, cheek 84 (15.4%), forehead 36 (6.6%), periorbital region 36 (6.6%), ear 15 (2.8%), post-auricular area 14 (2.6%), pre-auricular area 13 (2.4%), chin 12 (2.2%), and upper lip 10 (1.8%). About one third of cases (32.2%) had giant BCCs > 5 cm diameter (Table 2). The most common clinical variant, either males or females, was the ulcerative type followed by the non-pigmented nodular type (Fig. 2).Table 2 Clinical criteria of the studied patients Male (N = 326) (59.9%) Female (N = 218) (40.1%) Statistical test and P value The whole studied patients (N = 544) Number Single 300 (92%) 26 (8%) 210 (96.3%) 8 (3.7%) χ2 = 4.1 P = 0.042 510 (93.8%) 34 (6.2%) Multiple Site Head 253 (77.6%) 12 (3.7%) 45 (13.8%) 16 (4.9%) 179 (82.1%) 7 (3.2%) 30 (13.8%) 2 (0.9%) χ2 = 6.7 P = 0.081 432 (79.4%) 19 (3.5%) 75 (13.8%) 18 (3.3%) Neck Trunk Extremities Size Non giant (≤ 5 Cm) 227 (69.6%) 99 (30.4%) 142 (65.1%) 76 (34.9%) χ2 = 1.2 P = 0.271 369 (67.8%) 175 (32.2%) Giant (> 5 Cm) Clinical variant Ulcerative 154 (47.2%) 90 (41.3%) χ2 = 6.3 P = 0.095 244 (44.9%) Superficial 10 (3.1%) 8 (3.7%) 18 (3.3%) Nodular (non-pigmented) 101 (31%) 89 (40.8%) 190 (34.9%) Nodular (pigmented) 61 (18.7%) 31 (14.2%) 92 (16.9%) χ2, chi-square test; NS, P value < 0.05 is considered significant; P value > 0.05 is considered non-significant Fig. 2 Different clinical presentations of BCC. a, b Giant BCC affecting the scalp with almost complete deroofing of the skin. c Multiple BCCs affecting the back. d Multiple BCCs affecting the nose and paranasal area. e Pigmented BCC affecting the right periorbital area. f Ulcerative BCC with marked telangiectasia located on the right temple region The mean duration of BCC was 3.9 ± 3.8 years, with no significant difference between males and females or giant and non-giant BCCs (Table 3). Regarding the pathological criteria, the nodular type was the most common variant followed by superficial BCCs (Table 4). There were no differences between giant or non-giant BCC regarding the pathological type (Table 5). Pigmented BCCs showed a slight likelihood of occurrence in male patients, while superficial BCCs were slightly more common than pigmented BCCs in female patients (Fig. 3).Table 3 Duration of BCCs in the studied patients Duration in years Statistical test and P value The whole studied patients 3.9 ± 3.8 Male 3.7 ± 3.5 MW = 34,280 P = 0.482 Female 4.2 ± 4.3 Giant BCC 3.7 ± 3.5 MW = 31,071 P = 0.474 Non giant 4.07 ± 3.9 MW Mann–Whitney U test; P value > 0.05 is considered non-significant Table 4 Pathological criteria of the studied patients Male (N = 326) (59.9%) Female (N = 218) (40.1%) Statistical test and P value The whole studied patients (N = 544) Histopathological variants Adenoid 20 (6.1%) 10 (4.6%) χ2 = 21.8 P = 0.025 30 (5.5%) Basosquamous 16 (4.9%) 6 (2.8%) 22 (4%) Fibroepithelioma of Pinkus 1 (0.3%) 0 (0%) 1 (0.2%) Keratotic 0 (0%) 1 (0.5%) 1 (0.2%) Infundibulocystic 1 (0.3%) 3 (1.4%) 4 (0.7%) Infiltrative 26 (8%) 18 (8.3%) 44 (8.1%) Micronodular 22 (6.7%) 12 (5.5%) 34 (6.3%) Mixed 10 (3.1%) 12 (5.5%) 22 (4%) Morpheaform 6 (1.8%) 4 (1.8%) 10 (1.8%) Nodular 150 (46%) 124 (56.9%) 274 (50.4%) Pigmented 38 (11.7%) 8 (3.7%) 46 (8.5%) Superficial 36 (11%) 20 (9.2%) 56 (10.3%) χ2, chi-square test; NS, P value < 0.05 is considered significant Table 5 Pathological criteria for giant and non-giant BCCs Giant (N = 175) Non- giant (N = 369) Statistical test and P value Histopathological variants Adenoid 11 (6.3%) 19 (5.1%) χ2 = 59.9 P < 0.001 Basosquamous 14 (8%) 8 (2.2%) Fibroepithelioma of Pinkus 0 (0%) 1 (0.3%) Keratotic 0 (0%) 1 (0.3%) Infundibulocystic 0 (0%) 4 (1.1%) Infiltrative 2 (1.1%) 42 (11.4%) Micronodular 19 (10.9%) 15 (4.1%) Mixed 9 (5.1%) 13 (3.5%) Morpheaform 2 (1.1%) 8 (2.2%) Nodular 96 (54.9%) 178 (48.2%) Pigmented 19 (10.9%) 27 (7.3%) Superficial 3 (1.7%) 53 (14.4%) χ2, chi-square test; NS, P value < 0.001 is considered highly significant Fig. 3 Different pathological types of BCC. a Nodular. b Superficial. c Micronodular. d Infiltrating. e Morpheaform. f Adenoid. (a, H&E × 100; b, c, H&E × 200; d-f, H&E × 400) A noteworthy finding is the increasing number of diagnosed cases with BCC in patients under the age of 30 years (Fig. 4). Although it’s a non-significant increase, this is an alarming sign that BCC can affect younger age more commonly nowadays.Fig. 4 Number of diagnosed cases of BCC per year in relation to age Discussion Basal cell carcinomas are common malignancies that usually show clear histomorphologic features, but in certain instances, they can display different patterns of differentiation leading to potential diagnostic confusion (Plaza et al. 2021). The incidence of BCCs varies depending on race and on geographic factors such as latitude and sun exposure. The reported incidence rates per 100,000 person-years are highest in Australia (> 1000/100,000), around 100 in the UK, and 15–16.5 in Japan (Cameron et al. 2019; Lomas et al. 2012). However, the rates continue to increase worldwide. In the USA, the age-adjusted incidence rates almost doubled from the late 1980s to the middle 2000s in both men and women (Wu et al. 2013). Pathobiologically, the majority of BCCs are caused by activation of the Hedgehog (HH) signaling pathway, which also serves as a therapeutic target. Following the discovery of a germline mutation in the patched homolog 1 (PTCH1) gene in basal cell nevus syndrome, mutations in genes associated with the HH signaling pathway, including PTCH1 and smoothened homolog (SMO), were discovered in sporadic BCCs (Tanese et al. 2018). Multiple treatment modalities have been proposed for BCC. The surgical approach (including Mohs’ micrographic surgery) is the most widely accepted method, while other non-surgical methods may be tried (El-Khalawany et al. 2022). Epidemiological criteria The results of this study showed that Egyptian patients with BCC showed slight predominance towards the male sex. These results are not different from what is reported in the literature as the male sex is a risk factor for BCC and the male to female ratio varied between 1.5–2 to 1 (Kim et al. 2019; Schreuder et al. 2022). This may be due to more frequent exposure of males to UV radiation which is related to the nature of their outdoor work. The mean age of presentation in our cohort was 61.6 ± 13.2 which is consistent with what is reported in the literature that BCC is common in the 6th and 7th decades (Tan et al. 2015; Nedved et al. 2014; Madan and Lear 2016). However, it should be noted that in this cohort females showed slight earlier onset than males. Similar finding was observed by Chlebicka et al. (2021). This could be explained in western countries by the frequent use of tanning bath by females (Kappelin et al. 2022; Garcias-Ladaria et al. 2017), which is not a common habit for Egyptian females due to religious and social customs. However, a Turkish study reported that females showed earlier onset of BCCs, and they share the religious customs and ethnic race with Egyptians (Ozkanli et al. 2020). Sun exposure is one of the most important risk factors for keratinocyte neoplasms (Kricker et al. 2017); this well explains that 71.3% of the studied cohort had a history of daily sun exposure. Studied patients with skin type III showed an insignificant increase rather than skin types II and IV. This could be explained by the fact that skin type III is more common in Egypt. Apart from 2020, the total number of diagnosed cases in this study was steadily increasing. This could be explained by the increased awareness of patients towards the condition along with the advisory campaigns that were held for early detection of skin cancer. The drop in the number of diagnosed cases in 2020 could be owed to the restrictions made during the COVID-19 pandemic that asked people to stay at home and not to attend hospitals except for emergencies. Overall, there is an increase in the incidence of BCC cases. This coincides with the international trend of BCC incidence (Kim et al. 2019; Schreuder et al. 2022; Cameron et al. 2019). Clinical criteria Solitary BCC was predominant in Egyptian patients which coincided with what is reported by Adachi et al. for Japanese patients with BCC (Adachi et al. 2018). A recent study from Netherlands showed that about 76–77% of patients had solitary BCC (Schreuder et al. 2022). As male gender is considered one of the risk factors for BCC, this might explain that most of the studied patients with multiple BCCs were males (Cameron et al. 2019). Most of the cases presented were in the head region and the nose was the most commonly affected site, which agrees with what is reported in the literature denoting that the chronically damaged skin areas are usually involved with BCCs (Chlebicka et al. 2021; Cameron et al. 2019; Kricker et al. 2017; Kasumagic-Halilovic et al. 2019). Vaca-Aguilera et al. (2019) reported that giant BCCs represent 1–2% of the whole BCCs. On the other hand, we reported a higher incidence (up to one third of cases) that was difficult to be explained either by the neglection of the tumor due to loss of significant symptoms or by the long duration of BCCs as our results showed no significant difference between giant and non-giant BCCs regarding the duration. The larger diameter of BCC in this study may owed to environmental, racial, or ethnical factors. Also, the mean duration in our cohort (3.9 years) was closely related to what is reported by Kumar et al. (2014) (4.7 years) and by Tan et al. (2015) (3.5 years). Most of the previous reports described that the most clinical variant of BCC is the nodular type representing about 50%-80% of BCCs (Cameron et al. 2019; Nagarajan et al. 2020). In this study, about one third of cases were nodular non-ulcerative, and non-pigmented; while ulceration occurred in about half of lesions which is a higher proportion in comparison to the previous reports. Ozkanli et al. (2020) reported ulceration in 28.6% of BCCs cases, while Yap (2010) reported ulceration in 18% of cases. This difference should be considered, as it may indicate a more progressive course of the tumor in this racial type. Histopathological criteria The most common pathological BCC variant in our cohort was the nodular type which is consistent with the data reported in the literature (Cameron et al. 2019; Tan et al. 2015; Ozkanli et al. 2020; Muzic et al. 2017). Regarding the giant BCC, Vaca-Aguilera et al. (2019) reported that infiltrating type was the most common pathological variant. However, in the present study, the nodular variant was the most common pathological variant of BCC in Egyptians regardless of the size of lesions. The second most common pathological variant in our cohort was the superficial type which is similar to the reported data in the literature. Cameron et al. reported that the second most common pathological variant of BCCs was the superficial type with a relative increase in incidence in females (Cameron et al. 2019). In this study, pigmented BCCs showed slight probabilities of occurrence in males than the superficial type and this may be contributed to the ability of darker skin for tanning and colonization with tumoral dendritic melanocytes (Tan et al. 2015). Unfortunately, we don’t have a national registry system for cases with BCC in Egypt. We hope that this study could open the eyes for the importance of such registry to exist in the near future. Conclusion Our results showed that the annual incidence of BCC is increasing among Egyptians. UV radiation is considered a high-risk factor of BCC leading to a higher affection of the head region and more prevalence of the tumor in men. This study also reported some features of BCC in Egyptians such as the long duration of the tumor, the early onset in females, the higher percentage of giant types, and the predominance of nodular type. To our knowledge, this is the first report describing the epidemiological and clinicopathological features of BCC among Egyptians. We hope this registry would help in improving the prognostic outcomes of BCC among Egyptians. Author contributions EKM, RMA, SA, and HENHMM contributed to the concept, design and execution of the study, data collection, drafting, and critical revision of the article. MAM, HMS, AS, AMA, GRM, and HAM contributed to the data collection, analysis, and interpretation. All authors approved the final version to be published. Funding Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Data availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Declarations Competing interests The authors declare no competing interests. Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Ethical approval This study was conducted in accordance with the Declaration of Helsinki and its amendments, and it was also approved by the Institutional Review Boards of all participating centers in the study. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish The authors affirm that participants provided informed consent for publication of the images included in this study. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Adachi K Yoshida Y Noma H Characteristics of multiple basal cell carcinomas: the first study on Japanese patients J Dermatol 2018 45 10 1187 1190 10.1111/1346-8138.14576 30035302 Altamura D Menzies SW Argenziano G Dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis J Am Acad Dermatol 2010 62 1 67 75 10.1016/j.jaad.2009.05.035 19828209 Cameron MC Lee E Hibler BP Basal cell carcinoma: epidemiology; pathophysiology; clinical and histological subtypes; and disease associations J Am Acad Dermatol 2019 80 2 303 317 10.1016/j.jaad.2018.03.060 29782900 Chlebicka I Stefaniak A Matusiak Ł Szepietowski JC Basal cell carcinoma: what new can be learned about the most common human cancer? A cross-sectional prospective study of 180 cases in a single centre Postepy Dermatol Alergol 2021 38 6 1086 1091 10.5114/ada.2021.106026 35126019 El-Khalawany M Saudi WM Ahmed E The combined effect of CO2 laser, topical diclofenac 3%, and imiquimod 5% in treating high-risk basal cell carcinoma J Cosmet Dermatol 2022 21 5 2049 2055 10.1111/jocd.14354 34333841 Garcias-Ladaria J Morales-Morato FJ Cuadrado Rosón M Rocamora V Basal cell carcinoma in young adults Actas Dermosifiliogr 2017 108 4 376 377 10.1016/j.ad.2016.10.012 27931953 Kappelin J Green AC Ingvar Å Incidence and trends of basal cell carcinoma in Sweden: a population-based registry study Br J Dermatol 2022 186 6 963 969 10.1111/bjd.20964 34939666 Kasumagic-Halilovic E Hasic M Ovcina-Kurtovic N A clinical study of basal cell carcinoma Med Arch 2019 73 6 394 398 10.5455/medarh.2019.73.394-398 32082007 Kim DP Kus KJB Ruiz E Basal cell carcinoma review Hematol Oncol Clin North Am 2019 33 1 13 24 10.1016/j.hoc.2018.09.004 30497670 Kricker A Weber M Sitas F Early life UV and risk of basal and squamous cell carcinoma in New South Wales, Australia Photochem Photobiol 2017 93 6 1483 1491 10.1111/php.12807 28710897 Kumar S Mahajan BB Kaur S A study of basal cell carcinoma in South asians for risk factor and clinicopathological characterization: a hospital based study J Skin Cancer 2014 2014 173582 10.1155/2014/173582 25530883 Lomas A Leonardi-Bee J Bath-Hextall F A systematic review of worldwide incidence of nonmelanoma skin cancer Br J Dermatol 2012 166 5 1069 1080 10.1111/j.1365-2133.2012.10830.x 22251204 Madan V Lear J Griffiths C Barker J Bleiker T Chalmers R Creamer D Basal cell carcinoma Rook’s textbook of dermatology 2016 9 Oxford, UK Wiley-Blackwell Muzic JG Schmitt AR Wright AC Incidence and trends of basal cell carcinoma and cutaneous squamous cell carcinoma: a population-based study in Olmsted County, Minnesota, 2000 to 2010 Mayo Clin Proc 2017 92 6 890 898 10.1016/j.mayocp.2017.02.015 28522111 Nagarajan P Tetzlaff MT Curry JL Migden M Chen L Silapunt S Histopathology of basal cell carcinoma and its variants Basal cell carcinoma 2020 Cham Springer 25 48 Nedved D Tonkovic-Capin V Hunt E Diagnostic concordance rates in the subtyping of basal cell carcinoma by different dermatopathologists J Cutan Pathol 2014 41 1 9 13 10.1111/cup.12256 24152016 Ozkanli S Soylemez T Keskin H A five-year retrospective analysis of basal cell carcinoma: a monocentric study Medeni Med J 2020 35 3 219 225 10.5222/MMJ.2020.92332 33110674 Plaza JA Pootrakul L Raghavan SS Reproducible histopathologic features in cases of basal cell carcinoma with neuroendocrine expression: a clinicopathologic study of 24 cases with a potential diagnostic pitfall Am J Dermatopathol 2021 43 12 903 907 10.1097/DAD.0000000000002082 34783706 Roewert-Huber J Lange-Asschenfeldt B Stockfleth E Kerl H Epidemiology and aetiology of basal cell carcinoma Br J Dermatol 2007 157 Suppl 2 47 51 10.1111/j.1365-2133.2007.08273.x 18067632 Schreuder K Hollestein L Nijsten TEC A nationwide study of the incidence and trends of first and multiple basal cell carcinomas in the Netherlands and prediction of future incidence Br J Dermatol 2022 186 3 476 484 10.1111/bjd.20871 34726263 Tan ES Ee M Shen L Basal cell carcinoma in Singapore: a prospective study on epidemiology and clinicopathological characteristics with a secondary comparative analysis between Singaporean Chinese and Caucasian patients Australas J Dermatol 2015 56 3 175 179 10.1111/ajd.12202 25179179 Tan ST Ghaznawie M Heenan PJ Dosan R Basal cell carcinoma arises from interfollicular layer of epidermis J Oncol 2018 2018 3098940 10.1155/2018/3098940 30356421 Tanese K Emoto K Kubota N Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors J Dermatol 2018 45 10 1181 1186 10.1111/1346-8138.14543 30035333 Vaca-Aguilera MR Guevara-Gutiérrez E Barrientos-García JG Tlacuilo-Parra A Giant basal cell carcinoma: clinical-histological characteristics of 115 cases Int J Dermatol 2019 58 12 1430 1434 10.1111/ijd.14455 30972736 Weedon D Patterson J Tumors of epidermis Weedon’s skin pathology 2015 4 Elsevier 784 829 Wu S Han J Li WQ Basal-cell carcinoma incidence and associated risk factors in U.S. women and men Am J Epidemiol 2013 178 6 890 897 10.1093/aje/kwt073 23828250 Yap FB Clinical characteristics of basal cell carcinoma in a tertiary hospital in Sarawak, Malaysia Int J Dermatol 2010 49 2 176 179 10.1111/j.1365-4632.2009.04342.x 20465642