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Abstract

Objective

Cutaneous basal cell carcinoma (BCC) exhibits numerous variants, ranging from non-aggressive to aggressive behavior. Androgen receptor (AR) and epidermal growth factor receptor (EGFR) are both expressed by BCC. This study aims to analyze the differences between aggressive and non-aggressive variants concerning AR and EGFR expression, as well as their relationship with each other.

Methods

Between 2019 and 2024, we analyzed all archival tissue blocks of patients with a diagnosis of BCC who underwent excision. Fifty-three cases with a diagnosis of superficial, nodular, infiltrative, and micronodular BCC were included in the study. Histologically, the infiltrative and micronodular variants were classified as highly aggressive; nodular and superficial variants less aggressive. These characteristics were compared with other features with respect to their statistical significance.

Result

We found a statistically significant relationship between AR, EGFR expression, and tumor variants. While the AR expression was high in superficial and nodular variants, it was weak in the infiltrative type. Whereas the EGFR expression, contrary to AR, was strong in infiltrative and micronodular variants, it was weak in nodular and superficial variants. There was a statistically significant reverse correlation between AR and EGFR (p = 0.005).

Conclusions

The AR expression in BCC is consistent with low-degree malignancy; conversely, EGFR expression is consistent with aggressiveness. We hope our findings lead to further discoveries in employing topical agents that activate AR, next to anti-EGFR agents. Our study is the first and only one that investigated BCC concerning morphological variants and their relationship with AR and EGFR.

Keywords

Basal cell carcinoma EGFR AR BCC subtypes aggressiveness

Introduction

Basal cell carcinoma (BCC) is the most common skin malignancy, and the incidence is progressively rising.^1–5 It constitutes 70% of all skin cancers in Australia and Europe. İntermittent and cumulative exposure to ultraviolet radiation is known to be the main cause.^2,6 Thus, it is more common in elderly people.⁷ In most cases, BCC progresses slowly, is locally invasive, seldom metastasizes, and can be removed by surgical excision.^3,4 BCC is different from other aggressive cutaneous malignancies such as malignant melanoma and SCC. The difference may be due to the presence of pH-sensitive proteins such as ASIC2, GPR31, and TRCP4 expressed more by the latter malignancies.^8,9 Nevertheless, occasionally BCC may take a destructive behavior and rarely metastasize.^3,7,10 Contrary to squamous cell carcinoma, BCC is not graded histologically; it is classified according to histological appearance.³ According to clinicopathological studies, some variants behave more aggressively than others.^3,5

Currently, there are three different main types of BCC: nodular, superficial, and infiltrative.¹¹ Nonetheless, there are also variants such as micronodular, morpheiform, and one with squamous differentiation; each with a different prognosis and recurrence risk.

Surgical excision is the main treatment option with a high cure rate. Albeit, especially for low-risk variants, non-invasive treatments such as photodynamic therapy and topical application of 5-fluorouracil, 5% imiquimod cream may be preferred.^5,12 In cases with locally aggressive, metastatic, and recurrent disease, surgery is the treatment of choice. In such cases, neoadjuvant treatment may be delivered ahead of definitive surgery. In patients for whom surgery is not an option, radiation therapy may be applied.^7,12,13 Recently, “Sonic Hedgehog Inhibitors (SHI)” have played a role in the treatment of local and metastatic BCC.^13,14 In cases refractory to SHI, immunotherapy may be considered as an alternative treatment.¹³ The presence of such a variety of treatment options forces us to divide BCC into aggressive and non-aggressive types concerning potential treatment modalities. Recent studies have led us to believe that infiltrative, morpheiform, and micronodular variants behave aggressively; whereas, nodular and superficial variants behave non-aggressively, being in the low-risk category.³

Androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily. Upon attachment to their respective ligands, it is moved to the nucleus from the cytosol and rearrange the target gene expression. ARs are expressed in the prostate gland, adrenal gland, and liver.^6,15 It is also expressed in the skin, especially in sebaceous gland cells, in keratinocytes of the pilosebaceous canal, in dermal fibroblasts, in basal keratinocytes of interfollicular epidermis, and dermal fibroblasts.^6,16 Recent investigations have reported that 78% of BCC express AR receptors.¹⁶ Earlier reports revealed no AR expression in benign tumors of follicular origin, which helps in differential diagnosis.^14,16–18

Epidermal growth factor receptor (EGFR) is a 170,000-kDa transmembrane glycoprotein. It plays a crucial role in cell division, differentiation, and proliferation in neoplasms. Reports indicate that excessive expression of EGFR correlates with poor prognosis.¹⁰ Additionally, EGFR also plays a role in cell invasion in addition to cell proliferation.^19–21 Particularly, together with specific integrins, it joins the production of structures responsible for cell migration through the basal membrane.¹⁹ Recently, investigators discovered that EGFR increases tumor invasion by enhancing the mobility of cells in breast cancer.²⁰

Numerous studies investigated the relationship between AR and EGFR, mostly in prostate cancers, but also including breast cancers, lung cancers, and ovarian cancers.²² Studies demonstrated that through the activation of AR, phosphorylation of EGFR is enhanced, subsequently leading to increased activation of EGFR.²³ Albeit, there are reports that it also inhibits EGFR activity through different mechanisms.^18,19 In a study on prostate cancer, AR-transfected androgen-independent prostate cancers (PC3, PC3-AR). In these cells, adhesion and invasion of the malignant cells are suppressed through AR integrin modulation.¹⁸ Furthermore, interfering with cell signaling between AR and EGFR diminishes the EGFR effect, thus contributing to the emergence of a low-degree malignancy phenotype carrying a better prognosis.^18,19

In skin cancers, besides the presence of independent studies regarding AR and EGFR, their numbers are limited. Specifically, there are no studies that investigated the relationship between AR and EGFR. In our study, we investigated AR and EGFR expression, their relationship with invasion, and aggressive behavior in cutaneous BCC variants that mostly cause local invasion but seldom metastasize. Specifically, the relationship of AR and EGFR with aggressive behavior and invasion. Additionally, we also investigated how they relate to each other concerning aggressive behavior. Our study is the first in the World literature that investigated the relationship between AR and EGFR in cutaneous BCC.

Materials and methods

Cases included in the study and exclusion criteria

During the 5 years between 2019 and 2024, all cases with BCC diagnosed following excisional biopsy had undergone a review of their slides and archival tissue blocks. Fifty-three cases with morphological appearance of nodular, infiltrative, micronodular, and superficial BCC were included in the study. Ones with mixed type, rarely seen subtypes, and ones that underwent incisional biopsy, as well as the ones for which we could not uncover the tissue blocks, were excluded from the study. We have registered their age, gender, and the location from which the tissue was removed.

Pathological tissue preparation and staining

Four-micron-thick slides were made from each paraffin block and stained with H&E. Additionally, two microscopic sections were made from each tissue block to prepare positively charged slides for immunohistochemical analysis. Each slide was processed in the DAKO Autostainer, one for EGFR and the other for AR staining. Two pathologists were double-blinded to interpret the slides independently under light microscopy, where the staining was dense.

İn H&E-stained slides, the subtype and the diameter of the tumor were confirmed. The tumor diameter was classified into three groups: tumor diameter < 1 cm, 1–1.9 cm, 2 and > 2 cm. The location of excised tissue on the human body was classified as trunk, ear and surrounding tissue, and face.

Pathological evaluation

For AR receptors, we counted the number of cells that showed nuclear positivity out of 100 cells in an area where staining is utmost densest. We based our scoring system on the Works of Bartos et al.⁶ and Asadi-Amoli et al.²⁴ The scoring was as follows: < % 1 positively stained cells:1+, %2–50 cells: 2+, and> %50 cells: 3 + . For EGFR, membranous and/or cytoplasmic staining was considered meaningful for scoring. We modified the scoring system of Dargaud et al.¹⁰ Henceforth, we scored < %25% positively stained cells: 1+, %26–50% positive cells: 2+, and> %50: 3 + .

Additionally, cutaneous BCCs are classified into aggressive (infiltrative and micronodular) and non-aggressive (nodular and superficial). Furthermore, they are evaluated according to AR, EGFR expression, tumor diameter, and other variables.

This study conforms to ‘REMARK’ guidelines.²⁵

This study was conducted following the Helsinki Declaration of 1975 as revised in 2024. The patient's identity is confidential. This is a retrospective study, an observational analysis. This research commenced in September 2024 and concluded in March 2025, spanning 6 months.

Statistical analysis

All statistical analyses were performed using the IBM SPSS 25.0 program.

Descriptive statistics, such as mean and standard deviation of variables, were used in the study.

Descriptive statistics in the analyses are stated as frequency (n), percentage (%), mean (X̄), standard deviation (SS), and minimum and maximum values.

Independent t-test, one-way analysis of variance, and Spearman Correlation analysis techniques were used in the analyses performed in the comparison of variables according to the personal information of the patients.

Statistical significance was assessed at the level of p < 0.05 in all obtained results.

Results

A total of 53 patients were included in this study: 39 males and 14 females. Their ages were between 41 and 94, with a mean age of 71.2. The distribution of tumor variants, their original location on the body, and their diameters are illustrated in Table 1.

Table 1.

Tumor localization and diameter according to BCC variants.

	BCC variants
	Infiltrative type (n = 18)	Micronodular type (n = 9)	Nodular type (n = 19)	Superficial type (n = 7)	Test x²/F*	p
Localization
Body	6 (28.6%)	5 (23.8%)	5 (23.8%)	5 (23.8%)	7.517	0.276
Ear	1 (25.0%)	0 (0.0%)	2 (50.0%)	1 (25.0%)
Face	11 (39.3%)	4 (14.3%)	12 (42.9%)	1 (3.5%)
Tumor diameter
< 1 cm	3 (16.6%)	1 (5.6%)	13 (72.2%)	1 (5.6%)	17.977	0.006
1–1,9 cm	11 (42.3%)	7 (26.9%)	3 (11.6%)	5 (19.2%)
> 2 cm	4 (44.5%)	1 (11.1%)	3 (33.3%)	1 (11.1%)

BCC: basal cell carcinoma.

The gender distribution of BCC variants was as follows: 83.3% of infiltrative type BCC were males, and only 16.7% were females. This shows the tendency of males to have the infiltrative type of BCC. There was equal distribution between males and females concerning the nodular type. There was no meaningful difference between AR and EGFR concerning gender, tumor localization, and tumor diameter.

A statistically meaningful relationship was discovered between tumor variants and AR, EGFR expression, as well as their diameter (p < 0.05). 69.6% of tumors with AR staining score < 1% were infiltrative type (Figure 1); whereas, 51.9% of the 2–50% staining scores are nodular type (Figure 2). All the ones that have more than 50% staining score were superficial type. These findings indicate the presence of a strong relationship between the tumor variants and AR staining characteristics.

Figure 1.

Less than 1 % AR expression on infiltrative BCC (AR X 200). BCC: basal cell carcinoma; AR: androgen receptor.

Figure 2.

Intense AR expression on nodular BCC (AR X 200). BCC: basal cell carcinoma; AR: androgen receptor.

When EGFR staining characteristics were compared with tumor variants, 88.9% of tumors expressing more than 50% EGFR staining were infiltrative types (Figure 3). None of the other tumor variants expressed similar staining characteristics. Tumors that expressed 26–50% EGFR staining; most of them were either the infiltrative type (43.5%) or micronodular type (34.8%). Among tumors expressing 1–25% EGFR, 76.2% were nodular type (Figure 4) and 57.3% superficial type. These findings indicate that infiltrative and micronodular types represent the highest percentage of EGFR and have statistical significance (p = 0.000).

Figure 3.

Intense EGFR expression on infiltrative BCC (EGFR X200). BCC: basal cell carcinoma; EGFR: epidermal growth factor receptor.

Figure 4.

Less than 1% EGFR expression on nodular BCC (EGFR X200). BCC: basal cell carcinoma; EGFR: epidermal growth factor receptor.

AR and EGFR staining characteristics according to tumor variants are shown in Figure 5.

Figure 5.

Summary of immunohistochemical AR (A) and EGFR (B) expression result in BCC variants. Blue bar: infiltrative type; red bar: micronodular type; green bar: nodular type; yellow bar: superficial type. The scoring of AR expression: < %1 positively stained cells: 1+, %2–50 cells: 2+, and > %50 cells: 3+. The scoring of EGFR expression: < %25 positively stained cells: 1+, %26–50 positive cells: 2+, and > %50: 3+. The ratios on the bar show the distribution of BCC types according to AR and EGFR scores. BCC: basal cell carcinoma; AR: androgen receptor; EGFR: epidermal growth factor receptor.

When tumor diameter was compared to tumor variants, a statistically meaningful relationship was discovered (p = 0.006). Most of the nodular variant BCC (76.2%) had < 1 cm, 42.3% were infiltrative, and 26.9% micronodular type had 1–1.9 cm. Among tumors larger than 2 cm, 44.4% were infiltrative type. These findings indicated that the larger tumors were mostly either infiltrative or micronodular variants.

When tumor behavior was compared with all the variables, there was a statistically meaningful correlation between tumor diameter and its aggressiveness. Aggressive tumors exhibited a larger diameter, which increased as the tumor's aggressive behavior escalated. Additionally, EGFR expression increased along with increasing tumor diameter, which was also statistically significant.

With escalating tumor aggressiveness, EGFR expression (staining intensity) increased, whereas AR expression declined. Consequently, there was a statistically meaningful reverse correlation between EGFR and AR expression (p = 0.005).

Discussion

BCCs are slowly growing, locally invasive malignancies. They are amenable to local excision, albeit they may recur frequently, metastasize, and even be life-threatening.⁴ Clinicopathological studies revealed that the clinical behavior of BCC correlates with morphological variants.^3,4 Thus, contrary to most malignancies. BCC cannot be graded according to histology; they are only classified according to their respective morphological features.^2–4 Pathologically, in some cases, it may not be easy to identify the morphological variant since they may display mixed morphological features. McKenzie et al.,⁵ when they classified these malignancies into high and low-risk categories, placed the infiltrative and micronodular variants into the high-risk category. They also reported that the changes in the tumor base and periphery determine the clinical behavior of these variants. In our study, we classified the infiltrative and micronodular variants as high risk; the superficial as well as the nodular variants, low risk. We specifically attempted to include the tumor base and periphery within the same pattern for the study to be credible.

During treatment planning in BCC, it is not only important whether they belong to an aggressive variant or not; moreover, also to patient characteristics, whether the location of the tumor is in an area that can be easily excised, the size of the tumor, and potential cosmetic changes should also be taken into account.^3,4,7 Treatment requires a multidisciplinary approach. In deciding the most suitable surgical approach and in cases where surgery is not an option, the pathologist plays an important role in selecting the appropriate local treatment.^{12,13,26–28} Thus, there is a need to examine the tissue for other markers such as AR and EGFR, next to the analysis of tissue concerning tumor variants.

There are limited studies investigating the value of AR expression in cutaneous BCC. Most of these studies focused on benign tumors such as trichoepithelioma or sebaceous carcinoma to differentiate from BCC.^{15,16,18,24,29} Among studies that evaluated the AR in BCC variants, Bartos et al.⁶ reported increased expression of AR specifically in superficial and nodular variants known to represent the low-risk group. They also reported that the infiltrative and noduloinfiltrative variants, representing the aggressive group, possessed low AR expression.⁶ These findings were supportive of our discoveries. In our study, we investigated the micronodular BCC variant separately and discovered that this variant might be mildly aggressive concerning AR expression.

Dargaud et al. investigated EGFR, Ki67, and aneuploidy in both recurrent and nonrecurrent BCC and reported that EGFR has no relationship with recurrence.¹⁰ This discovery is contrary to findings reported by Yerebakan et al.³⁰ The reason for such contrast may be that Dargaud et al. included in their study only superficial and nodular variants, considered non-aggressive among BCC. Whereas, in our study, we discovered that EGFR expression escalated along with the increasing degree of aggressiveness in BCC variants. Specifically, the presence of high EGFR expression in infiltrative variants in our study was similar to findings by Yerebakan et al. Although we did not include recurrence as a separate entity in our analysis, it is believed that aggressive types carry a high recurrence rate. Although recurrence is an important prognostic finding, recurrence will likely be affected by the completeness of surgical excision. Thus, we believe that the EGFR expression according to BCC variants has a more meaningful relationship with aggressiveness.

We have not found any study in the literatüre that investigated the relationship between AR and EGFR expression relative to tumor variants in cutaneous BCC. Nevertheless, numerous studies investigated such a relationship in prostate carcinoma.^19,31,32

Liu et al.²³ in their study reported 23 patients with oral squamous cell carcinoma that had AR expression with meaningfully associated phosphorylated EGFR. They claimed that the resultant phosphorylated EGFR enabled cell migration. Nevertheless, Bonaccorsi et al.³³ reported that in patients with prostatic carcinoma, AR expression decreased phosphorylated EGFR, thus, rendering them to assume a less malignant phenotype. In our study, contrary to Lui et al.,²³ we discovered a reverse correlation between AR and EGFR that was statistically significant (p < 0.005). This discovery is consistent with the findings of Bonaccorsi et al.

In another study, Bonaccorsi et al.¹⁹ reported that by transfecting AR to hormone-independent prostate carcinoma cells (PC3), the newly formed cancer cells (PC3-AR), through integrin modulation of AR, decreased their capacity for adhesion and invasion. Reports are indicating that through interaction with integrin, EGFR stimulates cell migration. Conversely, the presence of AR inhibits cell migration and consequently invasiveness. The findings in our study demonstrated that in infiltrative BCC, low AR coexisted with high EGFR. Thus, the reverse correlation between low AR and high EGFR expression was in complete agreement with the observations of Bonaccorsi et al. This is explained on the basis of such a relationship between AR, integrin, and EGFR.

Kalapurakal et al.³⁴ employed a monoclonal antibody named cetuximab in the treatment of aggressive, frequently recurrent BCC and attained a successful benefit. Scarpati et al.,³⁵ in their review, explored the concomitant use of radiation therapy with cetuximab in locally advanced nonmelanotic skin cancers. Similar to our study, they stated that EGFR is upregulated in aggressive BCC and SCC and benefits from anti-EGFR agents. Whereas, concomitant application of radiation therapy with cetuximab may result in severe cutaneous toxicity.³⁵ As a result, there is a need to discover other agents to use together with anti-EGFR agents.

Conclusion

We discovered that in aggressive BCC variants, AR expression is low, whereas EGFR expression is highly upregulated. We also demonstrated that high expression of AR renders BCC to assume much less malignant potential and follow a benign clinical course. This and the reverse correlation between AR and EGFR expression convinced us that AR plays an inhibitory role over EGFR. Given these findings, there is a need to discover topical agents that activate AR and have less toxicity in the treatment of BCC, next to anti-EGFR agents. We hope this study encourages the investigators to perform further studies in this respect. Additionally, our study is also important since it is the first and only one investigating the morphological variants, AR, and EGFR interactions in cutaneous BCC.

Footnotes

Acknowledgments

We acknowledge and express our deep appreciation for the technical assistance provided by Sirma Sivrikoz in designing the figures.

ORCID iD

Oya Nermin Sivrikoz

Ethical considerations

Our study is a retrospective observational study. According to Article 2, subparagraph (2) of the Clinical Research Legislation of the Ministry of Health of the Republic of Turkey, it is outside the scope of ethical approval. Written informed consent forms were obtained from all patients.

Author contributions

ONS designed the study and made the initial interpretation of all the slides and special stains. She is the principal contributor to the authorship; THY is a surgeon, she was involved in obtaining tissue samples; IO is a second pathologist who independently reviewed all the slides; SMS, is a senior author, contributed to the design and interpretation of data, and did major auditing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/ or publication of this article.

Data availability statement

Data will be available from the authors upon reasonable request.

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