Introduction
Actinic keratosis (AK) is a common intraepidermal dysplasia with potential for progression to cutaneous squamous cell carcinoma (cSCC). The condition affects about 25% of adults, with prevalence rising from 4.6% in those aged 60–69 to 14.57% in individuals over 80 [1]. Clinically, AK presents with hyperkeratosis and erythema, primarily on chronically sun-exposed areas, with ultraviolet (UV) radiation being the key etiological factor [2, 3]. The annual risk of AK evolving into invasive squamous cell carcinoma (iSCC) ranges from 0.025% to 16% [4]. Features such as induration, bleeding, pain, and increased lesion size suggest malignant transformation [5]. AK is also linked to field cancerization (FC), a phenomenon characterized by genetically altered subclinical changes surrounding visible lesions, predisposing to malignancy [6]. Molecular studies implicate oncogenic and tumor suppressor gene dysregulation in AK and non-melanoma skin cancers (NMSCs). Increasing attention has been directed toward signal transduction pathways involved in AK pathogenesis. This review explores key proliferation markers (Ki-67, p53, matrix metalloproteinases [MMPs]) and inflammation markers (cyclooxygenase-2 [COX-2], minichromosome maintenance protein 2 [MCM2]) in AK. Particular attention is given to their potential utility in moni-toring AK treatment, particularly with photodynamic therapy (PDT). A summary of the relevant studies is provided in Table 1.
Table 1
Summary of results of studies on markers of proliferation and inflammation in actinic keratosis, including in the context of photodynamic therapy, available in the literature and mentioned in our review article. Results shown are from studies considered important in terms of actinic keratoses
| Marker | Study | Study group | Treatment modalities in the study | Results |
|---|---|---|---|---|
| Ki-67 | Khoadeini et al., 2013 [8] | cSCCs (n = 10); BCCs (n = 30); KAs (n = 8); TEs (n = 2) | No | Ki-67 immunoexpression: BCCs 57.3%, SCCs 47.7%, KAs 37.5%, TEs 0%. All BCC, SCC, KA samples Ki-67-positive; TE negative. |
| Miola et al., 2019 [9] | AKs (n = 38) | No | Significant difference in p53 and Ki-67 immunoexpression between photo-protected and exposed skin (p < 0.05). Ki-67 immunoexpression correlated with KIN and sun exposure. | |
| Xu et al., 2021 [10] | AKs (n = 30); cSCCs (n = 30); BD (n = 30); normal skin/control group (n = 30) | No | Ki-67-positive cells in 60% of AKs. Higher in AK than controls. Ki-67 positivity rate in cSCC was higher than in AK (χ2 = 9.32, p < 0.01). It correlated with mTOR in cSCC, BD, and AK. | |
| Campione et al., 2022 [11] | AKs (n = 30) | Yes: 0.8% piroxicam cream (n = 10), PDT (n = 10), and ingenol mebutate gel (n = 10) | Ki-67 immunoexpression significantly decreased after treatment with all three modalities (ANOVA, p < 0.01). | |
| Gellen et al., 2019 [12] | AKs (n = 11) – 11 patients with multiple (at least 15) AKs on the scalp, face, hands, or forearms | Yes: c-5ALA-PDT and Er:YAG laser-assisted 5ALA-PDT in a split-site manner | The number of Ki-67-positive cells decreased at 48 h (p = 0.002) and 3 months (p = 0.009) after Er:YAG-5ALA-PDT. The post-c-5ALA-PDT decrease was not significant. The number of p53- and Ki-67-positive cells significantly decreased 3 months after treatment; however, abnormal cells were not entirely eradicated. | |
| Abdalla et al., 2022 [13] | AKs (n = 29) | Yes: dl-PDT | The number of Ki-67-positive cells decreased or remained unchanged after dl-PDT (AK lesions and FC). | |
| Bagazgoitia et al., 2011 [14] | AKs (n = 22) | Yes: MAL-cPDT | Ki-67 immunopositivity overexpressed in 91% AKs. Decreased in 77% after treatment (p < 0.0001) and returned to levels comparable to control skin. | |
| p53 | Page et al., 2017 [17] | Transgenic mice models | No | p53 immunoexpression absence in stratified epithelia → higher tumor incidence, growth, malignancy. Moreover, mice with epidermal p53 loss exhibit greater histological diversity in tumor types. Tumor suppression role confirmed. |
| Miola et al., 2019 [14] | AKs (n = 38) | No | See Ki-67 results section. | |
| Bakshi et al., 2020 [18] | AKs (n = 26); 26 subjects with multiple AKs (610 AKs in total) | No | p53 immunoexpression higher in AKs than regressed AKs (p < 0.01). Moreover, higher in sun-exposed skin. | |
| Javor et al., 2020 [19] | AKs (n = 43) | No | p53-immunopositive cells > 50% in 90.7% of AKs. Higher in older patients (p = 0.0093) and facial AKs (p = 0.03). A significant correlation between the p53 staining index and the grade of dysplasia (p = 0.006). | |
| Balcere et al., 2023 [20] | AKs (n = 22); SCCIS (n = 7): AK/ SCCIS in total (n = 29); normal skin/control group (n = 8) | No | p53 immunoexpression increased with cumulative sun exposure and aging, decreased with sunscreen. | |
| p53 | Hua et al., 2019 [21] | In vivo – mice (n = 30) | Yes: ALA-PDT and then exposed to UVB light (ALA-PDT-UVB group; n = 10), exposed to UVB alone (UVB group; n = 10) and untreated/control group; (n=10) | At 48 hours after UVB irradiation, Ki-67 immunoexpression lower in ALA-PDT-UVB vs. UVB group (p < 0.05). |
| In vitro – human keratinocyte cell line (HaCaT) cells | Yes: one treated with ALA-PDT, the other untreated (control group) – both exposed to UVB light | Higher p53 immunoexpression in UVB-irradiated groups (p < 0.05). Increased p53 in ALA-PDT-treated samples vs. untreated (p < 0.05). | ||
| Abdalla et al., 2022 [13] | AKs (n = 29) | Yes: dl-PDT | p53 immunoexpression remained positive in 92.86% of AKs, decreased in 7.14% (p = 0.03) after treatment. In FC: p53 immunoexpression decreased in 25% of AKs after dl-PDT. | |
| Gellen et al., 2019 [17] | AKs (n = 11) – 11 patients with multiple (at least 15) AKs on the scalp, face, hands, or forearms | Yes: c-5ALA-PDT and Er:YAG laser-assisted 5ALA-PDT in a split-site manner | p53-immunopositivity decreased at 48 h and remained lower at 3 months following both Er:YAG-5ALA-PDT and c-5ALA-PDT (p < 0.001). Additionally, the number of p53- and Ki-67-positive cells significantly declined 3 months after treatment, though abnormal cells were not entirely eliminated. | |
| Bagazgoitia et al., 2011 [19] | AKs (n = 22) | Yes: MAL-cPDT | p53 immunoexpression decreased in 50% of cases (p < 0.002) after treatment. Complete loss of p53 immunoexpression, which is typically absent in healthy skin, was observed in 5.0% of AKs. | |
| Matrix metalloproteinases (MMPs) | Hernandez-Perez et al., 2012 [32] | AKs (n = 24); SCCIS (n = 27); SCCWD (n = 28); SCCMPD (n = 20) | No | Mean MMP-2 immunoexpression: AK 3.33, SCCIS 4.07 (tumoral); AK 1.42, SCCIS 3.26 (stromal, p < 0.05). MMP-9: AK 4.33, SCCIS 4.11 (tumoral); AK 4.29, SCCIS 4.41 (stromal, NS). MMP-14 immunoexpression higher in SCCIS vs. AK (tumoral: 2.41 vs. 1.58, p < 0.05). Stromal MMP-2 immunoexpression higher in SCCIS and SCCWD/SCCMPD vs. AK (p < 0.05). MMP-14 immunoexpression correlated with invasion. Elevated stromal MMP-2 immunoexpression linked to progression. |
| Lee et al., 2013 [33] | In vivo: UVB-induced cSCC in mice: UVB-irradiated group (n = 10); and the UVB-non-irradiated/control group (n = 6) | No | MMP-2 and MMP-9 immunoexpression higher in SCC vs. controls. Upregulated mRNA expression levels for MMP-2 and MMP-9, with a significant increase in MMP-9 expression in UVB-induced SCCs. | |
| In vivo: cSCCs (n = 4); and normal skin/control group (n = 4) | No | MMP-2 and MMP-9 levels upregulated in SCCWD tumor extracts vs. adjacent normal skin in humans. | ||
| Poswar et al., 2014 [35] | AKs (n = 13); SCC (n = 12); BCC (n = 29) | No | Higher MMP-2 immunoexpression in AK stroma vs. BCC (p = 0.039). Correlated with dysplasia severity. | |
| Campione et al., 2022 [11] | AKs (n = 30) | Yes: 0.8% piroxicam cream (n = 10), PDT (n = 10), and ingenol mebutate gel (n = 10) | MMP-1 and MMP-2 immunoexpression decreased after treatment (p < 0.01). Decrease in MMP expression observed in both the epidermis and dermis (comparable across all three treatment modalities). MMP-1 and MMP-2 expression correlated positively with severe solar elastosis and a high histopathological grade of AK. | |
| Cyclooxygenase type 2 (COX-2) | Kim et al., 2006 [43] | AKs (n = 10); SCC (n = 10); BCC (n = 10); BD (n = 10); porokeratosis (n = 10) | No | COX-2 immunoexpression in 50% of AKs. No correlation with p53 immunoexpression. |
| Wu et al., 2007 [44] | AKs (n = 11); cSCC (n = 17); BD (n = 19); SK (n = 12); Normal skin/control group (n = 13) | No | COX-2 immunoexpression higher in AK than SK (p < 0.01), but no correlation between AK and SK (p > 0.05). | |
| Amirnia et al., 2014 [45] | AKs (n = 4); cSCC (n = 17); BCC (n = 32); BD (n = 9) | No | COX-2 immunoexpression in 100% of AKs with an intensity score of 4+. Higher COX-2 immunoexpression in AK vs. normal skin (p < 0.023). | |
| Athanassiadou et al., 2013 [46] | AKs (n = 43); SCC (n = 38); SCC arising on AK (SCC/AK) (n = 9) | No | Weak/no COX-2 immunostaining in 58.1% of AKs. Strong/moderate in 39.5%/34.2% SCCs, respectively. “Mixed” SCC/AK: 88.9% of moderate COX-2 immunostaining (p < 0.0001). | |
| Adamska et al., 2018 [47] | AKs (n = 94) | No | No significant difference in COX-2-positive cells between KIN1 and KIN2 (p = 0.4848). | |
| Lee et al., 2013 [33] | In vivo: UVB-induced cSCC in mice: UVB-irradiated group (n = 10); and UVB-non-irradiated/ control group (n = 6) | No | COX-2 immunoexpression detected in 9/10 UVB-induced SCCs, absent in normal skin. mRNA and protein levels of COX-2 upregulated in mouse and human SCCs after chronic UVB exposure. | |
| In vivo: cSCCs (n = 4); and normal skin/control group (n = 4) | No | COX-2 immunoexpression upregulated in 100% SCC samples vs. control group. | ||
| Minichromosome maintenance protein 2 (MCM2) | Stojkovic-Filipovic et al., 2016 [46] | AKs (n = 91); SCC (n = 174); BD (n = 50) | No | Basal expression of MCM2, MCM5, and MCM7 more frequent in AK. Diffuse distribution and higher positivity in BD vs. AK (p < 0.001), KIN3 vs. KIN1/KIN2, and SCCPD vs. SCCWD. |
| Shin et al., 2010 [57] | AKs (n = 34) | No | MCM2 immunoexpression increased with AK grade (p = 0.000). Significant differences between grades I, II, III (p < 0.05). | |
| Rymsza et al., 2022 [58] | AKs (n = 22); cSCC (n = 57); Normal skin (control group, n = 17) | No | MCM2 immunoexpression higher in cSCC, AK vs. controls (p = 0.01). Correlated with Ki-67 (p = 0.01) and p53 immunoexpression (p = 0.04) in AK. No correlation observed in cSCC. |
[i] AKs – actinic keratoses, BCCs – basal cell carcinomas, cSCCs – cutaneous squamous cell carcinomas, KAs – keratoacanthomas, TEs – trichoepitheliomas, KIN – keratinocyte intraepidermal neoplasia, BD – Bowen disease, PDT – photodynamic therapy, c-5ALA-PDT – conventional 5-aminolevulinic acid PDT, 5ALA-PDT – Er:YAG laser-assisted 5-aminolevulinic acid PDT, dl-PDT – daylight PDT, FC – field cancerization, MAL-cPDT – methyl aminolevulinic acid-cPDT, SCCIS – SCC in situ, SCCWD – SCC well differentiated, SCCMPD – SCC moderately to poorly differentiated, SCCPD – SCC poorly differentiated, SK – seborrheic keratosis
Ki-67
Ki-67 is a key proliferation marker essential for DNA replication, expressed in all cell cycle phases except G0. It is normally found in the basal epidermal layer and is strongly linked to tumor growth. Its increased expression in sun-damaged skin and FC indicates a high proliferative capacity in AK [7].
Studies confirm elevated Ki-67 immunoexpression in AK lesions. Kho-adeini et al. [8] reported widespread Ki-67 and p53 immunopositivity in malignant epithelial tumors, including SCCs and basal cell carcinomas (BCCs). Miola et al. [9] found significantly higher (p < 0.05) Ki-67 immunoexpression levels in AK and FC than in photoprotected skin, correlating with keratinocyte intraepidermal neoplasia (KIN) and sun exposure. It suggests that they are strong candidates for characterizing FC. Xu et al. [10] found that Ki-67 was more highly immunoexpressed in AK than in controls (p < 0.01) and was correlated with mTOR (rapamycin) pathway activation – associated with tumor proliferation in cSCC, Bowen disease (BD) and AK.
Furthermore, Ki-67 was analyzed as a therapeutic marker as well. Ki-67 immunoexpression declines following AK treatment, supporting its role as a biomarker of therapeutic response. Firstly, Campione et al. [11] observed a significant Ki-67 immunoexpression reduction after AK treatment with piroxicam, PDT, and ingenol mebutate gel, further supporting the efficacy of these therapies. Then, Gellen et al. [12] reported a marked decrease in Ki-67 and p53 immunoexpression levels three months after PDT. The study protocol consisted of conventional 5-aminolevulinic acid PDT (c-5ALA-PDT) and Er:YAG laser-assisted 5-aminolevulinic acid PDT (5ALA-PDT) as a pretreatment in a split-site manner. However, abnormal cells persisted, suggesting incomplete lesion clearance. Abdalla et al. [13] found that daylight PDT (dl-PDT) reduced or stabilized Ki-67 immunoexpression, but persistent immunoexpression may indicate higher recurrence risk. Their findings suggest that multiple treatments may be necessary for complete lesion clearance. Bagazgoitia et al. [14] observed Ki-67 overexpression in 91% of AKs, which declined in 77% of cases after conventional PDT with methyl aminolevulinic acid (MAL-cPDT) (p < 0.0001), suggesting selective targeting of highly proliferative cells. In this study, PDT reduced the number of Ki-67-immunopositive cells, and therefore induced a reduction in the proliferative activity of the epidermis. This could be due to nonselective damage of the lesional area, secondary to the higher penetration of the photosensitizer through defects in the stratum corneum present in AKs. Additionally, selective destruction of cells with a higher proliferative rate is also likely.
These reports suggest that Ki-67 could be considered a marker of complete clearance of AK lesions as a result of therapy, including PDT. Additionally, we might be able to implement some widely available methods not only in research but also in clinical practice.
p53
p53 regulates DNA repair and apoptosis, with its mutations being the most common genetic alterations in human neoplasms. While absent in healthy skin, p53 is immunoexpressed in sun-exposed skin, AKs (26–50%), and SCCs (12–64%) [15]. UV-induced TP53 mutations are a crucial event in AK and cSCC development, leading to keratinocyte resistance to apoptosis [16].
Several studies have highlighted the role of p53 in the progression of AK to SCC. Page et al. [17] reported that TP53 loss accelerates tumor growth and malignancy in mouse models, reinforcing its tumor suppressor function in different epidermal cell types. Subsequently, Miola et al. [9] confirmed higher p53 and Ki-67 immunoexpression levels in AK and FC compared to photoprotected skin (p < 0.05). Bakshi et al. [18] observed a progressive (after 3, 6, 9, and 11 months) increase in p53 immunoexpression from sun-damaged skin to AK and SCC, supporting its role as a biomarker of AK progression. Their analysis found significantly increased p53 immunoexpression in AK, BCC, SCC, and sun-exposed skin samples compared to non- sun-exposed and regressed AKs. These findings suggest that p53 may be a good biomarker of AK progression. Similarly, Javor et al. [19] found p53 immunostaining intensity correlated with dysplasia severity (p = 0.006) and cumulative lifetime UV exposure (p < 0.0093) in AK (samples collected from facial, lower and upper limbs, trunk, and scalp areas). Balcere et al. [20] reported higher p53 immunoexpression levels in AK/SCC lesions, associating its expression with aging and sun exposure (p < 0.05), while sunscreen use reduced p53 immunostaining. Essentially, progression from AK to SCC is associated with increased p53 immunostaining. The p53 immunoexpression changes following AK treatment, yet its post-therapy persistence suggests incomplete lesion clearance. Hua et al. [21] found that ALA-PDT activated p53 and reduced UVB- induced apoptosis in both mice and human keratinocytes, demonstrating a protective DNA damage response. Abdalla et al. [13] reported that after dl-PDT, p53 immunoexpression remained positive in 92.86% of AK lesions (p = 0.03) and the majority (75%) of skin samples from FC maintained positive. This indicates that PDT does not reverse existing mutations. Similar findings were observed for FC – the majority (75%) of skin samples from FC remained immunopositive. Gellen et al. [12] observed a significant p53 immunoexpression reduction three months after c-5ALA-PDT and Er:YAG-laser-assisted 5ALA-PDT, but abnormal cells persisted, reinforcing the need for multiple treatments. Bagazgoitia et al. [14] found that p53 immunoexpression decreased in 50% of AKs after PDT (p < 0.002), with only 5% showing complete p53 loss, suggesting that single-session PDT may be insufficient for eliminating actinic damage. Based on their findings, it seems reasonable to recommend at least two treatments. The minimal number of treatments necessary to clear carcinogenic changes completely has not yet been established.
p53 is a valuable marker of proliferation and progression in AK but may be less reliable for monitoring treatment efficacy than Ki-67, as its expression often persists after therapy. These findings suggest that multiple PDT sessions may be necessary for complete lesion clearance.
Matrix metalloproteinases
Alterations in the tumor microenvironment, including basement membrane (BM) and extracellular matrix (ECM) remodeling, inflammatory infiltration, and microbial interactions, contribute to cSCC progression [22, 23]. Notably, collagens XV and XVIII, absent in early AK, reappear in advanced cSCC, indicating tumor-driven matrix reorganization [22]. MMPs, a family of zinc-dependent proteases, play a crucial role in BM degradation, ECM remodeling, and tumor invasion. Secreted by tumor cells, stromal fibroblasts, and inflammatory cells, MMPs facilitate growth factor activation, inflammation, and metastasis [24, 25]. Studies in knockout mice demonstrate that MMP-2, -7, and -9 contribute to tumor progression, while MMP-1 overexpression enhances carcinogenesis [26–30]. Among MMPs, MMP-2 and -9, which degrade collagen IV, have been widely stu-died in SCC, though their role remains controversial [31].
Firstly, Hernandez-Perez et al. [32] confirmed MMP-2, -9, and -14 overimmunoexpression in AK, with MMP-14 immunoexpression levels decreasing with invasion, suggesting its prognostic potential. Then Lee et al. [33] demonstrated UVB-induced MMP-2 and -9 upregulation in both mouse and human SCCs, linking MMP activity to inflammation-driven tumorigenesis. Moreover, evidence from recent studies suggests that dense inflammatory infiltrate is more associated with well- or moderately differentiated SCC than poorly differentiated SCC, which suggests that the degree of inflammation is related to the differentiation status in cSCC [34]. Poswar et al. [35] found higher MMP-2 immunoexpression in AK than in BCC (p = 0.039) but no significant difference between AK and SCC in both the stroma and parenchyma. Increased MMP-2 immunoexpression levels in high-grade AK suggest its early role in malignant transformation, highlighting MMP-2 as a potential therapeutic target. Campione et al. [16] reported a significant reduction in MMP-1 and -2 immunoexpression after treatment with piroxicam, PDT, and ingenol mebutate gel, supporting their role as biomarkers of treatment efficacy.
To sum up, MMPs, particularly MMP-1 and MMP-2, may serve as promising markers of AK treatment response, while MMP-14 shows potential as a prognostic indicator of malignant transformation. Ultimately, further research is needed to establish their role in PDT monitoring and therapeutic targeting.
Cyclooxygenase type 2
Inflammation is an important feature of the progression of AK and cSCC, driven by UV-induced epidermal damage, immunosuppression, and alterations in T-cell subsets [36]. Organ transplant recipients (OTRs) who receive immunosuppressive therapy face a nearly 250-fold increased risk of cSCC, underscoring the role of immune dysregulation in carcinogenesis [37]. There is substantial evidence from experiments in animal models and epidemiologic studies that cyclooxygenases are intimately involved in the promotion and progression stages of NMSCs, making them excellent potential targets for the prevention of NMSCs [38]. There are two major cyclooxygenase isoforms: COX-1 and COX-2. COX-2, an inducible enzyme absent in normal tissues, is upregulated by UV radiation and contributes to angiogenesis, apoptosis inhibition, tumor proliferation, and immunosuppression [38, 39]. Elevated COX-2 expression has been documented in colorectal, esophageal, gastric, and breast cancers, as well as in skin malignancies [40]. UV-induced COX-2 increases prostaglandin E2 (PGE2) production, promoting tumor cell proliferation, immune evasion, and SCC invasion. Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly diclofenac, are already widely used to target COX-2 in AK treatment.
Epidemiological studies on a substantial cohort confirmed that regular NSAID use reduces AK and SCC incidence statistically significantly, particularly with long-term exposure (> 7 years) [41, 42].
Kim et al. [43] reported COX-2 overimmunoexpression in AK, SCC, BCC, and BD, though its correlation with p53 was not statistically significant (p > 0.05). Similarly, Wu et al. [44] and Amirnia et al. [45] confirmed higher COX-2 immunoexpression levels in AK, SCC, and BD, suggesting its potential as a therapeutic target [44, 45]. Moreover, in the study of Wu et al. [44], COX-2 immunoexpression was positively correlated with high p63 immunoexpression in malignant skin tumors. Then, Athanssiadou et al. [46] found weak or absent COX-2 immunoexpression in 58.10% of AKs, whereas moderate-to-strong staining was observed in SCCs (34.2 and 39.5%, respectively) and mixed SCC/AK cases (88.9%) (p < 0.0001). A Polish study detected no significant correlation between COX-2 immunoexpression and AK stage (a substantial group of 94 AK samples), suggesting that COX-2 immunoexpression levels are independent of age, sex, or skin phenotype. Despite slightly higher levels of COX-2 immunoexpression in KIN2 (lesions with keratinocytic atypia in the lower two-thirds of the epidermis) AK lesions compared to KIN1 (lesions with keratinocytic atypia in the lower one-third of the epidermis) (with no expression in KIN3, lesions with full-thickness keratinocytic atypia involving the entire epidermis), no statistically significant correlations between the intensity of COX-2 reaction and AK stage were found [47]. Finally, Lee et al. [33] found that UVB-induced SCCs exhibited COX-2 upregulation, absent in normal control skin.
In summary, COX-2 immunoexpression is elevated in AK and SCC, though findings on its significance remain inconsistent. While NSAIDs show potential in reducing AK risk, further research on a more representative group is needed. To the best of our knowledge, there are no reports investigating changes in COX-2 expression in the context of various AK treatments, including with PDT.
Minichromosome maintenance protein 2
Minichromosome maintenance proteins (MCM) regulate DNA replication and cell-cycle progression, with MCM 2–7 essential for initiation and inhibition of DNA replication and elongation. Expressed in dividing cells but absent in quiescent cells, they serve as proliferation markers [48]. MCM dysregulation has been linked to various cancers, including breast, lung, prostate, and oral SCC, as well as dermatological conditions such as malignant melanoma (MM), Merkel cell carcinoma, BCC and T-cell lymphopro-liferative skin disorders [49–54].
Despite its relevance, few studies from PubMed have explored MCM2 in AK. To start with, Stojkovic-Filipovic et al. [55] analyzed MCM2, MCM5, and MCM7 immunoexpression in AK (n = 91), BD (n = 50), and SCC (n = 174). MCM2 immunoexpression levels increased with dysplasia severity, suggesting a role in the progression of both in situ and iSCC [55]. Furthermore, Shin et al. [56] reported higher MCM2 immunoexpression in more atypical AKs, aligning with Stojkovic-Filipovic’s findings. Ultimately, Rymsza et al. [57] found MCM2 overimmunoexpression in AK and SCC (p = 0.01), correlating with Ki-67 and p53 immuno-expression in AK (p = 0.01, p = 0.04, respectively). However, these correlations were not observed in SCC, limiting MCM2’s utility as a proliferation marker in cSCC.
To sum up, MCM2 shows diagnostic potential in AK, correlating with lesion severity and proliferation markers. However, its role in SCC progression remains unclear, requiring further validation in larger cohorts.
Conclusions
AK is a precancerous skin condition with potential progression to squamous cell carcinoma (cSCC). This brief review does not exhaust the complex topic of potential markers of proliferation and inflammation in AK. Key molecular markers, including Ki-67, p53, MMPs, COX-2, and MCM2, play crucial roles in AK pathogenesis, progression, and treatment response. Ki-67 and MMPs indicate proli-feration and therapeutic efficacy, while p53 highlights malignant transformation but often persists after treatment. COX-2 is linked to inflammation, but its clinical relevance remains uncertain. MCM2 correlates with AK severity but requires further validation. These biomarkers offer valuable insights for diagnosis and therapy, with potential integration into clinical practice for improved AK management.
