{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:53:05Z","timestamp":1791564785427,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ESF","award":["8.2.2.0\/20\/I\/004"],"award-info":[{"award-number":["8.2.2.0\/20\/I\/004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Age and cumulative exposure to ultraviolet (UV) light are primary contributors to skin cancer development. Regulatory proteins within the cell cycle are essential for the homeostasis of squamous epithelium. Methods: This study assessed the expression of immunohistochemical markers p53, p63, p16, Ki67, Cyclin D, Bcl-2, and CD31 in keratinocyte intraepithelial neoplasia (actinic keratosis and squamous cell carcinoma in situ) compared to normal skin. The objective was to distinguish disease-specific changes from those attributable to ageing and sun exposure in elderly skin. Results. Analysis included 22 actinic keratoses (AK), 7 in situ squamous cell carcinomas (SCC), and 8 normal skin biopsies. The mean age was 78.1 years for the AK\/SCC group and 73.8 years for controls, with no significant age difference noted between the groups. The AK\/SCC group exhibited a higher occurrence of amorphous masses, higher intensity of p53, lower Bcl-2 expression in the epidermis, higher Bcl-2 expression in the dermis, and higher CD31 expression in the dermis, all of which were statistically significant (p &lt; 0.05). Conclusions: The study identifies distinct differences in the presence of amorphous masses and the expression levels of p53, Bcl-2, and CD31 between sun-exposed skin and in situ cutaneous squamous cell carcinomas, including actinic keratoses.<\/jats:p>","DOI":"10.3390\/jcm12237291","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T06:51:28Z","timestamp":1700808688000},"page":"7291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Expression of p53, p63, p16, Ki67, Cyclin D, Bcl-2, and CD31 Markers in Actinic Keratosis, In Situ Squamous Cell Carcinoma and Normal Sun-Exposed Skin of Elderly Patients"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4523-7629","authenticated-orcid":false,"given":"Alise","family":"Balcere","sequence":"first","affiliation":[{"name":"Department of Dermatology and Venereology, Riga Stradi\u0146\u0161 University, LV-1010 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u0101ris","family":"Sperga","sequence":"additional","affiliation":[{"name":"Department of Pathology of Infectious Diseases, Riga East University Hospital, LV-1006 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0937-6157","authenticated-orcid":false,"given":"Ingr\u012bda","family":"\u010c\u0113ma","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery and Oral Medicine, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gun\u0101rs","family":"Lauskis","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery and Oral Medicine, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9120-5869","authenticated-orcid":false,"given":"Maksims","family":"Zolovs","sequence":"additional","affiliation":[{"name":"Statistics Unit, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"},{"name":"Institute of Life Sciences and Technology, Daugavpils University, LV-5401 Daugavpils, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u0101ra","family":"Rone Kupfere","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Riga Stradi\u0146\u0161 University, LV-1010 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Kr\u016bmi\u0146a","sequence":"additional","affiliation":[{"name":"Department of Infectiology, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"ref_1","first-page":"1002","article-title":"Nonmelanoma Skin Cancer\u2014From Actinic Keratosis to Cutaneous Squamous Cell Carcinoma","volume":"16","author":"Schmitz","year":"2018","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1111\/jdv.15494","article-title":"Skin Diseases Are More Common than We Think: Screening Results of an Unreferred Population at the Munich Oktoberfest","volume":"33","author":"Tizek","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000491820","article-title":"Prevalence of Actinic Keratosis in Patients Attending General Practitioners in Switzerland","volume":"234","author":"Dziunycz","year":"2018","journal-title":"Dermatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1365-2133.2007.07860.x","article-title":"Actinic Keratosis Is an Early in Situ Squamous Cell Carcinoma: A Proposal for Reclassification","volume":"156","author":"Patel","year":"2007","journal-title":"Br. J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.abd.2019.10.004","article-title":"Actinic Keratoses: Review of Clinical, Dermoscopic, and Therapeutic Aspects","volume":"94","author":"Reinehr","year":"2019","journal-title":"Bras. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1038\/jid.2013.134","article-title":"Prevalence of Actinic Keratosis and Its Risk Factors in the General Population: The Rotterdam Study","volume":"133","author":"Flohil","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.jaad.2021.03.111","article-title":"Evaluation of Dermatoscopic Criteria for Early Detection of Squamous Cell Carcinoma Arising on an Actinic Keratosis","volume":"86","author":"Papageorgiou","year":"2022","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/jdv.14151","article-title":"From Actinic Keratosis to Squamous Cell Carcinoma: Pathophysiology Revisited","volume":"31","year":"2017","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_9","first-page":"103","article-title":"Histopathological Subtyping of Actinic Keratosis and It\u2019s Coexistence with Nonmelanotic Skin Cancers in Gaziantep and Malatya Regions","volume":"50","author":"Aydin","year":"2016","journal-title":"Turkderm\u2014Turk Arch Dermatol Venereol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1111\/jdv.14901","article-title":"The Depth of Follicular Extension in Actinic Keratosis Correlates with the Depth of Invasion in Squamous Cell Carcinoma: Implication for Clinical Treatment","volume":"32","author":"Vargas","year":"2018","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Moses, M.A., George, A.L., Sakakibara, N., Mahmood, K., Ponnamperuma, R.M., King, K.E., and Weinberg, W.C. (2019). Molecular Mechanisms of P63-Mediated Squamous Cancer Pathogenesis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143590"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1080\/14656566.2018.1523896","article-title":"Current Developments in Pharmacotherapy for Actinic Keratosis","volume":"19","author":"Campione","year":"2018","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s00403-020-02104-y","article-title":"P53 Staining Index and Zonal Staining Patterns in Actinic Keratoses","volume":"313","author":"Javor","year":"2021","journal-title":"Arch. Dermatol. Res."},{"key":"ref_14","first-page":"439","article-title":"Immunohistochemical Staining of P16 in Squamous Cell Carcinomas of the Genital and Extragenital Area","volume":"102","year":"2011","journal-title":"Actas Dermosifiliogr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1111\/bjd.18338","article-title":"The Clinical Course of Actinic Keratosis Correlates with Underlying Molecular Mechanisms","volume":"182","author":"Bakshi","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1038\/s41467-020-16475-3","article-title":"Chronic Expression of P16INK4a in the Epidermis Induces Wnt-Mediated Hyperplasia and Promotes Tumor Initiation","volume":"11","author":"Azazmeh","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"181","DOI":"10.4103\/0019-5154.110824","article-title":"Immunohistochemical Evaluation of P53 and Ki67 Expression in Skin Epithelial Tumors","volume":"58","author":"Khodaeiani","year":"2013","journal-title":"Indian J. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00403-010-1101-0","article-title":"The Role of KLF4 in UVB-Induced Murine Skin Tumor Development and Its Correlation with Cyclin D1, P53, and P21Waf1\/Cip1 in Epithelial Tumors of the Human Skin","volume":"303","author":"Choi","year":"2011","journal-title":"Arch. Dermatol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2012.01.031","article-title":"Bcl-2 Family Members: Essential Players in Skin Cancer","volume":"320","author":"Nys","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.4103\/0019-5154.113935","article-title":"Reduced P53 Staining in Actinic Keratosis Is Associated with Squamous Cell Carcinoma: A Preliminary Study","volume":"58","author":"Alchorne","year":"2013","journal-title":"Indian. J. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Piipponen, M., Riihil\u00e4, P., Nissinen, L., and K\u00e4h\u00e4ri, V.M. (2021). The Role of P53 in Progression of Cutaneous Squamous Cell Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13184507"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/j.1468-3083.2009.03337.x","article-title":"Expression of P53 and P16 in Actinic Keratosis, Bowenoid Actinic Keratosis and Bowen\u2019s Disease","volume":"24","author":"Bagazgoitia","year":"2010","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.prp.2009.01.010","article-title":"The Expression of P63 and P53 in Keratoacanthoma and Intraepidermal and Invasive Neoplasms of the Skin","volume":"205","author":"Sakiz","year":"2009","journal-title":"Pathol. Res. Pract."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Smirnov, A., Anemona, L., Novelli, F., Piro, C.M., Annicchiarico-Petruzzelli, M., Melino, G., and Candi, E. (2019). P63 Is a Promising Marker in the Diagnosis of Unusual Skin Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225781"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.1016\/j.tripleo.2006.09.011","article-title":"Cyclin D1 Expression in Oral Squamous Cell Carcinoma and Verrucous Carcinoma: Correlation with Histological Differentiation","volume":"103","author":"Angadi","year":"2007","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1111\/cup.12623","article-title":"Expression of G1\/S-Cyclins and Cyclin-Dependent Kinase Inhibitors in Actinic Keratosis and Squamous Cell Carcinoma","volume":"43","author":"Brasanac","year":"2016","journal-title":"J. Cutan. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"De Wispelaere, N., Rico, S.D., Bauer, M., Luebke, A.M., Kluth, M., B\u00fcscheck, F., Hube-Magg, C., H\u00f6flmayer, D., Gorbokon, N., and Weidemann, S. (2022). High Prevalence of P16 Staining in Malignant Tumors. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0262877"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/jdv.14514","article-title":"Epithelial-to-mesenchymal transition contributes to invasion in squamous cell carcinomas originated from actinic keratosis through the differentiated pathway, whereas proliferation plays a more significant role in the classical pathway","volume":"32","author":"Carrato","year":"2018","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.ad.2022.05.012","article-title":"Expression Profile of CD10, BCL-2, P63, and EMA in the Normal Skin and Basal Cell Carcinomas: An Immunohistochemical Reappraisal","volume":"113","author":"Hussein","year":"2022","journal-title":"Actas Dermosifiliogr."},{"key":"ref_30","first-page":"343","article-title":"Assessment of BCL-2 Expression in Actinic Keratosis, Keratoacanthoma and Seborrheic Keratosis Cases","volume":"26","author":"Onder","year":"2019","journal-title":"Ann. Med. Res."},{"key":"ref_31","unstructured":"Abreu-Velez, A.M., Brown, V.M., and Howard, M.S. (2016). Advances in Dermatology Research, Nova Science."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/jdv.16680","article-title":"Histopathological Predictor of the Progression from Actinic Keratosis to Squamous Cell Carcinoma: Quantitative Computer-Aided Image Analysis","volume":"35","author":"Lee","year":"2021","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_33","unstructured":"Stuart, L.N. (2023, August 01). Stains & CD Markers CD31. Available online: https:\/\/www.pathologyoutlines.com\/topic\/cdmarkerscd31.html."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Daneluzzi, C., Seyed Jafari, S.M., Hunger, R., and Bossart, S. (2022). The Immunohistochemical Assessment of Neoangiogenesis Factors in Squamous Cell Carcinomas and Their Precursors in the Skin. J. Clin. Med., 11.","DOI":"10.3390\/jcm11154494"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.2340\/00015555-2710","article-title":"A Novel Actinic Keratosis Field Assessment Scale for Grading Actinic Keratosis Disease Severity","volume":"97","author":"Cerio","year":"2017","journal-title":"Acta Derm. Venereol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/jdv.14512","article-title":"Actinic Keratoses Show Variable Histological Basal Growth Patterns\u2014A Proposed Classification Adjustment","volume":"32","author":"Schmitz","year":"2018","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1093\/aje\/kwj137","article-title":"Expression of P53 Tumor Suppressor Protein in Sun-Exposed Skin and Associations with Sunscreen Use and Time Spent Outdoors: A Community-Based Study","volume":"163","author":"Xu","year":"2006","journal-title":"Am. J. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1001\/jamadermatol.2016.4070","article-title":"Anatomical Distributions of Basal Cell Carcinoma and Squamous Cell Carcinoma in a Population-Based Study in Queensland, Australia","volume":"153","author":"Subramaniam","year":"2017","journal-title":"JAMA Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e14817","DOI":"10.1111\/dth.14817","article-title":"The Diagnostic Value of P63, P16, and P53 Immunohistochemistry in Distinguishing Seborrheic Keratosis, Actinic Keratosis, and Bowen\u2019s Disease","volume":"34","author":"Nasiri","year":"2021","journal-title":"Dermatol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/bjd.14970","article-title":"Photodynamic Therapy Using Intense Pulsed Light for Treating Actinic Keratoses and Photoaged Skin of the Dorsal Hands: A Randomized Placebo-Controlled Study","volume":"176","author":"Kohl","year":"2017","journal-title":"Br. J. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1001\/jamadermatol.2021.0372","article-title":"Ten-Year Follow-up of Persons with Sun-Damaged Skin Associated with Subsequent Development of Cutaneous Squamous Cell Carcinoma","volume":"157","author":"Madani","year":"2021","journal-title":"JAMA Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/jemt.23043","article-title":"Correlations between Histopathologic and Dermoscopic Findings in Korean Actinic Keratosis","volume":"82","author":"Lee","year":"2019","journal-title":"Microsc. Res. Tech."},{"key":"ref_43","unstructured":"(2023, May 07). Central Statistical Bureau of Latvia Life Expectancy in Latvia in 2021, Available online: https:\/\/stat.gov.lv\/en\/statistics-themes\/population\/population\/5661-life-expectancy."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1093\/aje\/kwk055","article-title":"Measures of Cumulative Exposure from a Standardized Sun Exposure History Questionnaire: A Comparison with Histologic Assessment of Solar Skin Damage","volume":"165","author":"Karagas","year":"2007","journal-title":"Am. J. Epidemiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.ad.2010.01.008","article-title":"Solar Elastosis in Cutaneous Squamous Cell Carcinoma","volume":"101","author":"Brufau","year":"2010","journal-title":"Actas Dermosifiliogr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1046\/j.1365-2133.2002.04720.x","article-title":"Inflammation Is Associated with Progression of Actinic Keratoses to Squamous Cell Carcinomas in Humans","volume":"146","author":"Berhane","year":"2002","journal-title":"Br. J. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.ajpath.2019.10.019","article-title":"P53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling","volume":"190","author":"Piipponen","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1111\/exd.13349","article-title":"Analysis of Apoptosis-Associated Molecules Erythroid Differentiation Regulator 1, Bcl-2 and P53 in Actinic Keratosis after Treatment with Ingenol Mebutate","volume":"26","author":"Woo","year":"2017","journal-title":"Exp. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"121","DOI":"10.4103\/aam.aam_56_18","article-title":"Inflammation and Cancer","volume":"18","author":"Singh","year":"2019","journal-title":"Ann. Afr. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"45825","DOI":"10.18632\/oncotarget.17573","article-title":"Tumor Cell-Specific AIM2 Regulates Growth and Invasion of Cutaneous Squamous Cell Carcinoma","volume":"8","author":"Farshchian","year":"2017","journal-title":"Oncotarget"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/23\/7291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:29:22Z","timestamp":1760131762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/23\/7291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,24]]},"references-count":50,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["jcm12237291"],"URL":"https:\/\/doi.org\/10.3390\/jcm12237291","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,24]]}}}