{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T13:02:44Z","timestamp":1776949364247,"version":"3.51.4"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Actinic keratoses (AKs) are considered early in situ forms of cutaneous squamous cell carcinoma (cSCC). However reliable histopathological or molecular markers for predicting the risk of progression are still lacking. The aim of this study was to investigate the relationship between immunohistochemical markers and basal proliferation patterns of AKs in order to identify histopathological associations that may be relevant for malignant transformation. Methods: A total of 97 AK samples from facial and scalp areas were retrospectively analyzed and classified according to their basal proliferation pattern (Pro I: non-proliferative and Pro III: proliferative). Immunohistochemical staining was performed for Ki-67, p53, p16 and podoplanin. In addition, histopathological parameters such as R\u00f6wert-Huber grade, inflammatory infiltrate, parakeratosis, elastosis and the presence of acantholysis were evaluated. Results: Pro III lesions were significantly more frequently associated with higher R\u00f6wert-Huber grades (AK III: 47.9% vs. 14.3%; p = 0.0004) and with acantholysis (p = 0.0004). No significant differences between the groups were found for Ki-67, p53 and p16. Podoplanin expression, however, was significantly higher in Pro III lesions (93.7% vs. 57.1%, p &lt; 0.0001) and was predominantly localized basally. The combination of a PRO III pattern and podoplanin positivity identified a distinct histopathological subgroup associated with features linked to progression. Conclusions: Podoplanin expression, especially in combination with PRO III pattern and acantholysis, characterizes a histologically and biologically distinct AK subgroup. In contrast, Ki-67, p53 and p16 showed no additional discriminative value in this cohort. Podoplanin could therefore be a useful addition to existing classification systems and in the future support risk-adapted treatment decision. However, prospective longitudinal studies are required to determine its prognostic value.<\/jats:p>","DOI":"10.3390\/cancers18091340","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:04:42Z","timestamp":1776945882000},"page":"1340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunohistological Characterization of Actinic Keratoses with Varying Degrees of Proliferation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8300-1268","authenticated-orcid":false,"given":"Vasileios","family":"Dervenis","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conrad","family":"Falkenberg","sequence":"additional","affiliation":[{"name":"CentroDerm Clinic, Heinz-Fangman-Stra\u00dfe 57, 42287 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Knebel","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN and REI (UniKiD), Medical Faculty and University Hospital Duesseldorf, Heinrich Heine University Duesseldorf, 40255 Duesseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9627-2179","authenticated-orcid":false,"given":"Lutz","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany"},{"name":"CentroDerm Clinic, Heinz-Fangman-Stra\u00dfe 57, 42287 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Dirschka","sequence":"additional","affiliation":[{"name":"CentroDerm Clinic, Heinz-Fangman-Stra\u00dfe 57, 42287 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"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":"1","DOI":"10.1159\/000366525","article-title":"Epidemiology of actinic keratoses","volume":"Volume 46","author":"Green","year":"2015","journal-title":"Current Problems in Dermatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1016\/j.jid.2017.04.020","article-title":"Incidence, Mortality, and Trends of Nonmelanoma Skin Cancer in Germany","volume":"137","author":"Leiter","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1056\/NEJMoa2024040","article-title":"Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis","volume":"384","author":"Blauvelt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1111\/jdv.14682","article-title":"Actinic keratosis area and severity index (AKASI) is associated with the incidence of squamous cell carcinoma","volume":"32","author":"Schmitz","year":"2018","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1067\/mjd.2000.103339","article-title":"The risk of progression to invasive disease","volume":"42","author":"Glogau","year":"2000","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/jdv.12848","article-title":"Actinic keratosis with atypical basal cells (AK I) is the most common lesion associated with invasive squamous cell carcinoma of the skin","volume":"29","author":"Carrato","year":"2015","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_9","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_10","first-page":"213","article-title":"Treatment-resistant actinic keratoses are characterized by distinct clinical and histological features","volume":"156","author":"Schmitz","year":"2021","journal-title":"Ital. J. Dermatol. Venerol."},{"key":"ref_11","first-page":"1591","article-title":"Expression of Podoplanin in Non-melanoma Skin Cancers and Actinic Keratosis","volume":"36","author":"Szepietowski","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_12","first-page":"138","article-title":"Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue","volume":"8","author":"Remmele","year":"1987","journal-title":"Pathologe"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/0190-9622(91)70113-G","article-title":"A double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck","volume":"24","author":"Olsen","year":"1991","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1111\/bjd.16536","article-title":"Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses","volume":"180","author":"Schmitz","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1097\/DAD.0000000000002499","article-title":"Acantholytic Nodular Basal Cell Carcinoma","volume":"45","author":"Kanitakis","year":"2023","journal-title":"Am. J. Dermatopathol."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","unstructured":"Elsbroek, L., Reuschlein, K., Karsai, S., Geueke, A., von Petersdorff-Campen, M., Bresch, M., Steinkraus, V., Weisenseel, P., Wolf, P., and Winnefeld, M. (2025). Primary keratinocyte model of actinic keratosis reveals UV-induced DNA damage accumulation and persistent IFN signaling. J. Investig. Dermatol., Online ahead of print.","DOI":"10.1016\/j.jid.2025.11.018"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Falkenberg, C., Dirschka, T., Gilbert, G., Stockfleth, E., Homey, B., and Schmitz, L. (2023). Basal Proliferation and Acantholysis May Represent Histological High-Risk Factors for Progression into Invasive Squamous Cell Carcinoma: A Comparison Study in Solid Organ Transplant Recipients and Matched Immunocompetent Patients. Cancers, 15.","DOI":"10.3390\/cancers15061765"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2024146S","DOI":"10.5826\/dpc.1403S1a146S","article-title":"Epidemiology and Risk Factors of Actinic Keratosis. What is New for The Management for Sun-Damaged Skin","volume":"14","author":"Thamm","year":"2024","journal-title":"Dermatol. Pract. Concept."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"929","DOI":"10.3923\/pjbs.2009.929.933","article-title":"Expression of P27, Ki67 and P53 in squamous cell carcinoma, actinic keratosis and Bowen disease","volume":"12","author":"Talghini","year":"2009","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_21","first-page":"691","article-title":"P53, p16 and Ki67 immunoexpression in cutaneous squamous cell carcinoma and its precursor lesions","volume":"57","author":"Marinescu","year":"2016","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/00000372-200402000-00004","article-title":"P27 and mib1 expression in actinic keratosis, Bowen disease, and squamous cell carcinoma","volume":"26","author":"Oh","year":"2004","journal-title":"Am. J. Dermatopathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1111\/j.1600-0560.1992.tb01366.x","article-title":"Mutant p53 expression in solar keratosis: An immunohistochemical study","volume":"19","author":"Sim","year":"1992","journal-title":"J. Cutan. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1159\/000018216","article-title":"Overexpression of p53 protein associated with proliferative activity and histological degree of malignancy in solar keratosis","volume":"199","author":"Shimizu","year":"1999","journal-title":"Dermatology"},{"key":"ref_25","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":"Neto","year":"2013","journal-title":"Indian J. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1097\/PAT.0b013e328360c064","article-title":"Immunohistochemical staining for p16 is a useful adjunctive test in the diagnosis of Bowen\u2019s disease","volume":"45","author":"Harvey","year":"2013","journal-title":"Pathology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1097\/01.MP.0000032536.48264.D1","article-title":"Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin","volume":"15","author":"Hodges","year":"2002","journal-title":"Mod. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1111\/exd.14344","article-title":"Podoplanin is required for tumor cell invasion in cutaneous squamous cell carcinoma","volume":"30","author":"Schwab","year":"2021","journal-title":"Exp. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1159\/000450920","article-title":"Characterisation of Prognosis and Invasion of Cutaneous Squamous Cell Carcinoma by Podoplanin and E-Cadherin Expression","volume":"232","author":"Hesse","year":"2016","journal-title":"Dermatology"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/9\/1340\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:12:44Z","timestamp":1776946364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/9\/1340"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cancers18091340"],"URL":"https:\/\/doi.org\/10.3390\/cancers18091340","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]}}}