Dermatovenereology
doi: 10.25005/2074-0581-2023-25-4-541-552
CURRENT VIEWS ON THE PATHOGENESIS AND EARLY DIAGNOSIS OF ACTINIC KERATOSIS

A.A. SYDIKOV1, G.B. PYAGAY2 ,, O.G. PYAGAY3

1Fergana Medical Institute of Public Health, Fergana, Republic of Uzbekistan
2Tashkent State Dental Institute, Tashkent, Republic of Uzbekistan
3Dermatology and Venereology Dispensary № 9, St. Petersburg, Russian Federation

Methods: The article provides an overview of the epidemiology and pathogenesis of actinic keratosis (AK) and its clinical differentiation from cutaneous squamous cell carcinoma (SCC). The authors present varying perspectives on the prognosis of the disease's development and its pathogenetic link to SCC, highlighting the significance of early diagnosis of the malignant transformation. Researchers suggest several markers, such as p16, p53, and p63, to identify the malignant transition in its early stages. The authors support their hypothesis by offering that mutations in genes that express these proteins directly impact the progression of the disease. Another group of authors, recognizing the significant role of inflammation in the pathogenesis of AK, suggest determining the level of various cytokines, emphasizing the essential role of UV radiation in triggering the entire pathogenetic cascade of AK development. Meanwhile, most authors acknowledge that various proteins act as early immunohistochemical (IHC) markers of an unfavorable disease prognosis. They describe the pathogenetic mechanisms of the effect of markers such as p16, p53, p63, and Bcl-2. Research is underway to identify new markers, such as claudin and T-cadherin. In August 2023, a search was conducted on the PubMed Clinical Queries database using keywords such as "actinic keratosis", "pathogenesis of actinic keratosis", and "progression of actinic keratosis to squamous cell carcinoma" to look for early markers of malignancy. The search strategy included clinical trials, observational studies, case reports, and literature reviews published in the last decade. However, sources without peer review, such as educational and methodological guidelines, recommendations, and conference proceedings, were excluded. The information obtained through this search was used to compile this article, and promising directions for the search for early malignancy markers were identified.

Keywords: Actinic keratosis, pathogenesis, clinical forms, early diagnostic markers, progression, squamous cell carcinoma, precancerous skin diseases.

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References
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7-30. https://doi.org/10.3322/caac.21590
  2. Khlebnikova AN, Obydenova KV, Sedova TG, Andryukhina VV. Diagnostika aktinicheskogo keratoza metodom dermatoskopii [Diagnosis of actinic keratosis by dermatoscopy]. Vestnik dermatologii i venerologii. 2017;2:45-52.
  3. Casari A, Chester J, Pellacani G. Actinic keratosis and non-invasive diagnostic techniques: An update. Biomedicines. 2018;6(1):8. https://doi.org/10.3390/ biomedicines6010008
  4. Michalak M, Pierzak M, Kręcisz B, Suliga E. Bioactive compounds for skin health: A review. Nutrients. 2021;13(1):203. https://doi.org/10.3390/nu13010203
  5. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1(8589):795-7. https://doi. org/10.1016/s0140-6736(88)91658-3
  6. Dotto GP. Multifocal epithelial tumors and field cancerization: Stroma as a primary determinant. J Clin Invest. 2014;124(4):1446-53. https://doi. org/10.1172/JCI72589
  7. Martinez RM, Pinho-Ribeiro FA, Steffen VS, Silva TC, Caviglione CV, Bottura C, et al. Topical formulation containing naringenin: Efficacy against ultraviolet B irradiation-induced skin inflammation and oxidative stress in mice. PLoS One. 2016;11(1):e0146296. https://doi.org/10.1371/journal.pone.0146296
  8. Saenz-Sardà X, Carrato C, Pérez-Roca L, Puig L, Ferrándiz C, Ariza A, Fernández-Figueras MT. 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. J Eur Acad Dermatol Venereol. 2018;32(4):581-6. https://doi. org/10.1111/jdv.14514
  9. Reinehr CPH, Bakos RM. Actinic keratoses: Review of clinical, dermoscopic, and therapeutic aspects. An Bras Dermatol. 2019;94(6):637-57. https://doi. org/10.1016/j.abd.2019.10.004
  10. Schmitz L, Kahl P, Majores M, Bierhoff E, Stockfleth E, Dirschka T. Actinic keratosis: Correlation between clinical and histological classification systems. J Eur Acad Dermatol Venereol. 2016;30(8):1303-7. https://doi.org/10.1111/ jdv.13626
  11. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372(6508):773-6. https://doi.org/10.1038/372773a0
  12. Ceilley RI, Jorizzo JL. Current issues in the management of actinic keratosis. J Am Acad Dermatol. 2013;68(1Suppl1):S28-38. https://doi.org/10.1016/j. jaad.2012.09.051
  13. Dotto GP. Multifocal epithelial tumors and field cancerization: Stroma as a primary determinant. J Clin Invest. 2014;124(4):1446-53. https://doi. org/10.1172/JCI72589
  14. Magalhães GM, Vieira ÉC, Garcia LC, De Carvalho-Leite MLR, Guedes ACM, Araújo MG. Update on human papilloma virus – part I: Epidemiology, pathogenesis, and clinical spectrum. An Bras Dermatol. 2021;96(1):1-16. https://doi. org/10.1016/j.abd.2020.11.003
  15. Barr BB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K, et al. Papillomavirus infection and skin cancer in renal allograft recipients. Lancet. 1989;2(8656):224-5. https://doi.org/10.1016/s0140-6736(89)90412-1
  16. Hufbauer M, Akgül B. Molecular mechanisms of human papillomavirus induced skin carcinogenesis. Viruses. 2017;9(7):187. https://doi.org/10.3390/ v9070187
  17. Hultin E, Arroyo Mühr LS, Lagheden C, Dillner J. HPV transcription in skin tumors. PLoS One. 2019;14(5):e0217942. https://doi.org/10.1371/journal. pone.0217942
  18. de Oliveira ECV, da Motta VRV, Pantoja PC, Ilha CSO, Magalhães RF, Galadari H, et al. Actinic keratosis – review for clinical practice. Int J Dermatol. 2019;58(4):400-7. https://doi.org/10.1111/ijd.14147
  19. Stockfleth E. The importance of treating the field in actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31 Suppl 2:8-11. https://doi.org/10.1111/jdv.14092
  20. Javor S, Gasparini G, Biatta CM, Cozzani E, Cabiddu F, Ravetti JL, et al. P53 staining index and zonal staining patterns in actinic keratoses. Arch Dermatol Res. 2021;313(4):275-9. https://doi.org/10.1007/s00403-020-02104-y
  21. Neto PD, Alchorne M, Michalany N, Abreu M, Borra R. Reduced P53 staining in actinic keratosis is associated with squamous cell carcinoma: A preliminary study. Indian J Dermatol. 2013;58(4):325. https://doi.org/10.4103/0019- 5154.113935
  22. Takada T. Overlapping tumor-specific expression of p53, p16INK4a, and sirtuin 1 in Bowen's disease: A case report. Clin Case Rep. 2020;8(12):3394-9. https:// doi.org/10.1002/ccr3.3400
  23. Mabeta P, Hull R, Dlamini Z. Lnc RNAs and the angiogenic switch in cancer: Clinical significance and therapeutic opportunities. Genes (Basel). 2022;13(1):152. https://doi.org/10.3390/genes13010152
  24. Hong R. The utility of p16 immunostaining in cutaneous keratinocytic lesion. Med Biol Sci Eng. 2019;2(2):40-5. https://doi.org/10.30579/mbse.2019.2.2.40
  25. Ali FR, Yiu ZZ, Fitzgerald D. Inflammation of actinic keratoses during paclitaxel chemotherapy. BMJ Case Rep. 2015;2015:bcr2015209925. https://doi. org/10.1136/bcr-2015-209925
  26. Bedir R, Güçer H, Şehitoğlu İ, Yurdakul C, Bağcı P, Üstüner P. The role of p16, p21, p27, p53 and Ki-67 expression in the differential diagnosis of cutaneous squamous cell carcinomas and keratoacanthomas: An immunohistochemical study. Balkan Med J. 2016;33(2):121-7. https://doi.org/10.5152/balkanmedj.2016.16442
  27. Steurer S, Riemann C, Büscheck F, Luebke AM, Kluth M, Hube-Magg C, et al. p63 expression in human tumors and normal tissues: A tissue microarray study on 10,200 tumors. Biomark Res. 2021;9(1):7. https://doi.org/10.1186/s40364- 021-00260-5
  28. Abbas O, Richards JE, Yaar R, Mahalingam M. Stem cell markers (cytokeratin 15, cytokeratin 19 and p63) in in situ and invasive cutaneous epithelial lesions. Mod Pathol. 2011;24(1):90-7. https://doi.org/10.1038/modpathol.2010.180
  29. Moses MA, George AL, Sakakibara N, Mahmood K, Ponnamperuma RM, King KE, et al. Molecular mechanisms of p63-mediated squamous cancer pathogenesis. Int J Mol Sci. 2019;20(14):3590. https://doi.org/10.3390/ijms20143590
  30. Verdolini R, Amerio P, Goteri G, Bugatti L, Lucarini G, Mannello B, et al. Cutaneous carcinomas and preinvasive neoplastic lesions. Role of MMP-2 and MMP-9 metalloproteinases in neoplastic invasion and their relationship with proliferative activity and p53 expression. J Cutan Pathol. 2001;28(3):120-6. https://doi. org/10.1034/j.1600-0560.2001.028003120.x
  31. Zioga C, Malamou-Mitsis VD, Kamina S, Agnantis NJ. Immunohistochemical detection of ras P21 oncoprotein in human skin lesions. Anticancer Res. 1995;15(3):1015-22.
  32. Tron VA, Tang L, Yong WP, Trotter MJ. Differentiation-associated overexpression of the cyclin-dependent kinase inhibitor p21waf-1 in human cutaneous squamous cell carcinoma. Am J Pathol. 1996;149(4):1139-46
  33. Brasanac D, Stojkovic-Filipovic J, Bosic M, Tomanovic N, Manojlovic-Gacic E. Expression of G1/S-cyclins and cyclin-dependent kinase inhibitors in actinic keratosis and squamous cell carcinoma. J Cutan Pathol. 2016;43(3):200-10. https:// doi.org/10.1111/cup.12623
  34. Nakagawa K, Yamamura K, Maeda S, Ichihashi M. bcl-2 expression in epidermal keratinocytic diseases. Cancer. 1994;74(6):1720-4. https://doi.org/10.1002/1097-0142(19940915)74:6<1720::aid-cncr2820740613>3.0.co;2-t
  35. Buechner S, Erne P, Resink TJ. T-Cadherin expression in the epidermis and adnexal structures of normal skin. Dermatopathology (Basel). 2016;3(4):68-78. https://doi.org/10.1159/000451024
  36. Arciniegas E, Carrillo LM, Rojas H, Ramírez R, Reyes O, Suárez A, et al. Mucin1 expression in focal epidermal dysplasia of actinic keratosis. Ann Transl Med. 2015;3(17):245. https://doi.org/10.3978/j.issn.2305-5839.2015.10.04
  37. Lee JS, Park HS, Yoon HS, Cho S. Claudin-1 expression decreases with increasing pathological grade in actinic keratosis and may be a marker of high-risk actinic keratosis. Clin Exp Dermatol. 2019;44(5):483-90. https://doi.org/10.1111/ ced.13810
  38. Niland S, Riscanevo AX, Eble JA. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci. 2021;23(1):146. https:// doi.org/10.3390/ijms23010146
  39. Kuznetsova EV, Snarskaya ES, Zavalishina LE, Tkachenko SB. Immunogistokhimicheskoe issledovanie osobennostey ekspressii matriksnykh metalloproteinaz 1, 9 v kozhe s dermatogeliozom, ochagakh aktinicheskogo keratoza i bazal'no-kletochnogo raka kozhi [Immunohistochemical study of the specific features of expression of matrix metalloproteinases 1, 9 in the photoaged skin, the foci of actinic keratosis and basal cell carcinoma]. Arkhiv patologii. 2016;78(6):17-22. https://doi.org/10.17116/patol201678617-22
  40. Tsukifuji R, Tagawa K, Hatamochi A, Shinkai H. Expression of matrix metalloproteinase-1, -2 and -3 in squamous cell carcinoma and actinic keratosis. Br J Cancer. 1999;80(7):1087-91. https://doi.org/10.1038/sj.bjc.6690468
  41. Poswar FO, Fraga CA, Farias LC, Feltenberger JD, Cruz VP, Santos SH, et al. Immunohistochemical analysis of TIMP-3 and MMP-9 in actinic keratosis, squamous cell carcinoma of the skin, and basal cell carcinoma. Pathol Res Pract. 2013;209(11):705-9. https://doi.org/10.1016/j.prp.2013.08.002
  42. Nikolov A, Popovski N. Role of gelatinases MMP-2 and MMP-9 in healthy and complicated pregnancy and their future potential as preeclampsia biomarkers. Diagnostics (Basel). 2021;11(3):480. https://doi.org/10.3390/diagnostics11030480
  43. Wang Q, Wang K, Tan X, Li Z, Wang H. Immunomodulatory role of metalloproteases in cancers: Current progress and future trends. Front Immunol. 2022;13:1064033. https://doi.org/10.3389/fimmu.2022.1064033
  44. Cai D, Ma X, Guo H, Zhang H, Bian A, Yu H, et al. Prognostic value of p16, p53, and pcna in sarcoma and an evaluation of immune infiltration. J Orthop Surg Res. 2022;17(1):305. https://doi.org/10.1186/s13018-022-03193-3
  45. Bologna-Molina R, Mosqueda-Taylor A, Molina-Frechero N, Mori-Estevez AD, Sánchez-Acuña G. Comparison of the value of PCNA and Ki-67 as markers of cell proliferation in ameloblastic tumors. Med Oral Patol Oral Cir Bucal. 2013;18(2):e174-9. https://doi.org/10.4317/medoral.18573.

Authors' information:

Sydikov Akmal Abdikakharovich,
Doctor of Medical Sciences, Full Professor, Rector of Fergana Medical Institute of Public Health
ORCID ID: 0000-0002-0909-7588
SPIN: 3812-8400
Author ID: 799109
E-mail: medik85@bk.ru

Pyagay Grigoriy Borisovich,
Candidate of Medical Sciences, Associate Professor of the Department of Dermato-oncopathology, Tashkent State Dental Institute
ORCID ID: 0000-0002-6456-6594
SPIN: 29417297
Author ID: 1106302
E-mail: gregbae@mail.ru

Pyagay Olga Grigorievna,
Dermatovenereologist, St. Petersburg Dermatology and Venereology Dispensary № 9
ORCID ID: 0000-0002-6379-5563
SPIN: 8357-9048
Author ID: 1206814
E-mail: olga.pyagay@gmail.com

Information about support in the form of grants, equipment, medications

The authors did not receive financial support from manufacturers of medicines and medical equipment

Conflicts of interest: No conflict

Address for correspondence:

Pyagay Grigoriy Borisovich
Candidate of Medical Sciences, Associate Professor of the Department of Dermato-oncopathology, Tashkent State Dental Institute

100213, Republic of Uzbekistan, Tashkent, Makhtumkuli str., 103

Tel.: +998 (901) 755133

E-mail: gregbae@mail.ru

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