Histological Alterations and Biochemical Markers of Skin Cancer: A Review
Keywords:
MM, BCC, SCC, Skin Cancer, EGFR amplificationAbstract
Skin cancer is a broad range of malignant and benign neoplasms that are common worldwide and more prevalent than many other cancer types. This condition involves the neoplastic proliferation of cells and tissues within the skin and can be associated with significant morbidity and mortality. This review summarizes the most recent advances regarding histopathologic changes and management of skin malignancy, which are classified by three types-Melanoma (MM), Basal Cell Carcinoma (BCC) Squamous Cell Carcinoma (SCC). They also show certain patterns of atypia, invasion and proliferative activity which is vital for histopathological diagnosis as well as prognostic stratification. Molecular changes demonstrate that mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) or NRAS (neuroblastoma RAS viral oncogene homolog) in the RAS signaling pathway, Hedgehog family of proteins and β-catenin may underlie differences in clinical outcome as they affect tumor progression and response to therapy, particularly in skin cancers. In recent years, encouraging results have been observed in the treatment of HCC through targeted therapies and immune checkpoint inhibitors as first- or second-line treatment objectives, resulting in improvement in the clinical outcomes of patients with HCC. However, these strategies are also faced with formidable challenges for clinical translation due to cancer-relapsing therapeutic resistance and tumor heterogeneity. Tumor microenvironmental [practices] like Ti [tumor infiltrating] immune cells, interaction with (the)extracellular matrix are also key to the tumor development and progression. High throughput technologies like molecular profiling and precision medicine provide new treatment markers as well as the means to individualize therapy. However, skin cancer represents one of the most heavily treated malignancies, especially with advanced disease. This would, in turn, integrate lithologic, molecular and therapeutic data into the diagnostic inferences standardized for patients—improving understanding & rational of treatment thereby enabling better reporting of outcomes.
References
Caraviello, C., Nazzaro, G., Tavoletti, G., Boggio, F., Denaro, N., Murgia, G., Passoni, E., Benzecry Mancin, V., & Marzano, A. V. (2025). Melanoma Skin Cancer: A Comprehensive Review of Current Knowledge. Cancers, 17(17), 2920. https://doi.org/10.3390/cancers17172920
Cives, M., Mannavola, F., Lospalluti, L., Sergi, M. C., Cazzato, G., Filoni, E., Cavallo, F., Giudice, G., Stucci, L. S., Porta, C., & Tucci, M. (2020). Non-Melanoma Skin Cancers: Biological and Clinical Features. International journal of molecular sciences, 21(15), 5394. https://doi.org/10.3390/ijms21155394
Combalia, A., & Carrera, C. (2020). Squamous Cell Carcinoma: An Update on Diagnosis and Treatment. Dermatology practical & conceptual, 10(3), e2020066. https://doi.org/10.5826/dpc.1003a66
Di Nardo, L., Pellegrini, C., Di Stefani, A., Fargnoli, M. C., & Peris, K. (2021). Molecular alterations in basal cell carcinoma subtypes. Scientific Reports, 11(1), 13206. https://doi.org/10.1038/s41598-021-92592-3
D'Orazio, J., Jarrett, S., Amaro-Ortiz, A., & Scott, T. (2013). UV radiation and the skin. International journal of molecular sciences, 14(6), 12222–12248. https://doi.org/10.3390/ijms140612222
Elder, D. E., Elenitsas, R., Rosenbach, M., Murphy, G. F., & Rubin, A. I. (2015). Lever’s histopathology of the skin (11th ed.). Wolters Kluwer.
Fabian, A., Krug, D., & Alkatout, I. (2020). Radiotherapy and Its Intersections with Surgery in the Management of Localized Gynecological Malignancies: A Comprehensive Overview for Clinicians. Journal of clinical medicine, 10(1), 93. https://doi.org/10.3390/jcm10010093
Fania, L., Didona, D., Di Pietro, F. R., Verkhovskaia, S., Morese, R., Paolino, G., Donati, M., Ricci, F., Coco, V., Ricci, F., Candi, E., Abeni, D., & Dellambra, E. (2021). Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches. Biomedicines, 9(2), 171. https://doi.org/10.3390/biomedicines9020171
Gershenwald, J. E., Scolyer, R. A., Hess, K. R., Sondak, V. K., Long, G. V., Ross, M. I., Lazar, A. J., Faries, M. B., Kirkwood, J. M., McArthur, G. A., Haydu, L. E., Eggermont, A. M. M., Flaherty, K. T., Balch, C. M., & Thompson, J. F. (2017). Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA: A Cancer Journal for Clinicians, 67(6), 472–492. https://doi.org/10.3322/caac.21409
Gonçalves Ferreira, I., Boff, A. L., Luzzato, L., Martins Souza, P. R., & Bevilaqua, M. (2021). Well-Differentiated Squamous Cell Carcinoma: Is Histological Differentiation a Relevant Prognostic Parameter?. Dermatology practical & conceptual, 11(2), e2021034. https://doi.org/10.5826/dpc.1102a34
Hadian, Y., Howell, J. Y., Ramsey, M. L., & Buckley, C. (2024, July 2). Cutaneous squamous cell carcinoma. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK441939
Hasan, N., Nadaf, A., Imran, M., Jiba, U., Sheikh, A., Almalki, W. H., Almujri, S. S., Mohammed, Y. H., Kesharwani, P., & Ahmad, F. J. (2023). Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches. Molecular cancer, 22(1), 168. https://doi.org/10.1186/s12943-023-01854-3
Hussein, Q., Abu Shugaer, M., Khattab, K., Al-Ali, A., & Al-Kofahi, M. (2025). Histopathological subtypes of cutaneous melanoma: Prognostic and molecular implications. Cureus, 17(8), e90670. https://doi.org/10.7759/cureus.90670
Koyuncuer, A. (2014). Histopathological evaluation of non-melanoma skin cancer. World Journal of Surgical Oncology, 12(1), 159. https://doi.org/10.1186/1477-7819-12-159
Krzyszczyk, P., Acevedo, A., Davidoff, E. J., Timmins, L. M., Marrero-Berrios, I., Patel, M., White, C., Lowe, C., Sherba, J. J., Hartmanshenn, C., O'Neill, K. M., Balter, M. L., Fritz, Z. R., Androulakis, I. P., Schloss, R. S., & Yarmush, M. L. (2018). The growing role of precision and personalized medicine for cancer treatment. Technology, 6(3-4), 79–100. https://doi.org/10.1142/S2339547818300020
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Rutkowski, P., Lao, C. D., Cowey, C. L., Schadendorf, D., Wagstaff, J., Dummer, R., Ferrucci, P. F., Smylie, M., Hogg, D., Hill, A., Mلrquez-Rodas, I., Haanen, J., Guidoboni, M., Maio, M., Schachter, J., … Ascierto, P. A. (2015). Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New England Journal of Medicine, 373(1), 23–34. https://doi.org/10.1056/NEJMoa1504030
Marzuka, A. G., & Book, S. E. (2015). Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. The Yale journal of biology and medicine, 88(2), 167–179.
Modrakowska, P., Balik, K., Maj, M., & Bajek, A. (2020). Novel therapies for advanced skin carcinomas. Postepy dermatologii i alergologii, 37(5), 660–670. https://doi.org/10.5114/ada.2020.100479
Müller, C. S. L., & Reichrath, J. (2014). Histology of melanoma and nonmelanoma skin cancer. In J. Reichrath (Ed.), Advances in Experimental Medicine and Biology (Vol. 810, pp. 141–159). Springer. https://doi.org/10.1007/978-1-4939-0437-2_8
Naik, P. P., & Desai, M. B. (2022). Basal Cell Carcinoma: A Narrative Review on Contemporary Diagnosis and Management. Oncology and therapy, 10(2), 317–335. https://doi.org/10.1007/s40487-022-00201-8
Paolino, G., Donati, M., Didona, D., Mercuri, S. R., & Cantisani, C. (2017). Histology of Non-Melanoma Skin Cancers: An Update. Biomedicines, 5(4), 71. https://doi.org/10.3390/biomedicines5040071
Pizzichetta, M. A., Polesel, J., Sini, M. C., Manca, A., Simi, S., Paliogiannis, P., Pinzani, C., Corsetti, P., Canzonieri, V., Astorino, S., Pasquini, P., Corradin, M. T., Sulfaro, S., Lombardo, M., Cerati, M., Moretti, G., Falduto, M., Maestrale, G. B., Cossu, A., Garutti, M., … Italian Melanoma Intergroup (IMI) and Società Italiana di Dermatologia Chirurgica, Oncologica, Correttiva ed Estetica (SIDCO) (2025). Clinical, Histopathological, Dermoscopic Features, and BRAF, NRAS, and Cell Cycle Genes' Mutation Status in Cutaneous Melanoma. Cancers, 17(16), 2688. https://doi.org/10.3390/cancers17162688
Puckett, Y., & Steele, R. B. (2025, November 7). Basal cell carcinoma. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482439/
Puckett, Y., Wilson, A. M., Farci, F., & Thevenin, C. (2024, July 2). Melanoma pathology. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459367/
Que, S. K. T., Zwald, F. O., & Schmults, C. D. (2018). Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. Journal of the American Academy of Dermatology, 78(2), 237–247. https://doi.org/10.1016/j.jaad.2017.08.059
Saldanha, G., Fletcher, A., & Slater, D. N. (2003). Basal cell carcinoma: A dermatopathological and molecular biological update. British Journal of Dermatology, 148(2), 195–202. https://doi.org/10.1046/j.1365-2133.2003.05151.x
Sergi, M. C., Ambrogio, F., Della Mura, M., Sorino, J., & Cazzato, G. (2025). Basal Cell Carcinoma: An Old Friend with Multiple Faces. Cancers, 17(6), 993. https://doi.org/10.3390/cancers17060993
Shokrollahi, K., Javed, M., Aeuyung, K., Ghattaura, A., Whitaker, I. S., O'Leary, B., James, W., & Murison, M. (2014). Combined carbon dioxide laser with photodynamic therapy for nodular and superficial basal cell carcinoma. Annals of plastic surgery, 73(5), 552–558. https://doi.org/10.1097/SAP.0b013e3182773ed2
Sol, S., Boncimino, F., Todorova, K., Waszyn, S. E., & Mandinova, A. (2024). Therapeutic Approaches for Non-Melanoma Skin Cancer: Standard of Care and Emerging Modalities. International journal of molecular sciences, 25(13), 7056. https://doi.org/10.3390/ijms25137056
Stockmann, C., Schadendorf, D., Klose, R., & Helfrich, I. (2014). The impact of the immune system on tumor: angiogenesis and vascular remodeling. Frontiers in oncology, 4, 69. https://doi.org/10.3389/fonc.2014.00069
Sutrisno, C. S. N., Pramita, D. H., & Dewi, I. P. (2025). Curative or Conservative Approaches: A Systematic Review of Surgical and Nonsurgical Treatments for Basal Cell Carcinoma. Cureus, 17(10), e95556. https://doi.org/10.7759/cureus.95556
Swetter, S. M., Tsao, H., Bichakjian, C. K., Curiel-Lewandrowski, C., Elder, D. E., Gershenwald, J. E., Guild, V., Grant-Kels, J. M., Halpern, A. C., Johnson, T. M., Sober, A. J., & Thompson, J. A. (2019). Guidelines of care for the management of primary cutaneous melanoma. Journal of the American Academy of Dermatology, 80(1), 208–250. https://doi.org/10.1016/j.jaad.2018.08.055
Tan, I. J., Pathak, G. N., & Silver, F. H. (2023). Topical Treatments for Basal Cell Carcinoma and Actinic Keratosis in the United States. Cancers, 15(15), 3927. https://doi.org/10.3390/cancers15153927
Thapa, R., Gurung, P., Hirachand, S., & Shrestha, S. B. (2018). Histomorphologic Profile of Skin Tumors. JNMA; journal of the Nepal Medical Association, 56(214), 953–957. https://doi.org/10.31729/jnma.3988
Voiculescu, V. M., Popescu, A. I., & Costache, M. (2025). Immunohistochemistry for Skin Cancers: New Insights into Diagnosis and Treatment of Melanoma. Cancers, 17(11), 1769. https://doi.org/10.3390/cancers17111769
Wang, X., Ma, S., Zhu, S., Zhu, L., & Guo, W. (2025). Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma. Biomedicines, 13(1), 225. https://doi.org/10.3390/biomedicines13010225
Winter, M., Ebner, S., Baum, V., Kiil, K., Rauschendorf, M. A., & Wild, P. J. (2026). Malignant Melanoma: Landscape of Molecular Markers. Biomedicines, 14(1), 157. https://doi.org/10.3390/biomedicines14010157
Zhou, J., Park, S., Dong, S., Tang, X., & Wei, X. (2025). Artificial intelligence-driven transformative applications in disease diagnosis technology. Medical review (2021), 5(5), 353–377. https://doi.org/10.1515/mr-2024-0097
