Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

Luca Fania, Dario Didona, Francesca Romana Di Pietro, Sofia Verkhovskaia, Roberto Morese, Giovanni Paolino, Michele Donati, Francesca Ricci, Valeria Coco, Francesco Ricci, Eleonora Candi, Damiano Abeni, Elena Dellambra, Luca Fania, Dario Didona, Francesca Romana Di Pietro, Sofia Verkhovskaia, Roberto Morese, Giovanni Paolino, Michele Donati, Francesca Ricci, Valeria Coco, Francesco Ricci, Eleonora Candi, Damiano Abeni, Elena Dellambra

Abstract

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen's disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management.

Keywords: Bowen’s disease; cemiplimab; dermoscopy; immunotherapy; keratinocyte carcinoma; non-melanoma skin cancer; radiotherapy; squamous cell carcinoma; therapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A): Bowen’s disease of the forehead; (B): keratoacanthoma of the nose; (C): ulcerated squamous cell carcinoma on the chin.
Figure 2
Figure 2
(A): Bowen’s disease. Hematoxylin and Eosin, 100× (B): Well-differentiated, invasive squamous cell carcinoma, hematoxylin and eosin, 20×. (C): Verrucous squamous cell carcinoma, hematoxylin and eosin, 20×.
Figure 3
Figure 3
(A): Adenosquamous squamous cell carcinoma. Hematoxylin and eosin, 200×. (B): Perineural squamous cell carcinoma. Hematoxylin and eosin, 100×. (C): Papillary squamous cell carcinoma. Hematoxylin and eosin, 40×.
Figure 4
Figure 4
(A): Clinical image of a 12 × 8 mm nonpigmented Bowen’s disease of the chest with dermoscopic features of dotted and glomerular vessels (↑) and scaly white-to-yellow surfaces (×). (B): Clinical image of a 30 × 12 mm pigmented Bowen’s disease of the leg with dermoscopic features of brown to gray globules/dots (↑) and structureless pigmentation (×) and dotted and glomerular vessels (>). (C): Clinical image of a 14 × 11 mm well differentiated cSCC of the scalp with dermoscopic features of keratin/scales (↑), blood spots (>), white structureless areas (×), and ulcerations (∞). (D) Clinical image of a 7 × 6 mm poorly differentiated cSCC of the ear with dermoscopic features of hairpin and linear-irregular vessels (↑) and ulcerations (×).
Figure 5
Figure 5
(a) Reflectance confocal microscopy (RCM) mosaic of a well differentiated cSCC (8 × 8mm). Yellow arrow shows a scale crust and ulceration in the lower part of the figure. (b) Green rectangle: a magnification of an RCM image (1 × 1.5 mm) at the epidermal layer shows atypical honeycomb pattern, which is characterized by thickened and broadened keratinocytes outlines of varying size and shape. (c) Red rectangle: a magnification of an RCM mosaic (1 × 1.5 mm) at the dermoepidermal junction layer shows round or coiled vessels (red arrows) that run through the dermal papillae perpendicularly to the lesion surface. (d) Blue rectangle: a magnification of an RCM mosaic (1 × 1 mm) at the spinous-granular layer shows a disarranged pattern characterized by architectural disarray and the presence of dendritic (blue arrows) and plump bright cells which represent pigmented keratinocytes and melanocytes infiltrating the epidermis.
Figure 6
Figure 6
Pathways involved in cutaneous squamous cell carcinoma (cSCC) pathogenesis. Molecular alterations, which drive cSCC development, have been identified in pathways involved in cell cycle regulation, apoptosis, senescence, differentiation, and mitogenic/survival. (A) The tumor suppressor genes p16INK4A and p14ARF control retinoblastoma (pRb) and p53 pathways, respectively. Their loss of function promotes cell cycle counteracting senescence or apoptosis. Aberrant activation of E2F transcription can also be due to cyclin D activation or pRb expression loss. pRb and p53 inactivation is also mediated by E6 and E7 (red hexagons) human papilloma virus (HPV) proteins. (B) EGF-R aberrant activation, p53 inactivation, or NOTCH gene mutations inactivate the NOTCH pathway. Inactivation of NOTCH abolishes the direct or IRF6-mediated suppression of ΔNp63, favoring proliferation, survival, and stemness. NOTCH inactivation also counteracts senescence and apoptosis mediated by its targets (HES1 and p21). Moreover, ΔNp63 upregulation represses the expression of HES1, p21, and p16INK4A. (C) RAS-RAF-MEK-ERK and PI3K/AKT/mTOR pathways share the up-stream proteins, such as tyrosine kinase receptors (RTK) and RAS. Activating mutations in RTK, RAS or inactivation of negative regulator RASA1 promotes cell proliferation and survival through constitutive activation of both pathways. Aberrant activation of these pathways can also derive by B-RAF or PI3K/AKT activation, or Phosphatase and tensin homolog (PTEN) inactivation. The RTKs and the downstream pathways can be targeted with several drugs (blue hexagons) to inhibit cSCC progression. However, both pathways can be activated by RAS mutations, present in photodamaged skin, as part of a compensatory mechanism that could drive resistance to therapeutic targeting strategies. Proteins with commonly accepted tumor promoting and suppressing functions are highlighted in orange and green, respectively. Activated or downregulated processes (circles, squares and arrows) are highlighted in dark orange and green, respectively. Block and dash arrows indicate direct or indirect interactions, respectively.

References

    1. Que S.K.T., Zwald F.O., Schmults C.D. Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J. Am. Acad. Dermatol. 2018;78:237–247. doi: 10.1016/j.jaad.2017.08.059.
    1. Martincorena I., Roshan A., Gerstung M., Ellis P., van Loo P., McLaren S., Wedge D.C., Fullam A., Alexandrov L.B., Tubio J.M., et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015;348:880–886. doi: 10.1126/science.aaa6806.
    1. Skulsky S.L., O’Sullivan B., McArdle O., Leader M., Roche M., Conlon P.J., O’Neill J.P. Review of high-risk features of cutaneous squamous cell carcinoma and discrepancies between the American Joint Committee on Cancer and NCCN Clinical Practice Guidelines In Oncology. Head Neck. 2017;39:578–594. doi: 10.1002/hed.24580.
    1. Kim J.Y.S., Kozlow J.H., Mittal B., Moyer J., Olenecki T., Rodgers P. Guidelines of care for the management of cutaneous squamous cell carcinoma. J. Am. Acad. Dermatol. 2018;78:560–578. doi: 10.1016/j.jaad.2017.10.007.
    1. Xiang F., Lucas R., Hales S., Neale R. Incidence of nonmelanoma skin cancer in relation to ambient UV radiation in white populations, 1978-2012: Empirical relationships. JAMA Dermatol. 2014;150:1063–1071. doi: 10.1001/jamadermatol.2014.762.
    1. Brougham N.D.L.S., Dennett E.R., Cameron R., Tan S.T. The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J. Surg. Oncol. 2012;106:811–815. doi: 10.1002/jso.23155.
    1. Nissinen L., Farshchian M., Riihilä P., Kähäri V.-M. New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma. Cell Tissue Res. 2016;365:691–702. doi: 10.1007/s00441-016-2457-z.
    1. Stratigos A.J., Garbe C., Dessinioti C., Lebbe C., Bataille V., Bastholt L., Dreno B., Concetta Fargnoli M., Forsea A.M., Frenard C., et al. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment. Eur. J. Cancer. 2020;128:83–102. doi: 10.1016/j.ejca.2020.01.008.
    1. Trakatelli M., Ulrich C., Del Marmol V., Euvrard S., Euvard S., Stockfleth E., Abeni D. Epidemiology of nonmelanoma skin cancer (NMSC) in Europe: Accurate and comparable data are needed for effective public health monitoring and interventions. Br. J. Dermatol. 2007;156:1–7. doi: 10.1111/j.1365-2133.2007.07861.x.
    1. Staples M.P., Elwood M., Burton R.C., Williams J.L., Marks R., Giles G.G. Non-melanoma skin cancer in Australia: The 2002 national survey and trends since 1985. Med. J. Aust. 2006;184:6–10. doi: 10.5694/j.1326-5377.2006.tb00086.x.
    1. Andersson E.M., Paoli J., Wastensson G. Incidence of cutaneous squamous cell carcinoma in coastal and inland areas of Western Sweden. Cancer Epidemiol. 2011;35:e69–e74. doi: 10.1016/j.canep.2011.05.006.
    1. Brewster D.H., Bhatti L.A., Inglis J.H.C., Nairn E.R., Doherty V.R. Recent trends in incidence of nonmelanoma skin cancers in the East of Scotland, 1992-2003. Br. J. Dermatol. 2007;156:1295–1300. doi: 10.1111/j.1365-2133.2007.07892.x.
    1. Katalinic A., Kunze U., Schäfer T. Epidemiology of cutaneous melanoma and non-melanoma skin cancer in Schleswig-Holstein, Germany: Incidence, clinical subtypes, tumour stages and localization (epidemiology of skin cancer) Br. J. Dermatol. 2003;149:1200–1206. doi: 10.1111/j.1365-2133.2003.05554.x.
    1. Stratigos A.J., Garbe C., Dessinioti C., Lebbe C., Bataille V., Bastholt L., Dreno B., Fargnoli M.C., Forsea A.M., Frenard C., et al. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 1. epidemiology, diagnostics and prevention. Eur. J. Cancer. 2020;128:60–82. doi: 10.1016/j.ejca.2020.01.007.
    1. Morris K.L., Luke M.C., Perna F.M. Prevalence of Skin Cancer Examination among Users of Indoor Tanning Beds. JAMA Dermatol. 2018;154:840–842. doi: 10.1001/jamadermatol.2018.1118.
    1. Green A.C., Olsen C.M. Cutaneous squamous cell carcinoma: An epidemiological review. Br. J. Dermatol. 2017;177:373–381. doi: 10.1111/bjd.15324.
    1. Fania L., Didona D., Morese R., Campana I., Coco V., Di Pietro F.R., Ricci F., Pallotta S., Candi E., Abeni D., et al. Basal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches. Biomedicines. 2020;8:449. doi: 10.3390/biomedicines8110449.
    1. Wehner M.R., Shive M.L., Chren M.-M., Han J., Qureshi A.A., Linos E. Indoor tanning and non-melanoma skin cancer: Systematic review and meta-analysis. BMJ. 2012;345:e5909. doi: 10.1136/bmj.e5909.
    1. Stern R.S. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet a therapy: A 30-year prospective study. J. Am. Acad. Dermatol. 2012;66:553–562. doi: 10.1016/j.jaad.2011.04.004.
    1. Chahoud J., Semaan A., Chen Y., Cao M., Rieber A.G., Rady P., Tyring S.K. Association Between β-Genus Human Papillomavirus and Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals-A Meta-analysis. JAMA Dermatol. 2016;152:1354–1364. doi: 10.1001/jamadermatol.2015.4530.
    1. Paradisi A., Waterboer T., Ricci F., Sampogna F., Pawlita M., Abeni D. Concomitant seropositivity for HPV 16 and cutaneous HPV types increases the risk of recurrent squamous cell carcinoma of the skin. Eur. J. Dermatol. 2020;30:493–498. doi: 10.1684/ejd.2020.3874.
    1. Pirie K., Beral V., Heath A.K., Green J., Reeves G.K., Peto R., McBride P., Olsen C.M., Green A.C. Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: The UK Million Women Study and meta-analysis of prospective studies. Br. J. Cancer. 2018;119:114–120. doi: 10.1038/s41416-018-0105-y.
    1. Dusingize J.C., Olsen C.M., Pandeya N.P., Subramaniam P., Thompson B.S., Neale R.E., Green A.C., Whiteman D.C. Cigarette Smoking and the Risks of Basal Cell Carcinoma and Squamous Cell Carcinoma. J. Invest. Dermatol. 2017;137:1700–1708. doi: 10.1016/j.jid.2017.03.027.
    1. Garrett G.L., Blanc P.D., Boscardin J., Lloyd A.A., Ahmed R.L., Anthony T., Bibee K., Breithaupt A., Cannon J., Chen A., et al. Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States. JAMA Dermatol. 2017;153:296–303. doi: 10.1001/jamadermatol.2016.4920.
    1. Omland S.H., Ahlström M.G., Gerstoft J., Pedersen G., Mohey R., Pedersen C., Kronborg G., Larsen C.S., Kvinesdal B., Gniadecki R., et al. Risk of skin cancer in patients with HIV: A Danish nationwide cohort study. J. Am. Acad. Dermatol. 2018;79:689–695. doi: 10.1016/j.jaad.2018.03.024.
    1. Omland S.H., Gniadecki R., Hædersdal M., Helweg-Larsen J., Omland L.H. Skin Cancer Risk in Hematopoietic Stem-Cell Transplant Recipients Compared With Background Population and Renal Transplant Recipients: A Population-Based Cohort Study. JAMA Dermatol. 2016;152:177–183. doi: 10.1001/jamadermatol.2015.3902.
    1. Fania L., Abeni D., Esposito I., Spagnoletti G., Citterio F., Romagnoli J., Castriota M., Ricci F., Moro F., Perino F., et al. Behavioral and demographic factors associated with occurrence of non-melanoma skin cancer in organ transplant recipients. G. Ital. Dermatol. Venereol. Organo Uff. Soc. Ital. Dermatol. Sifilogr. 2020;155:669–675. doi: 10.23736/S0392-0488.18.06099-6.
    1. Wu J.H., Cohen D.N., Rady P.L., Tyring S.K. BRAF inhibitor-associated cutaneous squamous cell carcinoma: New mechanistic insight, emerging evidence for viral involvement and perspectives on clinical management. Br. J. Dermatol. 2017;177:914–923. doi: 10.1111/bjd.15348.
    1. Peng L., Wang Y., Hong Y., Ye X., Shi P., Zhang J., Zhao Q. Incidence and relative risk of cutaneous squamous cell carcinoma with single-agent BRAF inhibitor and dual BRAF/MEK inhibitors in cancer patients: A meta-analysis. Oncotarget. 2017;8:83280–83291. doi: 10.18632/oncotarget.21059.
    1. Nagarajan P., Asgari M.M., Green A.C., Guhan S.M., Arron S.T., Proby C.M., Rollison D.E., Harwood C.A., Toland A.E. Keratinocyte Carcinomas: Current Concepts and Future Research Priorities. Clin. Cancer Res. 2019;25:2379–2391. doi: 10.1158/1078-0432.CCR-18-1122.
    1. Mohan S.V., Chang J., Li S., Henry A.S., Wood D.J., Chang A.L.S. Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma. JAMA Dermatol. 2016;152:527–532. doi: 10.1001/jamadermatol.2015.4330.
    1. Gandini S., Palli D., Spadola G., Bendinelli B., Cocorocchio E., Stanganelli I., Miligi L., Masala G., Caini S. Anti-hypertensive drugs and skin cancer risk: A review of the literature and meta-analysis. Crit. Rev. Oncol. Hematol. 2018;122:1–9. doi: 10.1016/j.critrevonc.2017.12.003.
    1. Tang H., Fu S., Zhai S., Song Y., Asgari M.M., Han J. Use of antihypertensive drugs and risk of keratinocyte carcinoma: A meta-analysis of observational studies. Pharmacoepidemiol. Drug Saf. 2018;27:279–288. doi: 10.1002/pds.4384.
    1. Flohil S.C., van der Leest R.J.T., Arends L.R., Vries E., Nijsten T. Risk of subsequent cutaneous malignancy in patients with prior keratinocyte carcinoma: A systematic review and meta-analysis. Eur. J. Cancer. 2013;49:2365–2375. doi: 10.1016/j.ejca.2013.03.010.
    1. Ricci F., Paradisi A., Fania L., Pallotta S., Di Lella G., Sobrino L., Panebianco A., Abeni D. High melanoma risk in non-melanoma skin cancer patients under age 40: A large retrospective cohort study. G. Ital. Dermatol. Venereol. Organo Uff. Soc. Ital. Dermatol. Sifilogr. 2019 doi: 10.23736/S0392-0488.19.06276-X.
    1. Ashford B.G., Clark J., Gupta R., Iyer N.G., Yu B., Ranson M. Reviewing the genetic alterations in high-risk cutaneous squamous cell carcinoma: A search for prognostic markers and therapeutic targets. Head Neck. 2017;39:1462–1469. doi: 10.1002/hed.24765.
    1. Kossard S., Rosen R. Cutaneous Bowen’s disease. J. Am. Acad. Dermatol. 1992;27:406–410. doi: 10.1016/0190-9622(92)70208-W.
    1. Kallini J.R., Hamed N., Khachemoune A. Squamous cell carcinoma of the skin: Epidemiology, classification, management, and novel trends. Int. J. Dermatol. 2015;54:130–140. doi: 10.1111/ijd.12553.
    1. Schwartz R.A. Keratoacanthoma. J. Am. Acad. Dermatol. 1994;30:1–19. doi: 10.1016/S0190-9622(94)70001-X.
    1. Paolino G., Donati M., Didona D., Mercuri S.R., Cantisani C. Histology of Non-Melanoma Skin Cancers: An Update. Biomedicines. 2017;5:71. doi: 10.3390/biomedicines5040071.
    1. Esther R.J., Lamps L., Schwartz H.S. Marjolin ulcers: Secondary carcinomas in chronic wounds. J. South. Orthop. Assoc. 1999;8:181–187.
    1. Miller S.J. The National Comprehensive Cancer Network (NCCN) guidelines of care for nonmelanoma skin cancers. Dermatol. Surg. 2000;26:289–292. doi: 10.1111/j.1524-4725.2000.00005.x.
    1. Kempf W., Hantschke M., Kutzner H., Burgdorf W. Dermatopathologie. Springer; Berlin/Heidelberg, Germany: 2015.
    1. Zalaudek I., Argenziano G. Dermoscopy of actinic keratosis, intraepidermal carcinoma and squamous cell carcinoma. Curr. Probl. Dermatol. 2015;46:70–76. doi: 10.1159/000366539.
    1. Pan Y., Chamberlain A.J., Bailey M., Chong A.H., Haskett M., Kelly J.W. Dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. J. Am. Acad. Dermatol. 2008;59:268–274. doi: 10.1016/j.jaad.2008.05.013.
    1. Zalaudek I., Argenziano G., Leinweber B., Citarella L., Hofmann-Wellenhof R., Malvehy J., Puig S., Pizzichetta M.A., Thomas L., Soyer H.P., et al. Dermoscopy of Bowen’s disease. Br. J. Dermatol. 2004;150:1112–1116. doi: 10.1111/j.1365-2133.2004.05924.x.
    1. Mun J.-H., Kim S.-H., Jung D.-S., Ko H.-C., Kwon K.-S., Kim M.-B. Dermoscopic features of Bowen’s disease in Asians. J. Eur. Acad. Dermatol. Venereol. 2010;24:805–810. doi: 10.1111/j.1468-3083.2009.03529.x.
    1. Payapvipapong K., Tanaka M. Dermoscopic classification of Bowen’s disease. Australas. J. Dermatol. 2015;56:32–35. doi: 10.1111/ajd.12200.
    1. Yang Y., Lin J., Fang S., Han S., Song Z. What’s new in dermoscopy of Bowen’s disease: Two new dermoscopic signs and its differential diagnosis. Int. J. Dermatol. 2017;56:1022–1025. doi: 10.1111/ijd.13734.
    1. Zalaudek I., Giacomel J., Schmid K., Bondino S., Rosendahl C., Cavicchini S., Tourlaki A., Gasparini S., Bourne P., Keir J., et al. Dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: A progression model. J. Am. Acad. Dermatol. 2012;66:589–597. doi: 10.1016/j.jaad.2011.02.011.
    1. Rosendahl C., Cameron A., Argenziano G., Zalaudek I., Tschandl P., Kittler H. Dermoscopy of squamous cell carcinoma and keratoacanthoma. Arch. Dermatol. 2012;148:1386–1392. doi: 10.1001/archdermatol.2012.2974.
    1. Pyne J., Sapkota D., Wong J.C. Squamous cell carcinoma: Variation in dermatoscopic vascular features between well and non-well differentiated tumors. Dermatol. Pract. Concept. 2012;2:204a05. doi: 10.5826/dpc.0204a05.
    1. Yélamos O., Braun R.P., Liopyris K., Wolner Z.J., Kerl K., Gerami P., Marghoob A.A. Dermoscopy and dermatopathology correlates of cutaneous neoplasms. J. Am. Acad. Dermatol. 2019;80:341–363. doi: 10.1016/j.jaad.2018.07.073.
    1. Manfredini M., Longo C., Ferrari B., Piana S., Benati E., Casari A., Pellacani G., Moscarella E. Dermoscopic and reflectance confocal microscopy features of cutaneous squamous cell carcinoma. J. Eur. Acad. Dermatol. Venereol. 2017;31:1828–1833. doi: 10.1111/jdv.14463.
    1. Lallas A., Pyne J., Kyrgidis A., Andreani S., Argenziano G., Cavaller A., Giacomel J., Longo C., Malvestiti A., Moscarella E., et al. The clinical and dermoscopic features of invasive cutaneous squamous cell carcinoma depend on the histopathological grade of differentiation. Br. J. Dermatol. 2015;172:1308–1315. doi: 10.1111/bjd.13510.
    1. Rishpon A., Kim N., Scope A., Porges L., Oliviero M.C., Braun R.P., Marghoob A.A., Fox C.A., Rabinovitz H.S. Reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. Arch. Dermatol. 2009;145:766–772. doi: 10.1001/archdermatol.2009.134.
    1. Aghassi D., Anderson R.R., González S. Confocal laser microscopic imaging of actinic keratoses in vivo: A preliminary report. J. Am. Acad. Dermatol. 2000;43:42–48. doi: 10.1067/mjd.2000.105565.
    1. Incel P., Gurel M.S., Erdemir A.V. Vascular patterns of nonpigmented tumoral skin lesions: Confocal perspectives. Skin Res. Technol. Off. J. Int. Soc. Bioeng. Skin Int. Soc. Dig. Imag. Skin Int. Soc. Skin Imag. 2015;21:333–339. doi: 10.1111/srt.12197.
    1. Peppelman M., Nguyen K.P., Hoogedoorn L., van Erp P.E.J., Gerritsen M.-J.P. Reflectance confocal microscopy: Non-invasive distinction between actinic keratosis and squamous cell carcinoma. J. Eur. Acad. Dermatol. Venereol. 2015;29:1302–1309. doi: 10.1111/jdv.12806.
    1. Ahlgrimm-Siess V., Cao T., Oliviero M., Hofmann-Wellenhof R., Rabinovitz H.S., Scope A. The vasculature of nonmelanocytic skin tumors on reflectance confocal microscopy: Vascular features of squamous cell carcinoma in situ. Arch. Dermatol. 2011;147:264. doi: 10.1001/archdermatol.2010.416.
    1. Skobe M., Rockwell P., Goldstein N., Vosseler S., Fusenig N.E. Halting angiogenesis suppresses carcinoma cell invasion. Nat. Med. 1997;3:1222–1227. doi: 10.1038/nm1197-1222.
    1. Nguyen K.P., Peppelman M., Hoogedoorn L., van Erp P.E.J., Gerritsen M.-J.P. The current role of in vivo reflectance confocal microscopy within the continuum of actinic keratosis and squamous cell carcinoma: A systematic review. Eur. J. Dermatol. 2016;26:549–565. doi: 10.1684/ejd.2016.2872.
    1. Corchado-Cobos R., García-Sancha N., González-Sarmiento R., Pérez-Losada J., Cañueto J. Cutaneous Squamous Cell Carcinoma: From Biology to Therapy. Int. J. Mol. Sci. 2020;21:2956. doi: 10.3390/ijms21082956.
    1. Lane D.P. Cancer. p53, guardian of the genome. Nature. 1992;358:15–16. doi: 10.1038/358015a0.
    1. Campos M.A., Lopes J.M., Soares P. The genetics of cutaneous squamous cell carcinogenesis. Eur. J. Dermatol. 2018;28:597–605. doi: 10.1684/ejd.2018.3403.
    1. Di Nardo L., Pellegrini C., Di Stefani A., Del Regno L., Sollena P., Piccerillo A., Longo C., Garbe C., Fargnoli M.C., Peris K. Molecular genetics of cutaneous squamous cell carcinoma: Perspective for treatment strategies. J. Eur. Acad. Dermatol. Venereol. 2020;34:932–941. doi: 10.1111/jdv.16098.
    1. Li G., Tron V., Ho V. Induction of squamous cell carcinoma in p53-deficient mice after ultraviolet irradiation. J. Invest. Dermatol. 1998;110:72–75. doi: 10.1046/j.1523-1747.1998.00090.x.
    1. Brash D.E., Rudolph J.A., Simon J.A., Lin A., McKenna G.J., Baden H.P., Halperin A.J., Pontén J. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc. Natl. Acad. Sci. USA. 1991;88:10124–10128. doi: 10.1073/pnas.88.22.10124.
    1. Ziegler A., Jonason A.S., Leffell D.J., Simon J.A., Sharma H.W., Kimmelman J., Remington L., Jacks T., Brash D.E. Sunburn and p53 in the onset of skin cancer. Nature. 1994;372:773–776. doi: 10.1038/372773a0.
    1. Brash D.E., Ziegler A., Jonason A.S., Simon J.A., Kunala S., Leffell D.J. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J. Investig. Dermatol. Symp. Proc. 1996;1:136–142.
    1. Li Y.Y., Hanna G.J., Laga A.C., Haddad R.I., Lorch J.H., Hammerman P.S. Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin. Cancer Res. 2015;21:1447–1456. doi: 10.1158/1078-0432.CCR-14-1773.
    1. Yilmaz A.S., Ozer H.G., Gillespie J.L., Allain D.C., Bernhardt M.N., Furlan K.C., Castro L.T.F., Peters S.B., Nagarajan P., Kang S.Y., et al. Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors. Cancer. 2017;123:1184–1193. doi: 10.1002/cncr.30459.
    1. D’Arcangelo D., Tinaburri L., Dellambra E. The Role of p16INK4a Pathway in Human Epidermal Stem Cell Self-Renewal, Aging and Cancer. Int. J. Mol. Sci. 2017;18:1591. doi: 10.3390/ijms18071591.
    1. Sherr C.J. The INK4a/ARF network in tumour suppression. Nat. Rev. Mol. Cell Biol. 2001;2:731–737. doi: 10.1038/35096061.
    1. Brown V.L., Harwood C.A., Crook T., Cronin J.G., Kelsell D.P., Proby C.M. p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma. J. Invest. Dermatol. 2004;122:1284–1292. doi: 10.1111/j.0022-202X.2004.22501.x.
    1. Inman G.J., Wang J., Nagano A., Alexandrov L.B., Purdie K.J., Taylor R.G., Sherwood V., Thomson J., Hogan S., Spender L.C., et al. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nat. Commun. 2018;9:3667. doi: 10.1038/s41467-018-06027-1.
    1. Küsters-Vandevelde H.V.N., van Leeuwen A., Verdijk M.A.J., de Koning M.N.C., Quint W.G.V., Melchers W.J.G., Ligtenberg M.J.L., Blokx W.A.M. CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin. Int. J. Cancer. 2010;126:2123–2132. doi: 10.1002/ijc.24871.
    1. Bito T., Ueda M., Ahmed N.U., Nagano T., Ichihashi M. Cyclin D and retinoblastoma gene product expression in actinic keratosis and cutaneous squamous cell carcinoma in relation to p53 expression. J. Cutan. Pathol. 1995;22:427–434. doi: 10.1111/j.1600-0560.1995.tb00758.x.
    1. Shen Y., Xu J., Jin J., Tang H., Liang J. Cyclin D1 expression in Bowen’s disease and cutaneous squamous cell carcinoma. Mol. Clin. Oncol. 2014;2:545–548. doi: 10.3892/mco.2014.273.
    1. Huang K., Huang C., Shan K., Chen J., Li H. Significance of PC cell-derived growth factor and cyclin D1 expression in cutaneous squamous cell carcinoma. Clin. Exp. Dermatol. 2012;37:411–417. doi: 10.1111/j.1365-2230.2011.04275.x.
    1. Saawarn S., Astekar M., Saawarn N., Dhakar N., Gomateshwar Sagari S. Cyclin d1 expression and its correlation with histopathological differentiation in oral squamous cell carcinoma. Sci. World J. 2012;2012:978327. doi: 10.1100/2012/978327.
    1. Liang S.B., Furihata M., Takeuchi T., Iwata J., Chen B.K., Sonobe H., Ohtsuki Y. Overexpression of cyclin D1 in nonmelanocytic skin cancer. Virchows Arch. 2000;436:370–376. doi: 10.1007/s004280050461.
    1. Chiu C.P., Harley C.B. Replicative senescence and cell immortality: The role of telomeres and telomerase. Proceedings of the Society for Experimental Biology and Medicine. Soc. Exp. Biol. Med. 1997;214:99–106. doi: 10.3181/00379727-214-44075.
    1. Liu C.K., Shaffer P.M., Slaughter R.S., McCroskey R.P., Abbott M.T. Stoichiometry of the pyrimidine deoxyribonucleoside 2’-hydroxylase reaction and of the conversions of 5-hydroxymethyluracil to 5-formyluracil and of the latter to uracil-5-carboxylic acid. Biochemistry. 1972;11:2172–2176. doi: 10.1021/bi00761a025.
    1. Scott G.A., Laughlin T.S., Rothberg P.G. Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma. Mod. Pathol. 2014;27:516–523. doi: 10.1038/modpathol.2013.167.
    1. Lefort K., Mandinova A., Ostano P., Kolev V., Calpini V., Kolfschoten I., Devgan V., Lieb J., Raffoul W., Hohl D., et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev. 2007;21:562–577. doi: 10.1101/gad.1484707.
    1. Moretti F., Marinari B., Lo Iacono N., Botti E., Giunta A., Spallone G., Garaffo G., Vernersson-Lindahl E., Merlo G., Mills A.A., et al. A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias. J. Clin. Invest. 2010;120:1570–1577. doi: 10.1172/JCI40267.
    1. Stransky N., Egloff A.M., Tward A.D., Kostic A.D., Cibulskis K., Sivachenko A., Kryukov G.V., Lawrence M.S., Sougnez C., McKenna A., et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333:1157–1160. doi: 10.1126/science.1208130.
    1. Nicolas M., Wolfer A., Raj K., Kummer J.A., Mill P., van Noort M., Hui C., Clevers H., Dotto G.P., Radtke F. Notch1 functions as a tumor suppressor in mouse skin. Nat. Genet. 2003;33:416–421. doi: 10.1038/ng1099.
    1. Wang N.J., Sanborn Z., Arnett K.L., Bayston L.J., Liao W., Proby C.M., Leigh I.M., Collisson E.A., Gordon P.B., Jakkula L., et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc. Natl. Acad. Sci. USA. 2011;108:17761–17766. doi: 10.1073/pnas.1114669108.
    1. South A.P., Purdie K.J., Watt S.A., Haldenby S., den Breems N., Dimon M., Arron S.T., Kluk M.J., Aster J.C., McHugh A., et al. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J. Invest. Dermatol. 2014;134:2630–2638. doi: 10.1038/jid.2014.154.
    1. Smirnov A., Anemona L., Novelli F., Piro C.M., Annicchiarico-Petruzzelli M., Melino G., Candi E. p63 Is a Promising Marker in the Diagnosis of Unusual Skin Cancer. Int. J. Mol. Sci. 2019;20:5781. doi: 10.3390/ijms20225781.
    1. Duijf P.H.G., Vanmolkot K.R.J., Propping P., Friedl W., Krieger E., McKeon F., Dötsch V., Brunner H.G., van Bokhoven H. Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63. Hum. Mol. Genet. 2002;11:799–804. doi: 10.1093/hmg/11.7.799.
    1. Romano R.-A., Smalley K., Magraw C., Serna V.A., Kurita T., Raghavan S., Sinha S. ΔNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development. 2012;139:772–782. doi: 10.1242/dev.071191.
    1. Sen G.L., Boxer L.D., Webster D.E., Bussat R.T., Qu K., Zarnegar B.J., Johnston D., Siprashvili Z., Khavari P.A. ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. Dev. Cell. 2012;22:669–677. doi: 10.1016/j.devcel.2011.12.001.
    1. Reis-Filho J.S., Torio B., Albergaria A., Schmitt F.C. p63 expression in normal skin and usual cutaneous carcinomas. J. Cutan. Pathol. 2002;29:517–523. doi: 10.1034/j.1600-0560.2002.290902.x.
    1. Ha L., Ponnamperuma R.M., Jay S., Ricci M.S., Weinberg W.C. Dysregulated ΔNp63α inhibits expression of Ink4a/arf, blocks senescence, and promotes malignant conversion of keratinocytes. PLoS ONE. 2011;6:e21877. doi: 10.1371/journal.pone.0021877.
    1. Gatti V., Fierro C., Annicchiarico-Petruzzelli M., Melino G., Peschiaroli A. ΔNp63 in squamous cell carcinoma: Defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment. Mol. Oncol. 2019;13:981–1001. doi: 10.1002/1878-0261.12473.
    1. Pickering C.R., Zhou J.H., Lee J.J., Drummond J.A., Peng S.A., Saade R.E., Tsai K.Y., Curry J.L., Tetzlaff M.T., Lai S.Y., et al. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin. Cancer Res. 2014;20:6582–6592. doi: 10.1158/1078-0432.CCR-14-1768.
    1. Mauerer A., Herschberger E., Dietmaier W., Landthaler M., Hafner C. Low incidence of EGFR and HRAS mutations in cutaneous squamous cell carcinomas of a German cohort. Exp. Dermatol. 2011;20:848–850. doi: 10.1111/j.1600-0625.2011.01334.x.
    1. Fogarty G.B., Conus N.M., Chu J., McArthur G. Characterization of the expression and activation of the epidermal growth factor receptor in squamous cell carcinoma of the skin. Br. J. Dermatol. 2007;156:92–98. doi: 10.1111/j.1365-2133.2006.07603.x.
    1. Cañueto J., Cardeñoso E., García J.L., Santos-Briz Á., Castellanos-Martín A., Fernández-López E., Blanco Gómez A., Pérez-Losada J., Román-Curto C. Epidermal growth factor receptor expression is associated with poor outcome in cutaneous squamous cell carcinoma. Br. J. Dermatol. 2017;176:1279–1287. doi: 10.1111/bjd.14936.
    1. Nicholson R., Gee J., Harper M. EGFR and cancer prognosis. Eur. J. Cancer. 2001;37:9–15. doi: 10.1016/S0959-8049(01)00231-3.
    1. Oberholzer P.A., Kee D., Dziunycz P., Sucker A., Kamsukom N., Jones R., Roden C., Chalk C.J., Ardlie K., Palescandolo E., et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J. Clin. Oncol. 2012;30:316–321. doi: 10.1200/JCO.2011.36.7680.
    1. Su F., Viros A., Milagre C., Trunzer K., Bollag G., Spleiss O., Reis-Filho J.S., Kong X., Koya R.C., Flaherty K.T., et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 2012;366:207–215. doi: 10.1056/NEJMoa1105358.
    1. Chrisostomidis C., Konofaos P., Karypidis D., Lazaris A., Kostakis A., Papadopoulos O. The impact of Ets-1 oncoprotein and human endoglin (CD105) on the recurrence of non-melanoma skin cancers. Int. J. Dermatol. 2015;54:989–995. doi: 10.1111/ijd.12891.
    1. Keehn C.A., Smoller B.R., Morgan M.B. Ets-1 immunohistochemical expression in non-melanoma skin carcinoma. J. Cutan. Pathol. 2004;31:8–13. doi: 10.1046/j.0303-6987.2004.0158.x.
    1. Saxton R.A., Sabatini D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168:960–976. doi: 10.1016/j.cell.2017.02.004.
    1. Courtney K.D., Corcoran R.B., Engelman J.A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 2010;28:1075–1083. doi: 10.1200/JCO.2009.25.3641.
    1. Einspahr J.G., Calvert V., Alberts D.S., Curiel-Lewandrowski C., Warneke J., Krouse R., Stratton S.P., Liotta L., Longo C., Pellacani G., et al. Functional protein pathway activation mapping of the progression of normal skin to squamous cell carcinoma. Cancer Prev. Res. 2012;5:403–413. doi: 10.1158/1940-6207.CAPR-11-0427.
    1. Rodríguez-Paredes M., Esteller M. Cancer epigenetics reaches mainstream oncology. Nat. Med. 2011;17:330–339. doi: 10.1038/nm.2305.
    1. Vandiver A.R., Irizarry R.A., Hansen K.D., Garza L.A., Runarsson A., Li X., Chien A.L., Wang T.S., Leung S.G., Kang S., et al. Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol. 2015;16:80. doi: 10.1186/s13059-015-0644-y.
    1. Murao K., Kubo Y., Ohtani N., Hara E., Arase S. Epigenetic abnormalities in cutaneous squamous cell carcinomas: Frequent inactivation of the RB1/p16 and p53 pathways. Br. J. Dermatol. 2006;155:999–1005. doi: 10.1111/j.1365-2133.2006.07487.x.
    1. Sandoval J., Esteller M. Cancer epigenomics: Beyond genomics. Curr. Opin. Genet. Dev. 2012;22:50–55. doi: 10.1016/j.gde.2012.02.008.
    1. Darr O.A., Colacino J.A., Tang A.L., McHugh J.B., Bellile E.L., Bradford C.R., Prince M.P., Chepeha D.B., Rozek L.S., Moyer J.S. Epigenetic alterations in metastatic cutaneous carcinoma. Head Neck. 2015;37:994–1001. doi: 10.1002/hed.23701.
    1. Chiles M.C., Ai L., Zuo C., Fan C.-Y., Smoller B.R. E-cadherin promoter hypermethylation in preneoplastic and neoplastic skin lesions. Mod. Pathol. 2003;16:1014–1018. doi: 10.1097/01.MP.0000089779.35435.9D.
    1. Tanaka N., Odajima T., Ogi K., Ikeda T., Satoh M. Expression of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma. Br. J. Cancer. 2003;89:557–563. doi: 10.1038/sj.bjc.6601124.
    1. Rodríguez-Paredes M., Bormann F., Raddatz G., Gutekunst J., Lucena-Porcel C., Köhler F., Wurzer E., Schmidt K., Gallinat S., Wenck H., et al. Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin. Nat. Commun. 2018;9:577. doi: 10.1038/s41467-018-03025-1.
    1. Hervás-Marín D., Higgins F., Sanmartín O., López-Guerrero J.A., Bañó M.C., Igual J.C., Quilis I., Sandoval J. Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma. PLoS ONE. 2019;14:e0223341. doi: 10.1371/journal.pone.0223341.
    1. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705. doi: 10.1016/j.cell.2007.02.005.
    1. Eckert R.L., Adhikary G., Rorke E.A., Chew Y.C., Balasubramanian S. Polycomb group proteins are key regulators of keratinocyte function. J. Invest. Dermatol. 2011;131:295–301. doi: 10.1038/jid.2010.318.
    1. Ezhkova E., Pasolli H.A., Parker J.S., Stokes N., Su I., Hannon G., Tarakhovsky A., Fuchs E. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136:1122–1135. doi: 10.1016/j.cell.2008.12.043.
    1. Hernández-Ruiz E., Toll A., García-Diez I., Andrades E., Ferrandiz-Pulido C., Masferrer E., Yébenes M., Jaka A., Gimeno J., Gimeno R., et al. The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma. Carcinogenesis. 2018;39:503–513. doi: 10.1093/carcin/bgy016.
    1. Tampa M., Mitran C.I., Mitran M.I., Nicolae I., Dumitru A., Matei C., Manolescu L., Popa G.L., Caruntu C., Georgescu S.R. The Role of Beta HPV Types and HPV-Associated Inflammatory Processes in Cutaneous Squamous Cell Carcinoma. J. Immunol. Res. 2020;2020:5701639. doi: 10.1155/2020/5701639.
    1. McLaughlin-Drubin M.E., Münger K. Oncogenic activities of human papillomaviruses. Virus Res. 2009;143:195–208. doi: 10.1016/j.virusres.2009.06.008.
    1. Paradisi A., Waterboer T., Sampogna F., Tabolli S., Simoni S., Pawlita M., Abeni D. Seropositivity for human papillomavirus and incidence of subsequent squamous cell and basal cell carcinomas of the skin in patients with a previous nonmelanoma skin cancer. Br. J. Dermatol. 2011;165:782–791. doi: 10.1111/j.1365-2133.2011.10403.x.
    1. Astori G., Lavergne D., Benton C., Höckmayr B., Egawa K., Garbe C., de Villiers E.M. Human papillomaviruses are commonly found in normal skin of immunocompetent hosts. J. Invest. Dermatol. 1998;110:752–755. doi: 10.1046/j.1523-1747.1998.00191.x.
    1. Vasiljević N., Hazard K., Dillner J., Forslund O. Four novel human betapapillomaviruses of species 2 preferentially found in actinic keratosis. J. Gener. Virol. 2008;89:2467–2474. doi: 10.1099/vir.0.2008/001925-0.
    1. Toll A., Lloveras B., Masferrer E., Ferrándiz-Pulido C., García-Patos V., Gheit T., Pujol R.M., Tommasino M. Human beta papillomavirus DNA study in primary cutaneous squamous cell carcinomas and their corresponding metastases. Arch. Dermatol. Res. 2014;306:93–95. doi: 10.1007/s00403-013-1424-8.
    1. Albrengues J., Bertero T., Grasset E., Bonan S., Maiel M., Bourget I., Philippe C., Herraiz Serrano C., Benamar S., Croce O., et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 2015;6:10204. doi: 10.1038/ncomms10204.
    1. Campisi J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 2013;75:685–705. doi: 10.1146/annurev-physiol-030212-183653.
    1. Dotto G.P. Multifocal epithelial tumors and field cancerization: Stroma as a primary determinant. J. Clin. Invest. 2014;124:1446–1453. doi: 10.1172/JCI72589.
    1. Sasaki K., Sugai T., Ishida K., Osakabe M., Amano H., Kimura H., Sakuraba M., Kashiwa K., Kobayashi S. Analysis of cancer-associated fibroblasts and the epithelial-mesenchymal transition in cutaneous basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Hum. Pathol. 2018;79:1–8. doi: 10.1016/j.humpath.2018.03.006.
    1. Tinaburri L., Valente C., Teson M., Minafò Y.A., Cordisco S., Guerra L., Dellambra E. The Secretome of Aged Fibroblasts Promotes EMT-Like Phenotype in Primary Keratinocytes from Elderly Donors through BDNF-TrkB Axis. J. Invest. Dermatol. 2020 doi: 10.1016/j.jid.2020.08.019.
    1. Allen C.T., Ricker J.L., Chen Z., van Waes C. Role of activated nuclear factor-kappaB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head Neck. 2007;29:959–971. doi: 10.1002/hed.20615.
    1. Suarez-Carmona M., Hubert P., Gonzalez A., Duray A., Roncarati P., Erpicum C., Boniver J., Castronovo V., Noel A., Saussez S., et al. ΔNp63 isoform-mediated β-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma. Oncotarget. 2014;5:1856–1868. doi: 10.18632/oncotarget.1819.
    1. Brantsch K.D., Meisner C., Schönfisch B., Trilling B., Wehner-Caroli J., Röcken M., Breuninger H. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: A prospective study. Lancet Oncol. 2008;9:713–720. doi: 10.1016/S1470-2045(08)70178-5.
    1. Chren M.-M., Linos E., Torres J.S., Stuart S.E., Parvataneni R., Boscardin W.J. Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J. Invest. Dermatol. 2013;133:1188–1196. doi: 10.1038/jid.2012.403.
    1. Leibovitch I., Huilgol S.C., Selva D., Hill D., Richards S., Paver R. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years. J. Am. Acad. Dermatol. 2005;53:253–260. doi: 10.1016/j.jaad.2005.02.059.
    1. Marrazzo G., Zitelli J.A., Brodland D. Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone. J. Am. Acad. Dermatol. 2019;80:633–638. doi: 10.1016/j.jaad.2018.09.015.
    1. Brodland D.G., Zitelli J.A. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J. Am. Acad. Dermatol. 1992;27:241–248. doi: 10.1016/0190-9622(92)70178-I.
    1. Jambusaria-Pahlajani A., Miller C.J., Quon H., Smith N., Klein R.Q., Schmults C.D. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: A systematic review of outcomes. Dermatol. Surg. 2009;35:574–585. doi: 10.1111/j.1524-4725.2009.01095.x.
    1. Rowe D.E., Carroll R.J., Day C.L. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J. Am. Acad. Dermatol. 1992;26:976–990. doi: 10.1016/0190-9622(92)70144-5.
    1. Griffiths R.W., Feeley K., Suvarna S.K. Audit of clinical and histological prognostic factors in primary invasive squamous cell carcinoma of the skin: Assessment in a minimum 5 year follow-up study after conventional excisional surgery. Br. J. Plast. Surg. 2002;55:287–292. doi: 10.1054/bjps.2002.3833.
    1. Motaparthi K., Kapil J.P., Velazquez E.F. Cutaneous Squamous Cell Carcinoma: Review of the Eighth Edition of the American Joint Committee on Cancer Staging Guidelines, Prognostic Factors, and Histopathologic Variants. Adv. Anat. Pathol. 2017;24:171–194. doi: 10.1097/PAP.0000000000000157.
    1. Motley R., Kersey P., Lawrence C. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br. J. Plast. Surg. 2003;56:85–91. doi: 10.1016/S0007-1226(03)00028-6.
    1. Bonerandi J.J., Beauvillain C., Caquant L., Chassagne J.F., Chaussade V., Clavère P., Desouches C., Garnier F., Grolleau J.L., Grossin M., et al. Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions. J. Eur. Acad. Dermatol. Venereol. 2011;25(Suppl. 5):1–51. doi: 10.1111/j.1468-3083.2011.04296.x.
    1. Sapijaszko M., Zloty D., Bourcier M., Poulin Y., Janiszewski P., Ashkenas J. Non-melanoma Skin Cancer in Canada Chapter 5: Management of Squamous Cell Carcinoma. J. Cutan. Med. Surg. 2015;19:249–259. doi: 10.1177/1203475415582318.
    1. Chu M.B., Slutsky J.B., Dhandha M.M., Beal B.T., Armbrecht E.S., Walker R.J., Varvares M.A., Fosko S.W. Evaluation of the definitions of "high-risk" cutaneous squamous cell carcinoma using the american joint committee on cancer staging criteria and national comprehensive cancer network guidelines. J. Skin Cancer. 2014;2014:154340. doi: 10.1155/2014/154340.
    1. Stratigos A., Garbe C., Lebbe C., Malvehy J., Del Marmol V., Pehamberger H., Peris K., Becker J.C., Zalaudek I., Saiag P., et al. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur. J. Cancer. 2015;51:1989–2007. doi: 10.1016/j.ejca.2015.06.110.
    1. Löser C.R., Rompel R., Möhrle M., Häfner H.-M., Kunte C., Hassel J., Hohenleutner U., Podda M., Sebastian G., Hafner J., et al. S1 guideline: Microscopically controlled surgery (MCS) J. Dtsch. Dermatol. Ges. 2015;13:942–951. doi: 10.1111/ddg.12665.
    1. van Lee C.B., Roorda B.M., Wakkee M., Voorham Q., Mooyaart A.L., de Vijlder H.C., Nijsten T., van den Bos R.R. Recurrence rates of cutaneous squamous cell carcinoma of the head and neck after Mohs micrographic surgery vs. standard excision: A retrospective cohort study. Br. J. Dermatol. 2019;181:338–343. doi: 10.1111/bjd.17188.
    1. Veness M.J., Morgan G.J., Palme C.E., Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: Combined treatment should be considered best practice. Laryngoscope. 2005;115:870–875. doi: 10.1097/01.MLG.0000158349.64337.ED.
    1. Xiao Y., Yuan S., Liu F., Liu B., Zhu J., He W., Li W., Kan Q. Comparison between wait-and-see policy and elective neck dissection in clinically N0 cutaneous squamous cell carcinoma of head and neck. Medicine. 2018;97:e10782. doi: 10.1097/MD.0000000000010782.
    1. Cannon R.B., Dundar Y., Thomas A., Monroe M.M., Buchmann L.O., Witt B.L., Sowder A.M., Hunt J.P. Elective Neck Dissection for Head and Neck Cutaneous Squamous Cell Carcinoma with Skull Base Invasion. Otolaryngol. Head Neck Surg. Off. J. Am. Acad. Otolaryngol. Head Neck Surg. 2017;156:671–676. doi: 10.1177/0194599817691923.
    1. Morton C., Szeimies R.-M., Sidoroff A., Wennberg A.-M., Basset-Seguin N., Calzavara-Pinton P., Gilaberte Y., Hofbauer G., Hunger R., Karrer S., et al. European Dermatology Forum Guidelines on topical photodynamic therapy. Eur. J. Dermatol. 2015;25:296–311. doi: 10.1684/ejd.2015.2570.
    1. Patel R., Chang A.L.S. Immune Checkpoint Inhibitors for Treating Advanced Cutaneous Squamous Cell Carcinoma. Am. J. Clin. Dermatol. 2019;20:477–482. doi: 10.1007/s40257-019-00426-w.
    1. Migden M.R., Rischin D., Schmults C.D., Guminski A., Hauschild A., Lewis K.D., Chung C.H., Hernandez-Aya L., Lim A.M., Chang A.L.S., et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N. Engl. J. Med. 2018;379:341–351. doi: 10.1056/NEJMoa1805131.
    1. Lee A., Duggan S., Deeks E.D. Correction to: Cemiplimab: A Review in Advanced Cutaneous Squamous Cell Carcinoma. Drugs. 2020;80:939. doi: 10.1007/s40265-020-01332-w.
    1. Migden M.R., Khushalani N.I., Chang A.L.S., Lewis K.D., Schmults C.D., Hernandez-Aya L., Meier F., Schadendorf D., Guminski A., Hauschild A., et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: Results from an open-label, phase 2, single-arm trial. Lancet Oncol. 2020;21:294–305. doi: 10.1016/S1470-2045(19)30728-4.
    1. Rischin D., Migden M.R., Lim A.M., Schmults C.D., Khushalani N.I., Hughes B.G.M., Schadendorf D., Dunn L.A., Hernandez-Aya L., Chang A.L.S., et al. Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: Primary analysis of fixed-dosing, long-term outcome of weight-based dosing. J. Immunother. Cancer. 2020;8 doi: 10.1136/jitc-2020-000775.
    1. Ribero S., Stucci L.S., Daniels G.A., Borradori L. Drug therapy of advanced cutaneous squamous cell carcinoma: Is there any evidence? Curr. Opin. Oncol. 2017;29:129–135. doi: 10.1097/CCO.0000000000000359.
    1. Montaudié H., Viotti J., Combemale P., Dutriaux C., Dupin N., Robert C., Mortier L., Kaphan R., Duval-Modeste A.-B., Dalle S., et al. Cetuximab is efficient and safe in patients with advanced cutaneous squamous cell carcinoma: A retrospective, multicentre study. Oncotarget. 2020;11:378–385. doi: 10.18632/oncotarget.27434.
    1. William W.N., Feng L., Ferrarotto R., Ginsberg L., Kies M., Lippman S., Glisson B., Kim E.S. Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial. J. Am. Acad. Dermatol. 2017;77:1110–1113.e2. doi: 10.1016/j.jaad.2017.07.048.
    1. Brewster A.M., Lee J.J., Clayman G.L., Clifford J.L., Reyes M.J.T.N., Zhou X., Sabichi A.L., Strom S.S., Collins R., Meyers C.A., et al. Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J. Clin. Oncol. 2007;25:1974–1978. doi: 10.1200/JCO.2006.05.9873.
    1. Goyal U., Prabhakar N.K., Davuluri R., Morrison C.M., Yi S.K. Role of Concurrent Systemic Therapy with Adjuvant Radiation Therapy for Locally Advanced Cutaneous Head and Neck Squamous Cell Carcinoma. Cureus. 2017;9:e1784. doi: 10.7759/cureus.1784.
    1. Gellrich F.F., Hüning S., Beissert S., Eigentler T., Stockfleth E., Gutzmer R., Meier F. Medical treatment of advanced cutaneous squamous-cell carcinoma. J. Eur. Acad. Dermatol. Venereol. 2019;33:38–43. doi: 10.1111/jdv.16024.
    1. Behshad R., Garcia-Zuazaga J., Bordeaux J.S. Systemic treatment of locally advanced nonmetastatic cutaneous squamous cell carcinoma: A review of the literature. Br. J. Dermatol. 2011;165:1169–1177. doi: 10.1111/j.1365-2133.2011.10524.x.
    1. Trodello C., Pepper J.-P., Wong M., Wysong A. Cisplatin and Cetuximab Treatment for Metastatic Cutaneous Squamous Cell Carcinoma: A Systematic Review. Dermatol. Surg. 2017;43:40–49. doi: 10.1097/DSS.0000000000000799.
    1. Bertino G., Sersa G., de Terlizzi F., Occhini A., Plaschke C.C., Groselj A., Langdon C., Grau J.J., McCaul J.A., Heuveling D., et al. European Research on Electrochemotherapy in Head and Neck Cancer (EURECA) project: Results of the treatment of skin cancer. Eur. J. Cancer. 2016;63:41–52. doi: 10.1016/j.ejca.2016.05.001.
    1. Lansbury L., Bath-Hextall F., Perkins W., Stanton W., Leonardi-Bee J. Interventions for non-metastatic squamous cell carcinoma of the skin: Systematic review and pooled analysis of observational studies. BMJ. 2013;347:f6153. doi: 10.1136/bmj.f6153.
    1. Porceddu S.V. Prognostic factors and the role of adjuvant radiation therapy in non-melanoma skin cancer of the head and neck. Am. Soc. Clin. Oncol. Educ. Book. 2015:e513–e518. doi: 10.14694/EdBook_AM.2015.35.e513.
    1. Babington S., Veness M.J., Cakir B., Gebski V.J., Morgan G.J. Squamous cell carcinoma of the lip: Is there a role for adjuvant radiotherapy in improving local control following incomplete or inadequate excision? ANZ J. Surg. 2003;73:621–625. doi: 10.1046/j.1445-2197.2003.t01-1-02710.x.
    1. Likhacheva A., Awan M., Barker C.A., Bhatnagar A., Bradfield L., Brady M.S., Buzurovic I., Geiger J.L., Parvathaneni U., Zaky S., et al. Definitive and Postoperative Radiation Therapy for Basal and Squamous Cell Cancers of the Skin: Executive Summary of an American Society for Radiation Oncology Clinical Practice Guideline. Pract. Radiat. Oncol. 2020;10:8–20. doi: 10.1016/j.prro.2019.10.014.
    1. Cuperus E., Leguit R., Albregts M., Toonstra J. Post radiation skin tumors: Basal cell carcinomas, squamous cell carcinomas and angiosarcomas. A review of this late effect of radiotherapy. Eur. J. Dermatol. 2013;23:749–757. doi: 10.1684/ejd.2013.2106.
    1. Cassarino D.S., Derienzo D.P., Barr R.J. Cutaneous squamous cell carcinoma: A comprehensive clinicopathologic classification. Part one. J. Cutan. Pathol. 2006;33:191–206. doi: 10.1111/j.0303-6987.2006.00516-t1.x.
    1. Que S.K.T., Zwald F.O., Schmults C.D. Cutaneous squamous cell carcinoma: Management of advanced and high-stage tumors. J. Am. Acad. Dermatol. 2018;78:249–261. doi: 10.1016/j.jaad.2017.08.058.
    1. Concu R., Cordeiro M.N.D.S. Cetuximab and the Head and Neck Squamous Cell Cancer. Curr. Top. Med. Chem. 2018;18:192–198. doi: 10.2174/1568026618666180112162412.
    1. Maubec E. Update of the Management of Cutaneous Squamous-cell Carcinoma. Acta Derm. Venereol. 2020;100:adv00143. doi: 10.2340/00015555-3498.
    1. Cañueto J., Jaka A., Toll A. Utilidad de la radioterapia en adyuvancia en el carcinoma epidermoide cutáneo. Actas Dermosifiliogr. 2018;109:476–484. doi: 10.1016/j.ad.2018.03.007.
    1. Harris B.N., Pipkorn P., Nguyen K.N.B., Jackson R.S., Rao S., Moore M.G., Farwell D.G., Bewley A.F. Association of Adjuvant Radiation Therapy With Survival in Patients With Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck. JAMA Otolaryngol. Head Neck Surg. 2019;145:153–158. doi: 10.1001/jamaoto.2018.3650.
    1. Varra V., Smile T.D., Geiger J.L., Koyfman S.A. Recent and Emerging Therapies for Cutaneous Squamous Cell Carcinomas of the Head and Neck. Curr. Treat. Options Oncol. 2020;21:37. doi: 10.1007/s11864-020-00739-7.
    1. Gehl J., Sersa G., Matthiessen L.W., Muir T., Soden D., Occhini A., Quaglino P., Curatolo P., Campana L.G., Kunte C., et al. Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases. Acta Oncol. 2018;57:874–882. doi: 10.1080/0284186X.2018.1454602.
    1. Testori A., Tosti G., Martinoli C., Spadola G., Cataldo F., Verrecchia F., Baldini F., Mosconi M., Soteldo J., Tedeschi I., et al. Electrochemotherapy for cutaneous and subcutaneous tumor lesions: A novel therapeutic approach. Dermatol. Ther. 2010;23:651–661. doi: 10.1111/j.1529-8019.2010.01370.x.
    1. Di Monta G., Caracò C., Simeone E., Grimaldi A.M., Marone U., Di Marzo M., Vanella V., Festino L., Palla M., Mori S., et al. Electrochemotherapy efficacy evaluation for treatment of locally advanced stage III cutaneous squamous cell carcinoma: A 22-cases retrospective analysis. J. Transl. Med. 2017;15:82. doi: 10.1186/s12967-017-1186-8.
    1. Seyed Jafari S.M., Jabbary Lak F., Gazdhar A., Shafighi M., Borradori L., Hunger R.E. Application of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours: A systematic review and meta-analysis. Eur. J. Dermatol. 2018;28:287–313. doi: 10.1684/ejd.2018.3291.
    1. Saraiya M., Glanz K., Briss P.A., Nichols P., White C., Das D., Smith S.J., Tannor B., Hutchinson A.B., Wilson K.M., et al. Interventions to prevent skin cancer by reducing exposure to ultraviolet radiation: A systematic review. Am. J. Prev. Med. 2004;27:422–466. doi: 10.1016/j.amepre.2004.08.009.
    1. Gordon L.G., Rowell D. Health system costs of skin cancer and cost-effectiveness of skin cancer prevention and screening: A systematic review. Eur. J. Cancer Prevent. Off. J. Eur. Cancer Prevent. Organis. 2015;24:141–149. doi: 10.1097/CEJ.0000000000000056.
    1. Schmitt J., Haufe E., Trautmann F., Schulze H.-J., Elsner P., Drexler H., Bauer A., Letzel S., John S.M., Fartasch M., et al. Is ultraviolet exposure acquired at work the most important risk factor for cutaneous squamous cell carcinoma? Results of the population-based case-control study FB-181. Br. J. Dermatol. 2018;178:462–472. doi: 10.1111/bjd.15906.
    1. Strickland P.T., Vitasa B.C., West S.K., Rosenthal F.S., Emmett E.A., Taylor H.R. Quantitative carcinogenesis in man: Solar ultraviolet B dose dependence of skin cancer in Maryland watermen. J. Natl. Cancer Inst. 1989;81:1910–1913. doi: 10.1093/jnci/81.24.1910.
    1. Rosso S., Zanetti R., Martinez C., Tormo M.J., Schraub S., Sancho-Garnier H., Franceschi S., Gafà L., Perea E., Navarro C., et al. The multicentre south European study ‘Helios’. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br. J. Cancer. 1996;73:1447–1454. doi: 10.1038/bjc.1996.275.
    1. Schmitt J., Seidler A., Diepgen T.L., Bauer A. Occupational ultraviolet light exposure increases the risk for the development of cutaneous squamous cell carcinoma: A systematic review and meta-analysis. Br. J. Dermatol. 2011;164:291–307. doi: 10.1111/j.1365-2133.2010.10118.x.
    1. Henrikson N.B., Morrison C.C., Blasi P.R., Nguyen M., Shibuya K.C., Patnode C.D. Behavioral Counseling for Skin Cancer Prevention: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2018;319:1143–1157. doi: 10.1001/jama.2017.21630.
    1. Green A., Williams G., Nèale R., Hart V., Leslie D., Parsons P., Marks G.C., Gaffney P., Battistutta D., Frost C., et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: A randomised controlled trial. Lancet. 1999;354:723–729. doi: 10.1016/S0140-6736(98)12168-2.
    1. Roberts L.K., Beasley D.G. Commercial sunscreen lotions prevent ultraviolet-radiation-induced immune suppression of contact hypersensitivity. J. Invest. Dermatol. 1995;105:339–344. doi: 10.1111/1523-1747.ep12320339.
    1. Neale R., Russell A., Muller H.K., Green A. Sun exposure, sunscreen and their effects on epidermal Langerhans cells. Photochem. Photobiol. 1997;66:260–264. doi: 10.1111/j.1751-1097.1997.tb08652.x.
    1. Nijsten T.E., Stern R.S. Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: A nested cohort study. J. Am. Acad. Dermatol. 2003;49:644–650. doi: 10.1067/S0190-9622(03)01587-1.
    1. Bavinck J.N., Tieben L.M., van der Woude F.J., Tegzess A.M., Hermans J., ter Schegget J., Vermeer B.J. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: A double-blind, placebo-controlled study. J. Clin. Oncol. 1995;13:1933–1938. doi: 10.1200/JCO.1995.13.8.1933.
    1. Kraemer K.H., DiGiovanna J.J., Moshell A.N., Tarone R.E., Peck G.L. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N. Engl. J. Med. 1988;318:1633–1637. doi: 10.1056/NEJM198806233182501.
    1. McKenna D.B., Murphy G.M. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br. J. Dermatol. 1999;140:656–660. doi: 10.1046/j.1365-2133.1999.02765.x.
    1. George R., Weightman W., Russ G.R., Bannister K.M., Mathew T.H. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas. J. Dermatol. 2002;43:269–273. doi: 10.1046/j.1440-0960.2002.00613.x.
    1. Chen K., Craig J.C., Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: A systematic review of randomized controlled trials. Br. J. Dermatol. 2005;152:518–523. doi: 10.1111/j.1365-2133.2005.06347.x.
    1. Chen A.C., Martin A.J., Choy B., Fernández-Peñas P., Dalziell R.A., McKenzie C.A., Scolyer R.A., Dhillon H.M., Vardy J.L., Kricker A., et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N. Engl. J. Med. 2015;373:1618–1626. doi: 10.1056/NEJMoa1506197.
    1. Chen A.C., Martin A.J., Damian D.L. Nicotinamide for Skin-Cancer Chemoprevention. N. Engl. J. Med. 2016;374:789–790. doi: 10.1056/NEJMc1514791.
    1. Sidaway P. Skin cancer: Nicotinamide reduces new skin cancer risk. Nat. Rev. Clin. Oncol. 2016;13:4. doi: 10.1038/nrclinonc.2015.199.
    1. Fania L., Mazzanti C., Campione E., Candi E., Abeni D., Dellambra E. Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention. Int. J. Mol. Sci. 2019;20:5946. doi: 10.3390/ijms20235946.
    1. Johannesdottir S.A., Chang E.T., Mehnert F., Schmidt M., Olesen A.B., Sørensen H.T. Nonsteroidal anti-inflammatory drugs and the risk of skin cancer: A population-based case-control study. Cancer. 2012;118:4768–4776. doi: 10.1002/cncr.27406.
    1. Muranushi C., Olsen C.M., Pandeya N., Green A.C. Aspirin and nonsteroidal anti-inflammatory drugs can prevent cutaneous squamous cell carcinoma: A systematic review and meta-analysis. J. Invest. Dermatol. 2015;135:975–983. doi: 10.1038/jid.2014.531.
    1. Reinau D., Surber C., Jick S.S., Meier C.R. Nonsteroidal anti-inflammatory drugs and the risk of nonmelanoma skin cancer. Int. J. Cancer. 2015;137:144–153. doi: 10.1002/ijc.29357.
    1. Torti D.C., Christensen B.C., Storm C.A., Fortuny J., Perry A.E., Zens M.S., Stukel T., Spencer S.K., Nelson H.H., Karagas M.R. Analgesic and nonsteroidal anti-inflammatory use in relation to nonmelanoma skin cancer: A population-based case-control study. J. Am. Acad. Dermatol. 2011;65:304–312. doi: 10.1016/j.jaad.2010.05.042.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever