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Nonmelanoma Skin Cancer Actinic Keratosis and Squamous Cell Carcinoma

  • Birgit AignerEmail author
  • Franz Legat
  • Wolfgang Weger
Chapter
  • 567 Downloads

Abstract

Nonmelanoma skin cancer is the most common malignant tumor in Caucasians. Its pathogenesis is multifactorial. With a special focus on actinic keratosis and squamous cell carcinoma, we will give a short overview concerning basic knowledge and current histological classifications. Further, we discuss tumorigenesis and influencing factors, such as UV radiation, the inflammatory environment, hypoxia, presence of viruses, and the roles of the innate and adaptive immune system. Moreover, we give a short overview about targeted therapy of actinic keratosis and squamous cell carcinoma.

Keywords

Nonmelanoma skin cancer Actinic keratosis Squamous cell carcinoma Carcinogenesis 

References

  1. 1.
    Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol. 2002;146(61):1–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Hoey SE, Devereux CE, Murray L, Catney D, Gavin A, Kumar S, Donnelly D, Dolan OM. Skin cancer trends in Northern Ireland and consequences for provision of dermatology services. Br J Dermatol. 2007;156:1301–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Madan V, Lear JT, Szeimies RM. Non melanoma skin cancer. Lancet. 2010;375:673–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Martinez JC, Otley CC. The management of melanoma and non-melanoma skin cancer: a review for the primary care physician. Mayo Clin Proc. 2001;76:1253–65.CrossRefPubMedGoogle Scholar
  5. 5.
    Ratushny V, Gober MD, Hick R, Ridky TW, Sexkora JT. From keratinocyte to cancer: the pathogenesis and melding of cutaneous squamous cell cancer. J Clin Invest. 2012;122(2):464–72.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Salasche SJ. Epidemiology of actinic keratosis and squamous cell carcinoma. J Am Acad Dermatol. 2000;42:4–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Lambert SR, Mladkova N, Gulati A, Hamoudi R, Purdie K, Cerio R, Leigh I, Proby C, Harwood CA. Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling. Br J Cancer. 2014;110:520–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Pfister DG, Harpern AC. Skin squamous cell cancer: the tie is right for greater involvement of the medical oncologist. J Clin Oncol. 2007;25(15):1953–4.CrossRefPubMedGoogle Scholar
  9. 9.
    Rosso S, Zanetti R, Martinez C, Tormi MJ, Schraub S, Sancho-Garnier H, Franceschi S, Gafa L, Perea E, Navarro C, Laurent R, Schrameck C, Talamini R, Tumino R, Wechseler J. The multicenter 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(11):1447–54.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yoong C, De’Ambrosis B. Cutaneous invasive squamous cell carcinoma: 10-year experience and recommendations for follow up. Australas J Dermatol. 2009;50:261–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Ackerman AB. Solar keratosis is squamous cell carcinoma. Arch Dermatol. 2003;139:1216–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol. 2000;142:1154–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42:23–4.CrossRefPubMedGoogle Scholar
  14. 14.
    Jensen V, Prasad AR, Smith A, Raju M, Wendel CS, Schmelz M, Leyva W, Warneke J, Krouse RS. Prognostic criteria for squamous cell cancer of the skin. J Surg Res. 2010;159:509–16.CrossRefPubMedGoogle Scholar
  15. 15.
    Harwood CA, Leedham-Green M, Leigh IM, Proby CM. Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study. Arch Dermatol. 2005;141:456–64.CrossRefPubMedGoogle Scholar
  16. 16.
    Röwert-Huber J, Patel MJ, Forschner T, Ulrich C, Eberle J, Kerl H, Sterry W, Stockfleth E. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol. 2007;156(Suppl 3):8–12.CrossRefPubMedGoogle Scholar
  17. 17.
    Breuninger H, Eigentler T, Bootz F, Hauschild A, Kortmann RD, Wolff K, Stockfleth E, Szeimies RM, Rompel R, Garbe C, Grabbe S. Brief S2k guidelines- cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges. 2013;11(3):37–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Berman B, Cockerell CJ. Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation. J Am Acad Dermatol. 2013;68(1):10–9.CrossRefGoogle Scholar
  19. 19.
    Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffel DJ. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc. 1996;1:136–42.PubMedGoogle Scholar
  20. 20.
    Meyer N, Peyret-Lacombe A, Canguilhelm B, Medale-Giamarchi C, Mamouni K, Cristini A, Monferran S, Lamant L, Filleron T, Pradines A, Sordet O, Favre G. RhoB promotes cancer initiation by protecting keratinocytes from UVB- induced apoptosis but limits tumor aggressiveness. J Invest Dermatol. 2014;134:203–12.CrossRefPubMedGoogle Scholar
  21. 21.
    Buckman SY, Gresham A, Hale P, Hruza G, Anast J, Masferrer J, Pentland AP. Cox2 expression s induced by UVB exposure in human skin: implications for the development of skin cancer. Carcinogenesis. 1998;19:723–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, Korets L, Lam J, Tawfik D, DeNardo DG, Naldini L, de Visser KE, De Palma M, Coussens LM. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell. 2010;17:121–34.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Germano G, Allavena P, Mantovani A. Cytokines as a key component of cancer-related inflammation. Cytokine. 2008;43:374–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation and cancer. Cell. 2010;140:883–99.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mantovani A, Pierotti MA. Cancer and inflammation: a complex relationship. Cancer Lett. 2008;267:180–1.CrossRefPubMedGoogle Scholar
  27. 27.
    Gambichler T, Skrygan M, Hyun J, Bechara F, Tomi NS, Altmeyer P, Kreuter A. Cytokine mRNA expression in basal cell carcinoma. Arch Dermatol Res. 2006;298:139–41.CrossRefPubMedGoogle Scholar
  28. 28.
    Szepietowski JC, Walker C, McKenna DB, Hunter JA, McKenzie RC. Leukemia inhibitory factor and interleukin-8 expression in non melanoma skin cancers. Clin Exp Dermatol. 2001;26:72–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Yen HAT, Chiang LC, Wen KH, Tsai CC, Yu CL, Yu HS. The expression of cytokines by an established basal cell carcinoma cell line (BCC-1/KMC) compared with cultured normal keratinocytes. Arch Dermatol Res. 1996;288:157–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMedGoogle Scholar
  31. 31.
    Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, Mauri C, Coussens LM, Balkwill FR. B regulatory cells and the tumor-promoting actions of TNF -α during squamous carcinogenesis. Proc Natl Acad Sci U S A. 2011;108(26):10662–1066.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    De Visser KE, Coussens LM. The interplay between innate and adaptive immunity regulates cancer development. Cancer Immunol Immunother. 2005;54:1143–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation and cancer. J Clin Invest. 2007;117(5):1175–83.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    De Visser KE, Eichten A, Coussens LE. Paradoxical roles of the immune system during cancer development. Nature. 2006;6(1):24–37.Google Scholar
  35. 35.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bose F, Raeli L, Garutti C, Frigerio E, Cozzi A, Crimi M, Caprioli F, Scavelli R, Altomare G, Geginat J, Abrignani S, Reali E. Dual role of anti-TNF therapy: enhancement of TCR-mediated T cell activation in peripheral blood and inhibition of inflammation in target tissues. Clin Immunol. 2011;139:164–76.CrossRefPubMedGoogle Scholar
  37. 37.
    Zaidi RM, Merlino G. The two faces of interferon-γ in cancer. Clin Cancer Res. 2011;17(19):6118–24.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Pietrzak AT, Zalewska A, Chodorowska G, Krasowska D, Michalak-Stoma A, Nockowski P, Osemlak P, Paskowski T, Rolinski JM. Cytokines and anticytokines in psoriasis. Clin Chim Acta. 2008;394:7–21.CrossRefPubMedGoogle Scholar
  39. 39.
    Berhane T, Halliday GM, Cooke B, Barnetson RS. Inflammation is associated with progression of actinic keratosis to squamous cell carcinomas in humans. Br J Dermatol. 2002;146:810–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Hilbert DM, Kopf M, Mock BA, Köhler G, Rudikoff S. Interleukin 6 is essential for in vivo development of B lineage neoplasms. J Exp Med. 1995;182:243–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Smith CW, Chen Z, Dong G, Loukinova E, Pegram MY, Nicholas-Figueroa L, Van Waes C. The host environment promotes the development of primary and metastatic squamous cell carcinomas that constitutively express proinflammatory cytokines IL-1alpha, IL-6, GM-CSF, and KC. Clin Exp Metastasis. 1998;16(7):655–64.CrossRefPubMedGoogle Scholar
  42. 42.
    Matsuura H, Sakaue M, Subbaramaiahi K, Kamitani H, Eling TE, Dannenbergi AJ, Tanabe T, Inoue H, Arata J, Jetten AM. Regulation of cyclooxygenase-2 by interferon g and transforming growth factor a in normal human epidermal keratinocytes and squamous carcinoma cells. J Biol Chem. 1999;274(41):29138–48.CrossRefPubMedGoogle Scholar
  43. 43.
    Brocker EB, Zwaldo G, Holzmann B, Macher E, Sorg C. Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. Int J Cancer. 1988;41(4):526–7.CrossRefGoogle Scholar
  44. 44.
    Asadullah K, Döcke WD, Sabat R, Ebeling M, Volk HD, Sterry W. Interleukin-10 in der Dermatologie. Hautarzt. 1999;50:12–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ, Uyemura K. IL-10 production in cutaneous basal and squamous cell carcinomas. J Immunol. 1995;155:2240–7.PubMedGoogle Scholar
  46. 46.
    Huang SJ, Hijnen D, Murphy GF, Kupper TS, Calarese AW, Mollet IG, Schanbacher CF, Miller DM, Schmults D, Clark RA. Imiquimod enhances IFN-gamma production and effector function of T cells infiltrating human squamous cell carcinoma of the skin. J Invest Dermatol. 2009;126:2676–85.CrossRefGoogle Scholar
  47. 47.
    De Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 2005;7:411–23.CrossRefPubMedGoogle Scholar
  48. 48.
    Mantovani A, Biswas SK, GAldiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229:176–85.CrossRefPubMedGoogle Scholar
  49. 49.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Riihila PM, Nissinen LM, Ala-aho R, Kallajoki M, Grenman R, Meri S, Peltonen S, Peltonen J, Kähäri VM. Complement factor H: a biomarker for progression of cutaneous squamous cell cancer. J Invest Dermatol. 2014;134(2):498–506.CrossRefPubMedGoogle Scholar
  51. 51.
    Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011;364:656–65.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Arron ST, Jennings L, Nindl I, Rosl F, Bavinck BB, Seckin D, Trakatelli M, Murphy GM. Viral oncogenesis and its role in nonmelanoma skin cancer. Br J Dermatol. 2011;164:1201–13.CrossRefPubMedGoogle Scholar
  53. 53.
    Akgul B, Bostanci N, Westphal K, Nindl I, Navsaria H, Storey A, Pfister H. Human papillomavirus 5 and 8 E6 downregulate interleukin-8 secretion in primary human keratinocytes. J Gen Virol. 2010;91:888–92.CrossRefPubMedGoogle Scholar
  54. 54.
    Madkan VK, Cook-Norris RH, Steadman MC, Arora A, Mendoza N, Tyring SK. The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental cofactors. Br J Dermatol. 2007;57:228–41.CrossRefGoogle Scholar
  55. 55.
    Kaech SM, Wherry EJ. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity. 2007;27:393–405.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell. 2009;138:30–50.CrossRefPubMedGoogle Scholar
  57. 57.
    Wherry JE, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27:670–84.CrossRefPubMedGoogle Scholar
  58. 58.
    Klenerman P, Hill A. T cells and viral persistence: lessons from diverse infections. Nat Immunol. 2005;6(9):873–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Dreno B, Amici JM, Basset-Seguin N, Cribier B, Claudel JP, Richard MA. Management of actinic keratosis: a practical report and treatment algorithm from AKTeam expert clinicians. J Eur Acad Dermatol Venereol. 2014;28:1141–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Stockfleth E, Terhorst D, Hausschild A, Zouboulis CC, SChlaeger M, Oster-Schmidt C, Diiepgen T, Gollnick H, Korting HC, Merk H, Sterry W, Kerl K, Berking C. S1 Letilinie zur Behandlung der aktinischen Keratosen. 2011. AWMF Link: http://www.awmf.org/uploads/tx_szleitlinien/013-041l_S1_Aktinische_Keratose_2012-verlaengert.pdf.
  61. 61.
    Werner RN, Stockfleth E, Connolly SM, Correia O, Erdmann R, Foley P, Gupta AK, Jacobs A, Kerl H, Lim HW, Martin G, Paquet M, Pariser DM, Rosumeck S, Röwert-Huber HJ, Sahota A, Sangueza OP, Shumack S, Sporbeck B, Swanson NA, Torezan L, Nast A. Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis—International League of Dermatological Societies in cooperation with the European Dermatology Forum—Short version. J Eur Acad Dermatol Venereol. 2015;29(11):2069–79. doi: 10.1111/jdv.13180.CrossRefPubMedGoogle Scholar
  62. 62.
    Bonerandi JJ, Beauvillain CL, Chassagne JF, Chaussade V, Clavere P, Desouches C, Garnier F, Grossin M, Jourdain A, Lemonnier JY, Maillard H, Ortonna N, Rio E, Simon E, Sei JF, Grob JJ, Martin L. Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions. J Eur Acad Dermatol Venereol. 2011;25(5):1–51.CrossRefPubMedGoogle Scholar
  63. 63.
    Spallone G, Botti E, Costanzo A. Targeted therapy in non melanoma skin cancers. Cancers. 2011;3:2255–73.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  65. 65.
    Stratigos A, Garbe C, Lebbe C, Malvehy J, del Marmol V, Pehamberger H, Peris K, Becker JC, Zalaudek I, Saiag P, Middleton MR, Bastholt L, Testori A, Grob JJ. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51(14):1989–2007.CrossRefPubMedGoogle Scholar
  66. 66.
    Rudnick EW, Thareja S, Cherpelis B. Oral therapy for nonmelanoma skin cancer in patients with advanced disease and large tumor burden: a review of the literature with focus on a new generation of targeted therapies. Int J Dermatol. 2015;55(3):249–58. doi: 10.1111/ijd.12961.CrossRefPubMedGoogle Scholar
  67. 67.
    Galer CE, Corey CL, Wang Z, Younes MN, Gomez-Rivera F, Sa J, Ludwig DL, El-Naggar AK, Weber RS, Myers JN. Dual inhibition of epidermal growth factor receptor and insulin- like growth factor receptor 1 reduces angiogenesis and tumor growth in cutaneous squamous cell carcinoma. Head Neck. 2011;33:189–98.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Medical University of Graz, University Clinic of Dermatology and VenerologyGrazAustria

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