Opinion Statement
Non-melanoma skin cancer (NMSC) is the most common malignancy in the USA, with cutaneous squamous cell carcinomas (cSCCs) constituting approximately 20 % of all NMSC. While cSCCs typically behave in an indolent fashion and can be cured with local destructive or surgical methods, a small subset metastasizes and induces significant morbidity and mortality. Identifying and aggressively treating these “high-risk” cSCCs (HRcSCCs) is thus paramount. Recent improvements in staging cSCCs appear to offer better risk stratification than earlier staging criteria. Radiologic imaging and sentinel lymph node biopsy may be beneficial in certain cases of HRcSCC, although more studies are needed before these techniques should be uniformly incorporated into management. Surgery with complete margin control, such as that offered by the Mohs micrographic technique, represents the first-line treatment for these tumors. Radiation therapy is likely most beneficial in the adjuvant setting. Chemotherapy is typically best reserved for patients with metastatic or locally advance disease that is not controllable with surgical and/or radiation therapies. Newer targeted treatments, such as EGFR inhibitors and immunotherapies may offer greater efficacy in these settings, although further evaluation is needed.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med. 2001;344:975–83.
Rogers HW et al. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol. 2015;151:1081–6. An update on the epidemiology and continued increase of non-melanoma skin cancers in the US population.
Wright TI, Spencer JM, Flowers FP. Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol. 2006;54:933–46.
Lardaro T et al. Improvements in the staging of cutaneous squamous-cell carcinoma in the 7th edition of the AJCC cancer staging manual. Ann Surg Oncol. 2010;17(8):1979–80.
Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68:957–66. This study provides a contemporary analysis of the morbidity and mortality associated with cSCC.
DePry JL et al. Cutaneous malignant neoplasms in hematopoietic cell transplant recipients: a systematic review. JAMA Dermatol. 2015;151:775–82.
Shterzer N et al. Human papillomavirus types detected in skin warts and cancer differ in their transforming properties but commonly counteract UVB induced protective responses in human keratinocytes. Virology. 2014;468–470:647–59.
Schmults CD et al. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. JAMA Dermatol. 2013;149:541–7. A large retrospective cohort study examining clinical factors associated with metastasis and disease-specific death in cutaneous squamous cell carcinoma. Identifies factors including tumor size, deep invasion, poor differentiation, perineural invasion and location.
Jambusaria-Pahlajani A et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149:402–10. This study demonstrated a new staging methodology may be more effective at risk-stratifying cSCC patients than other established criteria.
Connolly SM, Baker DR, Coldiron BM, Fazio MJ, et al. AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol. 2012;67(4):531–50.
Lee CS et al. Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma. Nat Genet. 2014;46:1060–2.
Commandeur S et al. Epidermal growth factor receptor activation and inhibition in 3D in vitro models of normal skin and human cutaneous squamous cell carcinoma. Cancer Sci. 2012;103:2120–6.
O’Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management. J Am Acad Dermatol. 2011;65:253–61.
Chockalingam R, Downing C, Tyring SK. Cutaneous squamous cell carcinomas in organ transplant recipients. J Clin Med. 2015;4:1229–39.
Wang J et al. Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta-analysis. J Am Acad Dermatol. 2014;70:621–9.
Connolly K et al. Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one notch closer to control. Cancer Treat Rev. 2014;40:205–14.
Farasat S et al. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol. 2011;64:1051–9.
Brantsch KD et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9:713–20.
Clayman GL et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005;23:759–65.
Mullen JT et al. Invasive squamous cell carcinoma of the skin: defining a high-risk group. Ann Surg Oncol. 2006;13:902–9.
Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47:1–17. quiz 18–20.
National Comprehensive Cancer Network. Squamous Cell Skin Cancer. N Version 1. 2016. http://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf. Accessed December 1, 2015.
Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1992;27:241–8.
Karia PS et al. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32:327–34. This study provides a contemporary analysis of the morbidity and mortality associated with cSCC.
Parikh SA, Patel VA, Ratner D. Advances in the management of cutaneous squamous cell carcinoma. F1000prime Reports. 2014;6:70.
Miller SJ. Defining, treating, and studying very high-risk cutaneous squamous cell carcinomas. Arch Dermatol. 2010;146:1292–5.
Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91.
Smith KJ, Hamza S, Skelton H. Histologic features in primary cutaneous squamous cell carcinomas in immunocompromised patients focusing on organ transplant patients. Dermatol Surg. 2004;30:634–41.
Martorell-Calatayud A et al. Cutaneous squamous cell carcinoma: defining the high-risk variant. Actas Dermo-Sifiliográficas. 2013;104:367–79.
Martinez J-C et al. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139:301–6.
De Luca JF et al. Dermatologist and gastroenterologist awareness of the potential of immunosuppressants used to treat inflammatory bowel disease to cause non-melanoma skin cancer. Int J Dermatol. 2013;52:955–9.
van den Reek JMPA et al. Increased incidence of squamous cell carcinoma of the skin after long-term treatment with azathioprine in patients with auto-immune inflammatory rheumatic diseases. J Eur Acad Dermatol Venereol: JEADV. 2014;28:27–33.
Frierson HF, Deutsch BD, Levine PA. Clinicopathologic features of cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol. 1988;19:1397–402.
Anzai Y, Brunberg JA, Lufkin RB. Imaging of nodal metastases in the head and neck. J Magn Reson Imaging: JMRI. 1997;7:774–83.
Prehn RB et al. Influence of computed tomography on pretherapeutic tumor staging in head and neck cancer patients. Otolaryngol Head Neck Surg. 1998;119:628–33.
Stern WB et al. Computed tomography of the clinically negative neck. Head Neck. 1990;12:109–13.
Marrazzo G et al. Clinical and pathologic factors predictive of positive radiologic findings in high-risk cutaneous squamous cell carcinoma. Dermatol Surg. 2015;41:1405–10.
Yoon DY et al. CT, MR, US,18F-FDG PET/CT, and their combined use for the assessment of cervical lymph node metastases in squamous cell carcinoma of the head and neck. Eur Radiol. 2009;19:634–42.
Jambusaria-Pahlajani A et al. Uncertainty in the perioperative management of high-risk cutaneous squamous cell carcinoma among Mohs surgeons. Arch Dermatol. 2010;146:1225–31.
Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous and basal cell carcinoma: CT and MR detection and its impact on patient management and prognosis. Int J Radiat Oncol Biol Phys. 2001;49:1061–9.
Tomaszewski JM, Lau E, Corry J. Utility of positron emission tomography/computed tomography for nodal staging of cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. Am J Otolaryngol. 2014;35:66–9.
Navarrete-Dechent C et al. High-risk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: a literature review. J Am Acad Dermatol. 2015;73:127–37.
de Bree R, et al. Advances in diagnostic modalities to detect occult lymph node metastases in head and neck squamous cell carcinoma. Head Neck, 2014.
Fukushima S et al. Evaluation of sentinel node biopsy for cutaneous squamous cell carcinoma. J Dermatol. 2014;41:539–41.
Schmitt AR et al. Staging for cutaneous squamous cell carcinoma as a predictor of sentinel lymph node biopsy results: meta-analysis of American Joint Committee on Cancer criteria and a proposed alternative system. JAMA Dermatol. 2014;150:19–24.
Swanson NA. Mohs surgery. Technique, indications, applications, and the future. Arch Dermatol. 1983;119:761–73.
Leibovitch I et al. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol. 2005;53:253–60.
Belkin D, Carucci JA. Mohs surgery for squamous cell carcinoma. Dermatol Clin. 2011;29:161–174, vii.
Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma. Dermatol Surg. 2010;36:1544–53.
Alam M et al. Adverse events associated with Mohs micrographic surgery: multicenter prospective cohort study of 20,821 cases at 23 centers. JAMA Dermatol. 2013;149:1378–85.
Veness MJ et al. Squamous cell carcinoma of the lip. Patterns of relapse and outcome: reporting the Westmead Hospital experience, 1980-1997. Australas Radiol. 2001;45:195–9.
Caccialanza M et al. Relevance of dermatologic radiotherapy in the therapeutic strategy of skin epithelial neoplasms: excellent results in the treatment of lesions localized on eyelids and skin overlying the cartilage of the nose. Giornale Italiano Di Dermatol E Venereol: Organo Ufficiale, Società Italiana Di Dermatol E Sifilografia. 2013;148:83–8.
Veness M, Richards S. Role of modern radiotherapy in treating skin cancer. Australas J Dermatol. 2003;44:159–166. quiz 167–168.
Jambusaria-Pahlajani A et al. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg. 2009;35:574–85.
Oddone N et al. Metastatic cutaneous squamous cell carcinoma of the head and neck: the immunosuppression, treatment, extranodal spread, and margin status (ITEM) prognostic score to predict outcome and the need to improve survival. Cancer. 2009;115:1883–91.
Veness MJ. Treatment recommendations in patients diagnosed with high-risk cutaneous squamous cell carcinoma. Australas Radiol. 2005;49:365–76.
Jarkowski A. et al. Systemic therapy in advanced cutaneous squamous cell carcinoma (CSCC): The Roswell park experience and a review of the literature. Am J Clin Oncol, 2014.
Shin DM et al. Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol. 2002;20:364–70.
Maubec E et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol. 2011;29:3419–26. A phase II study of cetuximab in use of cutaneous squamous cell carcinoma, showing a 69 % disease control rate at 6 weeks.
Reigneau M et al. Efficacy of neoadjuvant cetuximab alone or with platinum salt for the treatment of unresectable advanced nonmetastatic cutaneous squamous cell carcinomas. Br J Dermatol. 2015;173:527–34.
Foote MC et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Ann Oncol. 2014;25:2047–52.
Engelhardt C et al. Metastatic cutaneous squamous cell carcinoma responding to erlotinib therapy. J Am Acad Dermatol. 2011;65:237–8.
Baltaci M et al. Treatment with gefitinib (ZD 1839) in a patient with advanced cutaneous squamous cell carcinoma. Br J Dermatol. 2005;153:234–6.
Chang AL, Kim J, Luciano R, Sullivan-Chang L, Colevas AD. A case report of unresectable cutaneous squamous cell carcinoma responsive to pembrolizumab, a programmed cell deatH PROTEAN 1 inhibitor. JAMA Dermatol. 2016;152(1):106–8.
Shimizu T et al. Epidermal growth factor receptor overexpression and genetic aberrations in metastatic squamous-cell carcinoma of the skin. Dermatology. 2001;202:203–6.
Uribe P, Gonzalez S. Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy. Pathol Res Pract. 2011;207:337–42.
Gaffney DC, Soyer HP, Simpson F. The epidermal growth factor receptor in squamous cell carcinoma: an emerging drug target. Australas J Dermatol. 2014;55:24–34.
Eder J, Simonitsch-Klupp I, Trautinger F. Treatment of unresectable squamous cell carcinoma of the skin with epidermal growth factor receptor antibodies—a case series. Eur J Dermatol: EJD. 2013;23:658–62.
Mavropoulos JC, Aldabagh B, Arron ST. Prospects for personalized targeted therapies for cutaneous squamous cell carcinoma. Semin Cutaneous Med Surg. 2014;33:72–5.
Clayburgh DR et al. Effects of epidermal growth factor receptor and insulin-like growth factor 1 receptor inhibition on proliferation and intracellular signaling in cutaneous SCCHN: potential for dual inhibition as a therapeutic modality. Head Neck. 2013;35:86–93.
Choi D-K et al. Clinicopathological roles of S100A8 and S100A9 in cutaneous squamous cell carcinoma in vivo and in vitro. Arch Dermatol Res. 2014;306:489–96.
Honeychurch J et al. Immuno-regulatory antibodies for the treatment of cancer. Expert Opin Biol Ther. 2015;15:787–801.
Pai SI. Adaptive immune resistance in HPV-associated head and neck squamous cell carcinoma. Oncoimmunology. 2013;2:e24065.
Agarwala SS. Practical approaches to immunotherapy in the clinic. Semin Oncol. 2015;42 Suppl 3:S20–7.
Lipson EJ et al. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol. 2014;32:e69–71.
Gildener-Leapman N, Ferris RL, Bauman JE. Promising systemic immunotherapies in head and neck squamous cell carcinoma. Oral Oncol. 2013;49:1089–96.
Perrett CM et al. Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. Brit J Dermatol. 2008;159:198–204.
Neuburg M. Transplant-associated skin cancer: role of reducing immunosuppression. J Nat Comprehensive Cancer Network: JNCCN. 2007;5:541–9.
Zwald FO et al. Duration of voriconazole exposure: an independent risk factor for skin cancer after lung transplantation. Dermatol Surg. 2012;38:1369–74.
Lebwohl M et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010–9.
Gupta AK et al. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;12:CD004415.
Willey A, Mehta S, Lee PK. Reduction in the incidence of squamous cell carcinoma in solid organ transplant recipients treated with cyclic photodynamic therapy. Dermatol Surg. 2010;36:652–8.
Bavinck JN et al. 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;13:1933–8.
Otley CC et al. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562–8.
Rossi AM, Hibler BP, Johnson-Jahangir H. Serum sirolimus level elevation induced by acitretin: report of a novel drug-drug interaction. J Drugs Dermatol: JDD. 2015;14:747–9.
Jirakulaporn T et al. Capecitabine for skin cancer prevention in solid organ transplant recipients. Clin Transpl. 2011;25:541–8.
Endrizzi BT, Lee PK. Management of carcinoma of the skin in solid organ transplant recipients with oral capecitabine. Dermatol Surg. 2009;35:1567–72.
Endrizzi B et al. Capecitabine to reduce nonmelanoma skin carcinoma burden in solid organ transplant recipients. Dermatol Surg. 2013;39:634–45.
Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26:976–90.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Teresa Fu declares that she has no conflict of interest.
Sumaira Z. Aasi has received compensation from Genentech for service as a consultant.
S. Tyler Hollmig declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Skin Cancer
Rights and permissions
About this article
Cite this article
Fu, T., Aasi, S.Z. & Hollmig, S.T. Management of High-Risk Squamous Cell Carcinoma of the Skin. Curr. Treat. Options in Oncol. 17, 34 (2016). https://doi.org/10.1007/s11864-016-0408-2
Published:
DOI: https://doi.org/10.1007/s11864-016-0408-2