Management of Skin Cancer in the High-Risk Patient

Skin Cancer (BY Kwong, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Skin Cancer

Opinion Statement

Skin cancer is the most common of human cancers and outnumbers all other types of cancer combined in the USA by over threefold. The majority of non-melanoma skin cancers are easily treated with surgery or locally destructive techniques performed under local anesthesia in the cost-effective outpatient setting. However, there is a subset of “high-risk” cases that prove challenging in terms of morbidity, mortality, adjuvant treatment required, as well as overall cost to the health care system. In our opinion, the term “high risk” when applied to skin cancer can mean one of three things: a high-risk tumor with aggressive histologic and/or clinical features with an elevated risk for local recurrence or regional/distant metastasis, a high-risk patient with the ongoing development of multiple skin cancers, and a high-risk patient based on immunosuppression. We have recently proposed classifying NMSC as a chronic disease in a certain subset of patients. Although no consensus definition exists for a chronic disease in medicine, there are three components that are present in most definitions: duration of at least 1 year, need for ongoing medical care, and functional impairment and/or alteration of activities of daily living (ADLs) and quality of life (QOL). Immunosuppression can refer to exogenous (organ or stem cell transplant patients,) or endogenous (HIV, leukemia, lymphoma, genodermatoses with DNA mismatch repair problems or other immunosuppression) causes. These patients are at risk for high-risk tumors and/or the development of multiple tumors.


High-risk Transplant Basal cell carcinoma Squamous cell carcinoma Skin cancer Mohs surgery Surgery Cetuximab Vismodegib Cisplatin Sonidegib Radiation Acetretin 5-fluoruracil Imiquimod 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1••.
    Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, Hwang WT, Gelfand JM, Whalen FM, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA dermatol. 2013;149(4):402–10 In a retrospective cohort study, a proposed alternative staging system to the AJCC stratifies T2 tumors and highlights a sub grouping, T2b, that is responsible most poor outcomes.CrossRefPubMedGoogle Scholar
  2. 2••.
    O'Bryan K, Sherman W, Niedt GW, Taback B, Manolidis S, Wang A, et al. An evolving paradigm for the workup and management of high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2013;69(4):595–602.e1 A retrospective case review of 27 patients in an effort to establish an aggressive protocol for the management of high risk and “very” high risk SCC. Very high risk SCC may have improved outcome cetuximab, radaition, and surgical resection.CrossRefPubMedGoogle Scholar
  3. 3.
    Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA dermatol. 2015;151(10):1081–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Ozgediz D, Smith EB, Zheng J, Otero J, Tabatabai ZL, Corvera CU. Basal cell carcinoma does metastasize. Dermatol Online J. 2008;14(8):5.PubMedGoogle Scholar
  5. 5.
    Wysong A, Aasi SZ, Tang JY. Update on metastatic basal cell carcinoma: a summary of published cases from 1981 through 2011. JAMA Dermatol. 2013;149(5):615–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Sutton A, Crew A, Wysong A. Redefinition of skin cancer as a chronic disease. JAMA Dermatol. 2015;1-2.Google Scholar
  7. 7•.
    Wehner MR, Linos E, Parvataneni R, Stuart SE, Boscardin WJ, Chren MM. Timing of subsequent new tumors in patients who present with basal cell carcinoma or cutaneous squamous cell carcinoma. JAMA Dermatol. 2015;151(4):382–8 A prospective observational study of 1,284 patients with a mean of 5.7 years of follow up that established many aspects of risk of NMSC development.CrossRefPubMedGoogle Scholar
  8. 8.
    Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2 Pt 1):177–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Frierson Jr 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(12):1397–402.Google Scholar
  10. 10.
    Davis S, Capjack L, Kerr N, Fedosejevs R. Clothing as protection from ultraviolet radiation: which fabric is most effective? Int J Dermatol. 1997;36(5):374–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Isedeh P, Osterwalder U, Lim HW. Teaspoon rule revisited: proper amount of sunscreen application. Photodermatol Photoimmunol Photomed. 2013;29(1):55–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Schneider J. The teaspoon rule of applying sunscreen. Arch Dermatol. 2002;138(6):838–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Newman MD, Stotland M, Ellis JI. The safety of nanosized particles in titanium dioxide- and zinc oxide-based sunscreens. J Am Acad Dermatol. 2009;61(4):685–92.CrossRefPubMedGoogle Scholar
  14. 14.
    Chang YJ, Myung SK, Chung ST, Kim Y, Lee EH, Jeon YJ, et al. Effects of vitamin treatment or supplements with purported antioxidant properties on skin cancer prevention: a meta-analysis of randomized controlled trials. Dermatol (Basel, Switzerland). 2011;223(1):36–44.CrossRefGoogle Scholar
  15. 15•.
    Chen AC, Martin AJ, Choy B, Fernandez-Penas P, Dalziell RA, McKenzie CA, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618–26 Nicotinamide in a phase 3, double blinded, randomized controlled trial, dosed at 500 mg orally twice daily for one year created a 23% reduction in new NMSCs and 13% reduction in actinic keratoses.CrossRefPubMedGoogle Scholar
  16. 16.
    RED BOOK Online: Truven Health Analytics; 2016 [02/15/2016]. Available from:
  17. 17.
    Nakamura K, Okuyama R, Saida T, Uhara H. Platinum and anthracycline therapy for advanced cutaneous squamous cell carcinoma. Int J Clin Oncol. 2013;18(3):506–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Endrizzi B, Ahmed RL, Ray T, Dudek A, Lee P. Capecitabine to reduce nonmelanoma skin carcinoma burden in solid organ transplant recipients. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al]. 2013;39(4):634–45.CrossRefGoogle Scholar
  19. 19.
    Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388–99.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20•.
    Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, Chandra K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(8):745–51 In an open label phase 2 trial of itraconazole for BCC, overall tumor size was decreased by 24%, cell proliferation by 45%, and activated hedgehog pathway activity by 65%.CrossRefGoogle Scholar
  21. 21•.
    Migden MR, Guminski A, Gutzmer R, Dirix L, KD L, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716–28 In an ongoing multicenter randomized, double blinded phase 2 trial, patients received either 200 mg or 800 mg of sonidegib. The 200 mg and 800 mg group achieved an objective response of 36% and 39% respectively.CrossRefPubMedGoogle Scholar
  22. 22.
    Danial C, Sarin KY, Oro AE, Chang AL. An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib. Clinical cancer research: an official journal of the American Association for Cancer Research. 2015.Google Scholar
  23. 23•.
    Chang AL, Solomon JA, Hainsworth JD, Goldberg L, McKenna E, Day BM, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014;70(1):60–9 In an open label, 2-cohort, multicenter study of vismodegib, patients received 150 mg daily until tumor progression or intolerable toxicity. 119 patients received a median of 5.5 months of treatment, with objective response in 46% of laBCC and 30% in mBCC.CrossRefPubMedGoogle Scholar
  24. 24.
    Basset-Seguin N, Hauschild A, Grob JJ, Kunstfeld R, Dreno B, Mortier L, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015;16(6):729–36.CrossRefPubMedGoogle Scholar
  25. 25•.
    Ally MS, Aasi S, Wysong A, Teng C, Anderson E, Bailey-Healy I, et al. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):904–11.e1 An open label trial to assess change in target tumor surgical defect area, pre and post vismodegib demonstrated a 27% reduction in area from baseline.CrossRefPubMedGoogle Scholar
  26. 26.
    Sofen H, Gross KG, Goldberg LH, Sharata H, Hamilton TK, Egbert B, et al. A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol. 2015;73(1):99–105.e1.CrossRefPubMedGoogle Scholar
  27. 27•.
    Reigneau M, Robert C, Routier E, Mamelle G, Moya-Plana A, Tomasic G, et al. Efficacy of neoadjuvant cetuximab alone or with platinum salt for the treatment of unresectable advanced nonmetastatic cutaneous squamous cell carcinomas. British J Dermatol. 2015;173(2):527–34 In an open label, single site, 2-cohort study, patients with locally advanced SCC considered to be inoperable were pretreated with one cycle of cetuximab, cisplatin, or carboplatin, plus 5-FU. 92% of patients on combination therapy became amenable to surgery and 78% achieved complete remission.CrossRefGoogle Scholar
  28. 28.
    Heath CH, Deep NL, Nabell L, Carroll WR, Desmond R, Clemons L, et al. Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2013;85(5):1275–81.CrossRefPubMedGoogle Scholar
  29. 29.
    Desai A, Kartono F, Del Rosso JQ. Systemic retinoid therapy: a status report on optimal use and safety of long-term therapy. Dermatol Clin. 2007;25(2):185–93 vi.CrossRefPubMedGoogle Scholar
  30. 30.
    Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, 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 Off J Am Soc Clin Oncol. 1995;13(8):1933–8.Google Scholar
  31. 31.
    Kadakia KC, Barton DL, Loprinzi CL, Sloan JA, Otley CC, Diekmann BB, et al. Randomized controlled trial of acitretin versus placebo in patients at high-risk for basal cell or squamous cell carcinoma of the skin (north central cancer treatment group study 969251). Cancer. 2012;118(8):2128–37.CrossRefPubMedGoogle Scholar
  32. 32.
    Pomerantz H, Hogan D, Eilers D, Swetter SM, Chen SC, Jacob SE, et al. Long-term efficacy of topical fluorouracil cream, 5 %, for treating actinic keratosis: a randomized clinical trial. JAMA dermatology. 2015;151(9):952–60.CrossRefPubMedGoogle Scholar
  33. 33.
    Jambusaria-Pahlajani A, Ortman S, Schmults CD, Liang C. Sequential curettage, 5-fluorouracil, and photodynamic therapy for field cancerization of the scalp and face in solid organ transplant recipients. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al]. 2016;42(Suppl 1):S66–72.CrossRefGoogle Scholar
  34. 34.
    Held L, Eigentler TK, Leiter U, Garbe C, Berneburg MJ. Effective combination of photodynamic therapy and imiquimod 5 % cream in the treatment of actinic keratoses: three cases. Biomed Res Int. 2013;2013:102698.CrossRefPubMedGoogle Scholar
  35. 35.
    Berman B, Nestor MS, Newburger J, Park H, Swenson N. Treatment of facial actinic keratoses with aminolevulinic acid photodynamic therapy (ALA-PDT) or ingenol mebutate 0.015 % gel with and without prior treatment with ALA-PDT. J drugs Dermatol JDD. 2014;13(11):1353–6.PubMedGoogle Scholar
  36. 36.
    Togsverd-Bo K, Lei U, Erlendsson AM, Taudorf EH, Philipsen PA, Wulf HC, et al. Combination of ablative fractional laser and daylight-mediated photodynamic therapy for actinic keratosis in organ transplant recipients—a randomized controlled trial. British J Dermatol. 2015;172(2):467–74.CrossRefGoogle Scholar
  37. 37.
    Chen CS, Sierra H, Cordova M, Rajadhyaksha M. Confocal microscopy-guided laser ablation for superficial and early nodular basal cell carcinoma: a promising surgical alternative for superficial skin cancers. JAMA dermatol. 2014;150(9):994–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lippert J, Smucler R, Vlk M. Fractional carbon dioxide laser improves nodular basal cell carcinoma treatment with photodynamic therapy with methyl 5-aminolevulinate. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al]. 2013;39(8):1202–8.CrossRefGoogle Scholar
  39. 39.
    Abide JM, Nahai F, Bennett RG. The meaning of surgical margins. Plast Reconstr Surg. 1984;73(3):492–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Kimyai-Asadi A, Goldberg LH, Jih MH. Accuracy of serial transverse cross-sections in detecting residual basal cell carcinoma at the surgical margins of an elliptical excision specimen. J Am Acad Dermatol. 2005;53(3):469–74.PubMedGoogle Scholar
  41. 41.
    Breuninger H, Dietz K. Prediction of subclinical tumor infiltration in basal cell carcinoma. J Dermatologic Surg Oncol. 1991;17(7):574–8.CrossRefGoogle Scholar
  42. 42.
    Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1992;27(2 Pt 1):241–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Stratigos A, Garbe C, Lebbe C, Malvehy J, del Marmol V, Pehamberger H, et al. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer (Oxford, England: 1990). 2015;51(14):1989–2007.CrossRefGoogle Scholar
  44. 44.
    Connolly SM, Baker DR, Coldiron BM, Fazio MJ, Storrs PA, Vidimos AT, 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. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al]. 2012;38(10):1582–603.CrossRefGoogle Scholar
  45. 45••.
    van Loo E, Mosterd K, Krekels GA, Roozeboom MH, Ostertag JU, Dirksen CD, et al. Surgical excision versus Mohs' micrographic surgery for basal cell carcinoma of the face: a randomised clinical trial with 10 year follow-up. European journal of cancer (Oxford, England: 1990). 2014;50(17):3011–20 A randomized trial of MMS versus surgical excision (SE) for high risk facial BCC. The 10-year recurrence rates were 4.4% for MMS and 12.2% for SE for treatment of primary tumors.Google Scholar
  46. 46.
    Narayanan K, Hadid OH, Barnes EA. Mohs micrographic surgery versus surgical excision for periocular basal cell carcinoma. Cochrane database Syst Rev. 2014;12:Cd007041.Google Scholar
  47. 47.
    Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell and squamous cell carcinomas of the skin. Int J Radiat Oncol Biol Phys. 2004;60(2):406–11.CrossRefPubMedGoogle Scholar
  48. 48.
    Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthetic Dermatol. 2010;3(4):39–48.Google Scholar
  49. 49.
    Cho M, Gordon L, Rembielak A, Woo TC. Utility of radiotherapy for treatment of basal cell carcinoma: a review. British J Dermatol. 2014;171(5):968–73.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Keck School of Medicine of USCLos AngelesUSA

Personalised recommendations