Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma
- Jennifer A DeSimone, MD
Jennifer A DeSimone, MD
- Assistant Professor
- Georgetown University Department of Dermatology
- Director, Cutaneous Lymphoma Program and Transplant Dermatology
- Inova Melanoma and Skin Cancer Center
- Pritesh S Karia, MPH
Pritesh S Karia, MPH
- Manager - Dermatologic Oncology Research Program
- Brigham and Women's Hospital
- Chrysalyne D Schmults, MD, MSCE
Chrysalyne D Schmults, MD, MSCE
- Director of Mohs and Dermatologic Surgery and the High-Risk Skin Cancer Clinic
- Brigham and Women's/Dana Farber Cancer Center
Cutaneous squamous cell carcinoma (SCC) is a relatively common malignancy derived from epidermal keratinocytes. Although most patients with cutaneous SCC present with localized disease that is cured with local treatment, tumor recurrence, metastasis, and death related to this disease occasionally occur. "High-risk" cutaneous SCCs are tumors that exhibit clinical or histologic features that have been associated with increased risk for aggressive tumor behavior. The best approach to the management of high-risk cutaneous SCC is not definitively known. Mohs micrographic surgery, surgical excision with complete tissue margin assessment, and radiation therapy are commonly used in the management of these lesions.
The clinical and pathological features of high-risk cutaneous SCC and the management of patients with these tumors will be reviewed here. The risk factors and diagnosis of cutaneous SCC, the treatment of low-risk cutaneous SCC, and systemic therapy for advanced cutaneous SCC are reviewed separately. (See "Epidemiology and risk factors for cutaneous squamous cell carcinoma" and "Clinical features and diagnosis of cutaneous squamous cell carcinoma (SCC)" and "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma" and "Treatment and prognosis of cutaneous squamous cell carcinoma" and "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas".)
Cutaneous squamous cell carcinoma (SCC) is the second most common human cancer with an estimated annual incidence of 186,157 to 419,843 cases in the United States . Cutaneous SCC may occur in individuals of all races and ethnicities, but most frequently occurs in people with light skin who sunburn easily. Highly-curable, localized cutaneous SCC occurs most frequently; locoregional or distant metastases develop in less than 1 percent to 5 percent of cases [2-6]. However, it has been estimated that deaths from cutaneous SCC are as common in the central and southern United States as deaths from many other common cancers including melanoma, leukemia, non-Hodgkin lymphoma, renal cancer, and bladder cancer . (See "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Epidemiology'.)
Although the literature supports a correlation between certain clinical and pathological features of cutaneous SCC with increased risk for tumor recurrence and metastasis (table 1), a lack of consensus over the definition of high-risk cutaneous SCC, a paucity of high-quality therapeutic studies, and the absence of a prognostic model that integrates multiple risk factors have made the prediction of patient outcomes and the formation of definitive management guidelines challenging. As an example, a survey-based study of 117 Mohs surgeons found a lack of consistency in the approach to the evaluation and management of high-risk SCC .
A wide variety of clinical and histopathologic factors have been proposed as indicators of increased risk for recurrence or metastasis of cutaneous squamous cell carcinoma (SCC). However, as noted above, a consensus on which features define high-risk cutaneous SCC has not been established; major entities such as the National Comprehensive Cancer Network (NCCN) and the American Joint Committee on Cancer (AJCC) describe dissimilar "high-risk" criteria (table 2A-B) [4,8]. In a retrospective study of 269 tumors, considerable discordance was observed between AJCC and NCCN definitions of high-risk cutaneous SCC. A small proportion of tumors were considered high-risk under the 2010 AJCC staging guidelines (14 percent), while a majority of tumors were considered high-risk under the NCCN guidelines (87 percent) . Examples of factors that have been associated with increased risk for metastasis or death on multivariate analysis in cohort studies include: clinical tumor diameter 2 cm or greater, depth of invasion >6 mm or beyond the subcutaneous fat, poor differentiation, perineural invasion, location on the ear, and immunosuppression [2,10-12]. These may be the most significant drivers of poor outcomes in SCC. However, all major characteristics that have been associated with aggressive tumor behavior are reviewed below (table 1).
- 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.
- Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008; 9:713.
- Samarasinghe V, Madan V, Lear JT. Management of high-risk squamous cell carcinoma of the skin. Expert Rev Anticancer Ther 2011; 11:763.
- Farasat S, Yu SS, Neel VA, 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.
- Rowe DE, Carroll RJ, Day CL Jr. 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.
- Brougham ND, Dennett ER, Cameron R, Tan ST. The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol 2012; 106:811.
- Jambusaria-Pahlajani A, Hess SD, Katz KA, et al. Uncertainty in the perioperative management of high-risk cutaneous squamous cell carcinoma among Mohs surgeons. Arch Dermatol 2010; 146:1225.
- http://www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf (Accessed on June 22, 2013).
- Chu MB, Slutsky JB, Dhandha MM, et al. 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.
- Jambusaria-pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol 2013.
- Schmults CD, Karia PS, Carter JB, 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.
- Haisma MS, Plaat BE, Bijl HP, et al. Multivariate analysis of potential risk factors for lymph node metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. J Am Acad Dermatol 2016; 75:722.
- Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg 2006; 32:1309.
- Wermker K, Kluwig J, Schipmann S, et al. Prediction score for lymph node metastasis from cutaneous squamous cell carcinoma of the external ear. Eur J Surg Oncol 2015; 41:128.
- Mullen JT, Feng L, Xing Y, et al. Invasive squamous cell carcinoma of the skin: defining a high-risk group. Ann Surg Oncol 2006; 13:902.
- Kraus DH, Carew JF, Harrison LB. Regional lymph node metastasis from cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1998; 124:582.
- Ross AS, Whalen FM, Elenitsas R, et al. Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study. Dermatol Surg 2009; 35:1859.
- Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 2002; 28:268.
- Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990; 94:624.
- Krediet JT, Beyer M, Lenz K, et al. Sentinel lymph node biopsy and risk factors for predicting metastasis in cutaneous squamous cell carcinoma. Br J Dermatol 2015; 172:1029.
- Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer 2006; 106:2389.
- Tavin E, Persky M. Metastatic cutaneous squamous cell carcinoma of the head and neck region. Laryngoscope 1996; 106:156.
- Veness MJ, Porceddu S, Palme CE, Morgan GJ. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007; 29:621.
- Levine DE, Karia PS, Schmults CD. Outcomes of Patients With Multiple Cutaneous Squamous Cell Carcinomas: A 10-Year Single-Institution Cohort Study. JAMA Dermatol 2015; 151:1220.
- Edwards MJ, Hirsch RM, Broadwater JR, et al. Squamous cell carcinoma arising in previously burned or irradiated skin. Arch Surg 1989; 124:115.
- Mendenhall WM, Ferlito A, Takes RP, et al. Cutaneous head and neck basal and squamous cell carcinomas with perineural invasion. Oral Oncol 2012; 48:918.
- Mendenhall WM, Amdur RJ, Hinerman RW, et al. Skin cancer of the head and neck with perineural invasion. Am J Clin Oncol 2007; 30:93.
- Balamucki CJ, Mancuso AA, Amdur RJ, et al. Skin carcinoma of the head and neck with perineural invasion. Am J Otolaryngol 2012; 33:447.
- Breuninger H, Schaumburg-Lever G, Holzschuh J, Horny HP. Desmoplastic squamous cell carcinoma of skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer 1997; 79:915.
- Salmon PJ, Hussain W, Geisse JK, et al. Sclerosing squamous cell carcinoma of the skin, an underemphasized locally aggressive variant: a 20-year experience. Dermatol Surg 2011; 37:664.
- Garcia C, Crowson AN. Acantholytic squamous cell carcinoma: is it really a more-aggressive tumor? Dermatol Surg 2011; 37:353.
- Yang A, Hanley A, Velazquez EF, Cassarino DS. Primary cutaneous myxoid spindle cell squamous cell carcinoma: a clinicopathologic study and review of the literature. J Cutan Pathol 2010; 37:465.
- Goepfert H, Dichtel WJ, Medina JE, et al. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg 1984; 148:542.
- Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol 2005; 23:759.
- Carter JB, Johnson MM, Chua TL, et al. Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study. JAMA Dermatol 2013; 149:35.
- Lin C, Tripcony L, Keller J, et al. Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features. Int J Radiat Oncol Biol Phys 2012; 82:334.
- Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011; 65:253.
- Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990; 49:506.
- Jensen P, Hansen S, Møller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999; 40:177.
- Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003; 348:1681.
- 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.
- Manyam BV, Gastman B, Zhang AY, et al. Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy. J Am Acad Dermatol 2015; 73:221.
- Frierson HF Jr, 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.
- Mehrany K, Weenig RH, Lee KK, et al. Increased metastasis and mortality from cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. J Am Acad Dermatol 2005; 53:1067.
- Mehrany K, Weenig RH, Pittelkow MR, et al. High recurrence rates of squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic leukemia. Dermatol Surg 2005; 31:38.
- Velez NF, Karia PS, Vartanov AR, et al. Association of advanced leukemic stage and skin cancer tumor stage with poor skin cancer outcomes in patients with chronic lymphocytic leukemia. JAMA Dermatol 2014; 150:280.
- Fine JD, Bauer EA, McGuire J, et al. Epidermolysis bullosa. In: Clinical, Epidemiologic and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry, The Johns Hopkins University Press, Baltimore, MD 2000. p.175.
- Pourreyron C, Cox G, Mao X, et al. Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression. J Invest Dermatol 2007; 127:2438.
- Sulica VI, Kao GF. Squamous-cell carcinoma of the scalp arising in lesions of discoid lupus erythematosus. Am J Dermatopathol 1988; 10:137.
- Mulwafu WK, Fagan JJ, Jessop S. Squamous cell carcinoma in black patients with discoid lupus erythematosus. S Afr J Surg 2006; 44:144.
- Gréco M, Kupfer-Bessaguet L, Delahaye JF, Plantin P. Multiple cutaneous squamous cell carcinomas arising in a patient with generalized morphea. Eur J Dermatol 2006; 16:90.
- Gmeinhart B, Hinterberger W, Greinix HT, et al. Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD). Bone Marrow Transplant 1999; 23:1197.
- Constantinou C, Widom K, Desantis J, Obmann M. Hidradenitis suppurativa complicated by squamous cell carcinoma. Am Surg 2008; 74:1177.
- Glazer ES, Bartels PH, Prasad AR, et al. Nuclear morphometry identifies a distinct aggressive cellular phenotype in cutaneous squamous cell carcinoma. Cancer Prev Res (Phila) 2011; 4:1770.
- Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol 2007; 25:2164.
- Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62:7350.
- Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998; 90:824.
- Ch'ng S, Low I, Ng D, et al. Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma. Hum Pathol 2008; 39:344.
- Giacchero D, Barrière J, Benezery K, et al. Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma--a report of eight cases. Clin Oncol (R Coll Radiol) 2011; 23:716.
- Maubec E, Petrow P, Scheer-Senyarich I, 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.
- Sweeny L, Dean NR, Magnuson JS, et al. EGFR expression in advanced head and neck cutaneous squamous cell carcinoma. Head Neck 2012; 34:681.
- Clark JR, Rumcheva P, Veness MJ. Analysis and comparison of the 7th edition American Joint Committee on Cancer (AJCC) nodal staging system for metastatic cutaneous squamous cell carcinoma of the head and neck. Ann Surg Oncol 2012; 19:4252.
- Breuninger H, Brantsch K, Eigentler T, Häfner HM. Comparison and evaluation of the current staging of cutaneous carcinomas. J Dtsch Dermatol Ges 2012; 10:579.
- Karia PS, Jambusaria-Pahlajani A, Harrington DP, 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.
- Kwon S, Dong ZM, Wu PC. Sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma: clinical experience and review of literature. World J Surg Oncol 2011; 9:80.
- Lansbury L, Bath-Hextall F, Perkins W, et al. Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies. BMJ 2013; 347:f6153.
- Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma. Dermatol Surg 2010; 36:1544.
- Leibovitch I, Huilgol SC, Selva D, 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.
- Leibovitch I, Huilgol SC, Selva D, et al. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia II. Perineural invasion. J Am Acad Dermatol 2005; 53:261.
- Ad Hoc Task Force, Connolly SM, Baker DR, 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; 67:531.
- Panizza B, Solares CA, Redmond M, et al. Surgical resection for clinical perineural invasion from cutaneous squamous cell carcinoma of the head and neck. Head Neck 2012; 34:1622.
- Solares CA, Lee K, Parmar P, et al. Epidemiology of clinical perineural invasion in cutaneous squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 2012; 146:746.
- LeBoeuf NR, Schmults CD. Update on the management of high-risk squamous cell carcinoma. Semin Cutan Med Surg 2011; 30:26.
- Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011; 65:263.
- Miller SJ, Alam M, Andersen J, et al. Basal cell and squamous cell skin cancers. J Natl Compr Canc Netw 2010; 8:836.
- 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; 60:406.
- Jambusaria-Pahlajani A, Miller CJ, Quon H, 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.
- Koyfman SA, Cooper JS, Beitler JJ, et al. ACR Appropriateness Criteria(®) Aggressive Nonmelanomatous Skin Cancer of the Head and Neck. Head Neck 2016; 38:175.
- Waxweiler W, Sigmon JR, Sheehan DJ. Adjunctive radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion. J Surg Oncol 2011; 104:104.
- Cox J. Radiation Oncology: Rationale, Techniques, Results, 8th ed, Mosby, Philadelphia 2003.
- Cranmer LD, Engelhardt C, Morgan SS. Treatment of unresectable and metastatic cutaneous squamous cell carcinoma. Oncologist 2010; 15:1320.
- Bumpous J. Metastatic cutaneous squamous cell carcinoma to the parotid and cervical lymph nodes: treatment and outcomes. Curr Opin Otolaryngol Head Neck Surg 2009; 17:122.
- O'Brien CJ, McNeil EB, McMahon JD, et al. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck 2002; 24:417.
- Veness MJ, Morgan GJ, Palme CE, 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.
- Wright TI, Spencer JM, Flowers FP. Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol 2006; 54:933.
- Toma S, Bonelli L, Sartoris A, et al. 13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group. Oncol Rep 2004; 11:1297.
- Brewster AM, Lee JJ, Clayman GL, 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.
- HIGH-RISK FEATURES
- Clinical features
- - Anatomic location
- - Tumor diameter
- - Recurrent tumors
- - Multiple tumors
- - Location in sites of chronic wounds, scars, or ionizing radiation
- - Neurologic symptoms
- Histologic features
- - Histologic grade and subtype
- - Tumor thickness
- - Perineural invasion
- Other features
- - Nuclear morphometry
- - Epidermal growth factor receptors
- Staging systems
- Tools for staging
- Sentinel lymph node biopsy
- - Mohs surgery
- - Excision with complete margin assessment
- - Conventional surgical excision
- - Extensive cases
- Radiation therapy
- Systemic therapy
- Management of nodal disease
- ORGAN TRANSPLANT RECIPIENTS
- ORAL RETINOIDS
- SUMMARY AND RECOMMENDATIONS