Highlights
- •Surgical excision with negative margins is an important goal whenever feasible.
- •Radiotherapy is indicated for inoperable cSCC or patients not suitable for surgical intervention.
- •Multidisciplinary board decisions are necessary in the management of patients with advanced disease.
- •Anti-PD-1 antibody therapy is first-line systemic treatment for locally advanced or mcSCC.
- •Follow-up evaluations depend on underlying risk characteristics.
Abstract
In order to update recommendations on treatment, supportive care, education and follow-up
of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary
panel of experts from the European Dermatology Forum, the European Association of
Dermato-Oncology and the European Organization of Research and Treatment of Cancer was
formed. Recommendations were based on evidence-based literature review, guidelines
and expert consensus. Treatment recommendations are presented for common primary cSCC
(low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or
inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent
cSCC type), first-line treatment is surgical excision with postoperative margin assessment
or microscopically controlled sugery. Safety margins containing clinical normal-appearing
tissue around the tumour during surgical excision and negative margins as reported
in the pathology report are necessary to minimise the risk of local recurrence and
metastasis. In case of positive margins, a re-excision shall be done, for operable
cases. Lymph node dissection is recommended for cSCC with cytologically or histologically
confirmed regional nodal involvement. Radiotherapy should be considered as curative
treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies
are the first-line systemic treatment for patients with metastatic or locally advanced
cSCC who are not candidates for curative surgery or radiation, with cemiplimab being
the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European
Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal
growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation
therapy. Multidisciplinary board decisions are mandatory for all patients with advanced
disease who require more than surgery. Patients should be engaged with informed decisions
on management and be provided with best supportive care to optimise symptom management
and improve quality of life. Frequency of follow-up visits and investigations for
subsequent new cSCC depend on underlying risk characteristics.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, et al. In: Group OLoEW, editor. The Oxford Levels of Evidence 2: Oxford Center for Evifdence-Based Medicine. https://www.cebm.net/index.aspx?o=5653. [Accessed23 April 2019].
- The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.J Surg Oncol. 2012; 106: 811-815
- Cetuximab-radiotherapy combination in the management of locally advanced cutaneous squamous cell carcinoma.J Med Imaging Radiat Oncol. 2019; 63: 257-263
- Advanced cutaneous squamous cell carcinoma: a retrospective analysis of patient profiles and treatment patterns-Results of a non-interventional study of the DeCOG.Eur J Cancer. 2018; 96: 34-43
- Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.Lancet Oncol. 2008; 9: 713-720
- Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma.J Invest Dermatol. 2013; 133: 1188-1196
- Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years.J Am Acad Dermatol. 2005; 53: 253-260
- Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma.Dermatol Surg. 2010; 36: 1544-1553
- Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone.J Am Acad Dermatol. 2019; 80: 633-638
- 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
- Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.BMJ. 2013; 347: f6153
- A confusing world: what to call histology of three-dimensional tumour margins?.J Eur Acad Dermatol Venereol. 2007; 21: 591-595
- S1 guideline: microscopically controlled surgery (MCS).J Dtsch Dermatol Ges. 2015; 13: 942-951
- Surgical margins for excision of primary cutaneous squamous cell carcinoma.J Am Acad Dermatol. 1992; 27: 241-248
- 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
- NCCN Clinical Practice Guidelines in Oncology. Squamous cell Skin Cancer.(version 2.2019-October 23)2018 (Available at)
- Effective excision of cutaneous squamous cell carcinoma of the face using analysis of intra-operative frozen sections from the whole specimen.J Surg Oncol. 2018; 117: 473-478
- False-negative rate of intraoperative frozen section margin analysis for complex head and neck nonmelanoma skin cancer excisions.Clin Exp Dermatol. 2015; 40: 834-838
- 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
- Excision margins for nonmelanotic skin cancer.Plast Reconstr Surg. 2003; 112: 57-63
- Squamocellular carcinoma of the skin: clinicopathological features predicting the involvement of the surgical margins and review of the literature.Dermatology. 2016; 232: 279-284
- British Association of D, British Association of Plastic S. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma.Br J Plast Surg. 2003; 56: 85-91
- Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions.J Eur Acad Dermatol Venereol. 2011; 25: 1-51
- Non-melanoma Skin Cancer in Canada Chapter 5: management of Squamous Cell Carcinoma.J Cutan Med Surg. 2015; 19: 249-259
- Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline.Eur J Cancer. 2015; 51: 1989-2007
- Guidelines of care for the management of cutaneous squamous cell carcinoma.J Am Acad Dermatol. 2018; 78: 560-578
- Clinical Practice Guidelines in Oncology. Cutaneous Melanoma.2019https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdfVersion: Version 1Date accessed: March 12, 2019
- Brief S2k guidelines – cutaneous squamous cell carcinoma.J Dtsch Dermatol Ges. 2013; 11 (39–47): 37-45
- Non-melanoma skin cancer: United Kingdom National Multidisciplinary Guidelines.J Laryngol Otol. 2016; 130: S125-S132
- 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: 976-990
- 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
- Management of regional metastatic disease in head and neck cutaneous malignancy. 1. Cutaneous squamous cell carcinoma.Br J Oral Maxillofac Surg. 2014; 52: 294-300
- Management of the neck in metastatic cutaneous squamous cell carcinoma of the head and neck.Curr Opin Otolaryngol Head Neck Surg. 2011; 19: 99-105
- Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland.Head Neck. 2002; 24: 417-422
- Patterns of lymph node spread of cutaneous squamous cell carcinoma of the head and neck.Head Neck. 2006; 28: 785-791
- Outcome of patients treated surgically for lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.Head Neck. 2011; 33: 999-1004
- Predicting the pattern of regional metastases from cutaneous squamous cell carcinoma of the head and neck based on location of the primary.Head Neck. 2010; 32: 1288-1294
- Treatment results of regional metastasis from cutaneous head and neck squamous cell carcinoma.Eur J Surg Oncol. 2003; 29: 81-86
- In patients with metastatic cutaneous head and neck squamous cell carcinoma to cervical lymph nodes, the extent of neck dissection does not influence outcome.J Laryngol Otol. 2013; 127: S2-S7
- Outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center.Head Neck. 2015; 37: 1808-1815
- Cutaneous metastatic squamous cell carcinoma to the parotid gland: analysis and outcome.Head Neck. 2004; 26: 727-732
- 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
- Elective neck dissection for head and neck cutaneous squamous cell carcinoma with skull base invasion.Otolaryngol Head Neck Surg. 2017; 156: 671-676
- Elective neck dissection in metastatic cutaneous squamous cell carcinoma to the parotid gland: a systematic review and meta-analysis.Head Neck. 2019; 41: 1131-1139
- European Dermatology Forum Guidelines on topical photodynamic therapy.Eur J Dermatol. 2015; 25: 296-311
- A review of the literature of surgical and nonsurgical treatments of invasive squamous cells carcinoma.BioMed Res Int. 2018; 2018: 9489163
- Efficacy of curettage alone for invasive cutaneous squamous cell carcinoma: a retrospective cohort study.J Am Acad Dermatol. 2017; 77: 582-584
- Successful treatment of keratoacanthoma with intralesional fluorouracil.J Am Acad Dermatol. 1980; 2: 212-216
- Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature.J Am Acad Dermatol. 2007; 56: 989-993
- An 18-year retrospective study on the outcomes of keratoacanthomas with different treatment modalities at a single academic centre.Br J Dermatol. 2017; 177: 1749-1751
- 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
- Radiotherapy for skin cancers of the face, head, and neck.Facial Plast Surg Clin North Am. 2019; 27: 131-138
- The role of radiotherapy in the management of non-melanoma skin cancer.Australas J Dermatol. 2019; 60: 265-272
- Outcomes of radiation therapy for advanced T3/T4 nonmelanoma cutaneous squamous cell and basal cell carcinoma.Br J Dermatol. 2018; 178: e30-e32
- Local control of 151 head and neck cutaneous squamous cell carcinoma after radiotherapy: a retrospective study on efficacy and prognostic factors.Clin Otolaryngol. 2017; 42: 851-855
- 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
- Outcomes of adjuvant radiotherapy following negative surgical margins for cutaneous squamous cell carcinoma.Dermatol Surg. 2019; 45: 1111-1116
- Local recurrence and quality of life after adjuvant radiation therapy in high-risk squamous cell carcinoma.Br J Dermatol. 2019; 180: 417-418
- Adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma.J Am Acad Dermatol. 1994; 30: 633-636
- High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease.Cancer. 2006; 106: 2389-2396
- What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion?.Cancer. 2007; 109: 1053-1059
- Postoperative concurrent chemoradiotherapy versus postoperative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: the randomized phase III TROG 05.01 trial.J Clin Oncol. 2018; 36: 1275-1283
- Outcomes of cutaneous squamous cell carcinoma in the head and neck region with regional lymph node metastasis: a systematic review and meta-analysis.JAMA Otolaryngol Head Neck Surg. 2019; 145: 352-360
- Predictors of outcome in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes: improved survival with the addition of adjuvant radiotherapy.Head Neck. 2012; 34: 1524-1528
- Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578
- Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma.Int J Radiat Oncol Biol Phys. 2013; 85: 1275-1281
- 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
- Role of concurrent systemic therapy with adjuvant radiation therapy for locally advanced cutaneous head and neck squamous cell carcinoma.Cureus. 2017; 9: e1784
- Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: a propensity score analysis.Oral Oncol. 2018; 78: 102-107
- Neoadjuvant intralesional methotrexate in cutaneous squamous cell carcinoma: a comparative cohort study.J Eur Acad Dermatol Venereol. 2016; 30: 1120-1124
- 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: 527-534
- A prospective clinical trial to assess lapatinib effects on cutaneous squamous cell carcinoma and actinic keratosis.ESMO Open. 2016; 1: e000003
- A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck.Clin Cancer Res. 2012; 18: 1435-1446
- In-transit metastasis from squamous cell carcinoma.Dermatol Surg. 2016; 42: 1285-1292
- In-transit metastasis from primary cutaneous squamous cell carcinoma in organ transplant recipients and nonimmunosuppressed patients: clinical characteristics, management, and outcome in a series of 21 patients.Dermatol Surg. 2004; 30: 651-655
- Electrochemotherapy for the management of cutaneous and subcutaneous metastasis: a series of 39 patients treated with palliative intent.J Surg Oncol. 2014; 109: 270-274
- Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy.Br J Cancer. 2018; 119: 429-434
- PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma.N Engl J Med. 2018; 379: 341-351
- Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017; 9: 34
- Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.Science. 2016; 351: 1463-1469
- Expression of programmed cell death ligand in cutaneous squamous cell carcinoma and treatment of locally advanced disease with pembrolizumab.JAMA Dermatol. 2017; 153: 299-303
- Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated.J Invest Dermatol. 2011; 131: 1322-1330
- CD200 upregulation in vascular endothelium surrounding cutaneous squamous cell carcinoma.JAMA Dermatol. 2013; 149: 178-186
European Medicines Agency. Libtayo. Summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/libtayo-epar-product-information_en.pdf Access date: 17 July 2019.
- Immunotherapy of Lymphoma and Myeloma: facts and Hopes.Clin Cancer Res. 2018; 24: 1002-1010
- Immune checkpoint inhibitor therapy in solid organ transplant recipients: a patient-centered systematic review.J Am Acad Dermatol. 2019; https://doi.org/10.1016/j.jaad.2019.07.005
- Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin.Anticancer Res. 2005; 25: 1205-1210
- Somatic mutation of epidermal growth factor receptor in a small subset of cutaneous squamous cell carcinoma.J Invest Dermatol. 2010; 130: 901-903
- Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma.Ann Oncol. 2014; 25: 2047-2052
- Complete remission of squamous cell carcinoma after treatment with panitumumab in a patient with cetuximab-induced anaphylaxis.JAMA Dermatol. 2016; 152: 343-345
- Gefitinib for patients with incurable cutaneous squamous cell carcinoma: a single-arm phase II clinical trial.J Am Acad Dermatol. 2017; 77 (1110–3 e2)
- Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase 2 clinical trial.Cancer. 2018; 124: 2169-2173
- Cisplatin and cetuximab treatment for metastatic cutaneous squamous cell carcinoma: a systematic review.Dermatol Surg. 2017; 43: 40-49
- Association of oncogenic mutations in patients with advanced cutaneous squamous cell carcinomas treated with cetuximab.JAMA Dermatol. 2017; 153: 291-298
- Cetuximab in metastatic squamous cell cancer of the skin: a Swiss case series.Dermatology. 2014; 229: 97-101
- 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: 3419-3426
- Efficacy and tolerance of cetuximab alone or combined with chemotherapy in locally advanced or metastatic cutaneous squamous cell carcinoma: an open study of 14 patients.Dermatology. 2016; 232: 721-730
- Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma–a report of eight cases.Clin Oncol (R Coll Radiol). 2011; 23: 716-718
- Locally advanced and unresectable cutaneous squamous cell carcinoma: outcomes of concurrent cetuximab and radiotherapy.J Skin Cancer. 2014; 2014: 284582
- Cetuximab as a component of multimodality treatment of high-risk cutaneous squamous cell carcinoma: a retrospective analysis from a single tertiary academic medical center.Dermatol Surg. 2019; 45: 254-267
- Response of cutaneous squamous cell carcinoma to treatment with cetuximab.Dermatol Surg. 2019; 45: 313-316
- Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck.Cancer Res. 1999; 59: 1935-1940
- Efficacy of cetuximab in the treatment of squamous cell carcinoma.J Dermatolog Treat. 2014; 25: 424-427
- Drug therapy of advanced cutaneous squamous cell carcinoma: is there any evidence?.Curr Opin Oncol. 2017; 29: 129-135
- Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy.J Clin Oncol. 1990; 8: 342-346
- Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin.J Cancer Res Clin Oncol. 2005; 131: 300-304
- Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged.Am J Clin Oncol. 2000; 23: 181-184
- Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer.J Clin Oncol. 2002; 20: 364-370
- Complete response of metastatic cutaneous squamous cell carcinoma to cetuximab plus paclitaxel.Eur J Dermatol. 2012; 22: 758-761
- Systemic therapy in advanced cutaneous squamous cell carcinoma (CSCC): the roswell park experience and a review of the literature.Am J Clin Oncol. 2016; 39: 545-548
- Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases.Acta Oncol. 2018; 57: 874-882
- Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach.Dermatol Ther. 2010; 23: 651-661
- 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
- Electrochemotherapy of unresectable cutaneous tumours with reduced dosages of intravenous bleomycin: analysis of 57 patients from the International Network for Sharing Practices of Electrochemotherapy registry.J Eur Acad Dermatol Venereol. 2018; 32: 1147-1154
- 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
- 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
www.clinicaltrials.gov Accessed on 5 May, 2019.
www.ClinicalTrials.gov. Study of adjuvant cemipllimab versus placebo after surgery and radiation therapy in patients with high risk cutaneous squamous cell carcinoma. Accessed on: 20 July 2019.
- Palliative radiotherapy for skin malignancies.Ann Palliat Med. 2017; 6: 165-172
Organization WH. WHO Definition of Palliative Care. https://www.who.int/cancer/palliative/definition/en/. Last accessed on 15 January 2019.
- Educational tips in the treatment of malignant ulcerating tumours of the skin.Eur J Surg Oncol. 2000; 26: 506-508
- Local wound care for malignant and palliative wounds.Adv Skin Wound Care. 2010; 23 (quiz 29–30): 417-428
- Pain prevalence in cancer patients: status quo or opportunities for improvement?.Curr Opin Support Palliat Care. 2017; 11: 99-104
- Effectiveness of the World Health Organization cancer pain relief guidelines: an integrative review.J Pain Res. 2016; 9: 515-534
- Topical morphine for treatment of cancer-related painful mucosal and cutaneous lesions: a double-blind, placebo-controlled cross-over clinical trial.Arch Med Sci. 2019; 15: 146-151
- Improved morphine-loaded hydrogels for wound-related pain relief.Pharmaceutics. 2019; : 11
- Integrated outpatient palliative care for patients with advanced cancer: a systematic review and meta-analysis.Palliat Med. 2019; 33: 123-134
- Risk of a second primary cancer after non-melanoma skin cancer in white men and women: a prospective cohort study.PLoS Med. 2013; 10: e1001433
- Timing of subsequent new tumors in patients who present with basal cell carcinoma or cutaneous squamous cell carcinoma.JAMA Dermatol. 2015; 151: 382-388
- Risk of subsequent cutaneous malignancy in patients with prior keratinocyte carcinoma: a systematic review and meta-analysis.Eur J Cancer. 2013; 49: 2365-2375
- Epidemiology of keratinocyte carcinomas after organ transplantation.Br J Dermatol. 2017; 177: 1208-1216
- A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population.Am J Transplant. 2013; 13: 119-129
- Needs and preferences of patients regarding basal cell carcinoma and cutaneous squamous cell carcinoma care: a qualitative focus group study.Br J Dermatol. 2019; 180: 122-129
Article info
Publication history
Published online: February 26, 2020
Accepted:
January 15,
2020
Received:
January 15,
2020
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
