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Guidelines of care for the management of cutaneous squamous cell carcinoma

Published:January 10, 2018DOI:https://doi.org/10.1016/j.jaad.2017.10.007
      Cutaneous squamous cell carcinoma (cSCC) is the second most common form of human cancer and has an increasing annual incidence. Although most cSCC is cured with office-based therapy, advanced cSCC poses a significant risk for morbidity, impact on quality of life, and death. This document provides evidence-based recommendations for the management of patients with cSCC. Topics addressed include biopsy techniques and histopathologic assessment, tumor staging, surgical and nonsurgical management, follow-up and prevention of recurrence, and management of advanced disease. The primary focus of these recommendations is on evaluation and management of primary cSCC and localized disease, but where relevant, applicability to recurrent cSCC is noted, as is general information on the management of patients with metastatic disease.

      Key words

      Abbreviations used:

      AAD (American Academy of Dermatology), AJCC (American Joint Committee on Cancer), BCC (basal cell carcinoma), BWH (Brigham and Women's Hospital), C&E (curettage and electrodesiccation), CT (computed tomography), 5-FU (5-fluorouracil), MM (malignant melanoma), MMS (Mohs micrographic surgery), NCCN (National Comprehensive Cancer Network), PI (principal investigator), RCT (randomized controlled trial), cSCC (cutaneous Squamous Cell carcinoma), SLNB (sentinel lymph node biopsy), SOTR (solid organ transplant recipient)

      Disclaimer

      Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care, nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient, and the known variability and biologic behavior of the disease. This guideline reflects the best available data at the time the guideline was prepared. The results of future studies may require revisions to the recommendations in this guideline to reflect new data.

      Scope

      This guideline addresses the management of patients with cutaneous squamous cell carcinoma (cSCC) from the perspective of a US dermatologist. Other forms of SCC, such as head and neck (ie, mucosal) SCC are outside the scope of this document, as is a discussion of cSCC in situ (Bowen disease). The primary focus of the guideline is on the most commonly considered and utilized approaches for the surgical and medical treatment of cSCC, but it also includes recommendations on appropriate biopsy techniques, staging, follow-up, and prevention of cSCC. A detailed discussion of specific chemotherapeutic or radiotherapeutic approaches for distant metastatic SCC falls outside the scope of this guideline. However, general recommendations regarding the management of patients with advanced or metastatic SCC are included to provide guidance and facilitate consultation with a physician or multidisciplinary group with specific expertise in SCC, such as a surgical, medical, or radiation oncologist, head and neck surgeon, plastic surgeon, or dermatologist specializing in SCC.

      Methods

      An expert work group was convened to determine the audience and scope of the guideline, and to identify important clinical questions in the biopsy, staging, treatment, and follow-up of cSCC (Table I). Work group members completed a disclosure of interests that was updated and reviewed for potential relevant conflicts of interest periodically throughout guideline development. If a potential conflict was noted, the work group member recused himself or herself from discussion and drafting of recommendations pertinent to the topic area of the disclosed interest.
      Table IClinical questions used to structure the evidence review
      • What is the standard grading system for BCC and cSCC?
      • What are the standard biopsy techniques for BCC and cSCC?
      • What pathologic and clinical information is useful in the pathology report for BCC and cSCC?
      • What are the benefits harm and effectiveness/efficacy of available treatments for BCC and cSCC?
        • Surgical treatment
          • Standard excision
          • Mohs micrographic surgery
          • Curettage and electrodesiccation
          • Cryosurgery
        • Topical therapy
          • Fluorouracil
          • Imiquimod
          • Other
        • Energy devices
          • Laser
          • Photodynamic therapy (MAL
            BCC only.
            and ALA)
          • Radiation therapy
      • What are effective treatment options for the management of advanced BCC and cSCC?
        • Hedgehog inhibitors
          BCC only.
      • What are the effective methods for follow-up and preventing recurrence and new primary keratinocyte cancer formation?
        • Oral and topical retinoids
        • Celecoxib
        • α-Difluoromethylornithine
        • Selenium
        • β-Carotene
      ALA, Aminolevulinic acid; BCC, basal cell carcinoma; cSCC, cutaneous squamous cell carcinoma; MAL, methylaminolevulinate.
      BCC only.
      An evidence-based approach was used and available evidence was obtained by using a systematic search and review of published studies from PubMed and the Cochrane Library databases from January 1960 through April 2015 for all identified clinical questions. A secondary search was subsequently undertaken to identify and review published studies from April 2015 to August 2016 to provide the most current information. Searches were prospectively limited to publications in the English language. As cSCC is traditionally known as a form of nonmelanoma skin cancer (NMSC), a term that also includes basal cell carcinoma (BCC), searches were collectively undertaken for literature on cSCC and BCC simultaneously, by using a set of search terms applicable to both cSCC and BCC. A parallel American Academy of Dermatology (AAD) guideline on BCC has also been developed.

      Bichakjian C, Armstrong A, Baum C, et al. Guidelines of care for the management of basal cell carcinoma. J Am Acad Dermatol. Online ahead of print. https://doi.org/10.1016/j.jaad.2017.10.006.

      MeSH (Medical Subject Headings) terms used in various combinations in the literature search included carcinoma, basal cell carcinoma, squamous cell carcinoma, skin neoplasms, stage(ing), grade(ing), score(ing), biopsy, pathology, prognosis, signs and symptoms, risk factors, curettage, electrodesiccation, excision, incomplete, cryosurgery, Mohs (micrographic) surgery, topical, fluorouracil, imiquimod, laser, radiotherapy, radiation, photochemotherapy, phototherapy, metastasis, vismodegib, sonidegib, prevention, prevention and control, and recurrence.
      A total of 1120 articles were reviewed for possible inclusion; 188 were retained on the basis of relevancy and the highest level of available evidence for the outlined clinical questions. Evidence tables were generated for these 188 studies and utilized by the work group in developing recommendations. Other current guidelines on cSCC were also evaluated.

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2015). Available at: www.nccn.org. Accessed April 1, 2015.

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2017). Available at: www.nccn.org. Accessed October 3, 2016.

      • Motley R.
      • Kersey P.
      • Lawrence C.
      Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma.
      The available evidence was evaluated by using a unified system called the Strength of Recommendation Taxonomy (SORT), which was developed by editors of the US family medicine and primary care journals (ie, American Family Physician, Family Medicine, Journal of Family Practice, and BMJ USA).
      • Ebell M.H.
      • Siwek J.
      • Weiss B.D.
      • et al.
      Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature.
      Evidence was graded using a 3-point scale based on the quality of study methodology (eg, randomized control trial [RCT], case-control, prospective/retrospective cohort, case series, etc), and the overall focus of the study (ie, diagnosis, treatment/prevention/screening, or prognosis) as follows:
      • I.
        Good-quality patient-oriented evidence (ie, evidence measuring outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life).
      • II.
        Limited-quality patient-oriented evidence.
      • III.
        Other evidence, including consensus guidelines, opinion, case studies, or disease-oriented evidence (ie, evidence measuring intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes).
      Clinical recommendations were developed on the basis of the best available evidence tabled in the guideline. These are ranked as follows:
      • A.
        Recommendation based on consistent and good-quality patient-oriented evidence. Recommendation based on consistent and good-quality patient-oriented evidence.
      • B.
        Recommendation based on inconsistent or limited-quality patient-oriented evidence.
      • C.
        Recommendation based on consensus, opinion, case studies, or disease-oriented evidence.
      In situations in which published evidence-based data were not available, expert opinion of the authors was utilized to generate clinical recommendations.
      This guideline has been developed in accordance with the AAD/AAD Association Administrative Regulations for Evidence-Based Clinical Practice Guidelines, which includes the opportunity for review and comment by the entire AAD membership and final review and approval by the AAD Board of Directors.

      American Academy of Dermatology. Administrative regulations; evidence-based clinical practice guidelines. Available at: www.aad.org/Forms/Policies/Uploads/AR/AR%20-%20Evidence-Based%20Clinical%20Guideline.pdf. Accessed December 1, 2014.

      An additional multidisciplinary panel of invited reviewers was utilized to provide cross-specialty comments on the draft guideline. This guideline will be considered current for a period of 5 years from the date of publication, unless reaffirmed, updated, or retired at or before that time.

      Introduction

      cSCC is the second most common skin cancer and the second most common form of keratinocyte carcinoma after BCC. Like BCC, cSCC is increasing in incidence throughout the world. In the United States, lifetime risk for development of cSCC is estimated at 9% to 14% for men and 4% to 9% for women.
      • Miller D.L.
      • Weinstock M.A.
      Nonmelanoma skin cancer in the United States: incidence.
      Each year in the United States, at least 200,000 to 400,000 new cases of cSCC are expected, and disease-related death occurs in more than 3000 people with cSCC.
      • Karia P.S.
      • Han J.
      • Schmults C.D.
      Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012.
      A Canadian study also detected an increase in annual incidence in cSCC of more than 200% in both men and women from 1960 to 2000.
      • Demers A.A.
      • Nugent Z.
      • Mihalcioiu C.
      • Wiseman M.C.
      • Kliewer E.V.
      Trends of nonmelanoma skin cancer from 1960 through 2000 in a Canadian population.
      According to a study of US health care workers that analyzed prospective questionnaires obtained from more than 250,000 participants enrolled in 3 large cohort studies from 1976 to 2008, the incidence of invasive cSCC increased over 18 years of follow-up.
      • Nguyen K.D.
      • Han J.
      • Li T.
      • Qureshi A.A.
      Invasive cutaneous squamous cell carcinoma incidence in US health care workers.
      Although many factors can increase the risk for cSCC, cumulative sun exposure, especially in childhood and youth, is of greatest importance. In recent years, immunosuppression, including that associated with organ transplantation,
      • Kim C.
      • Cheng J.
      • Colegio O.R.
      Cutaneous squamous cell carcinomas in solid organ transplant recipients: emerging strategies for surveillance, staging, and treatment.
      has emerged as an increasingly important contributor to tumorigenesis.
      cSCC can develop on any skin surface. In fair-skinned individuals, who are at highest risk, sun exposed areas, including the head and neck and the backs of the arms and hands, are common anatomic sites.
      • Alam M.
      • Ratner D.
      Cutaneous squamous-cell carcinoma.
      Awareness is growing that patients with skin of color are also at risk, with tumors in these patients sometimes emerging in sun-protected sites or in areas of chronic inflammation.
      • Agbai O.N.
      • Buster K.
      • Sanchez M.
      • et al.
      Skin cancer and photoprotection in people of color: a review and recommendations for physicians and the public.
      The treatment of cSCC has long been a substantial component of the clinical practice of dermatologists, who are well versed in the numerous available therapeutic options. These clinical practice guidelines provide evidence-based recommendations for clinical treatment and management of patients with cSCC. Information pertaining to widely utilized therapies, ranging from curettage and electrodesiccation (C&E) to Mohs micrographic surgery (MMS), is reviewed. The quality of the evidence regarding emerging treatment modalities, such as topical and systemic medications and devices, is also discussed. Recommendations regarding staging, biopsy technique, prevention, and follow-up are made on the basis of the best available literature.
      Recently, the diagnosis and treatment of cSCC among older adults with limited life expectancy has become an important and valid topic of discussion.
      • Linos E.
      • Schroeder S.A.
      • Chren M.M.
      Potential overdiagnosis of basal cell carcinoma in older patients with limited life expectancy.
      • Fosko S.W.
      Counterpoint: Limited life expectancy, basal cell carcinoma, health care today, and unintended consequences.
      A clear distinction between advanced age and limited life expectancy is critical to this debate, as they are by no means synonymous. Every dermatologist is familiar with healthy, energetic nonagenarians, who justifiably desire and deserve treatment of their cSCC with a modality that provides optimal cure rate and quality of life. Conversely, significant medical comorbidities at any age may justify a therapeutic option that may have a lower long-term cure rate but is most appropriate with regard to quality of life. In select circumstances and after careful consideration with their health care provider, patients may understandably prefer observation over any form of treatment. A thorough understanding of the entire spectrum of therapies available for cSCC and the evidence on which each treatment recommendation is based is critical to selecting and providing care optimally tailored to individual patients.
      Although many recommendations in these guidelines reaffirm prevailing knowledge and current practice, some recommendations highlight alternative therapeutic or preventive options that are less widely considered or are supported by insufficient evidence. As the incidence of keratinocyte carcinoma in the United States continues to increase,
      • Rogers H.W.
      • Weinstock M.A.
      • Feldman S.R.
      • Coldiron B.M.
      Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the U.S. population, 2012.
      a thorough understanding of the management of cSCC and the evidence on which recommendations are based is critically important for optimal patient care.

      Grading and staging

      A universally accepted staging system for risk stratification of cSCC is not yet available. Until 2010, cSCC was grouped in the American Joint Committee on Cancer (AJCC) staging manual with a multitude of other cutaneous malignancies.
      • Greene F.L.
      American Joint Committee on Cancer, American Cancer Society. AJCC Cancer Staging Manual.
      In the seventh edition of the staging manual, which was published in 2010, cSCC was specifically addressed in the chapter “Cutaneous Squamous Cell Carcinoma and Other Cutaneous Carcinomas.”
      • Edge S.B.
      American Joint Committee on Cancer, American Cancer Society. AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual.
      In the recently published eighth edition, cSCC is included in the chapter “Cutaneous Squamous Cell Carcinoma of the Head and Neck.”
      • Amin M.B.
      • Edge S.B.
      • Greene F.L.
      • et al.
      AJCC Cancer Staging Manual.
      Although the chapter focuses primarily on cSCC, the staging system applies to all histologic subtypes of carcinoma limited to the head and neck, with the exception of Merkel cell carcinoma.
      Several studies have evaluated various aspects of the seventh edition of the AJCC staging system for cSCC and consistently identified unsatisfactory prognostication among stage groups.
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      In 2013, Brunner et al noted the heterogeneous nature of stage group IV, and in 2014 they pointed out that nodal classification demonstrated less prognostic significance in cSCC than in mucosal SCC.
      • Brunner M.
      • Veness M.J.
      • Ch'ng S.
      • Elliott M.
      • Clark J.R.
      Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV.
      • Brunner M.
      • Ng B.C.
      • Veness M.J.
      • Clark J.R.
      Comparison of the AJCC N staging system in mucosal and cutaneous squamous head and neck cancer.
      In 2013, Jambusaria-Pahlajani et al proposed an alternative tumor classification system for cSCC on the basis of a retrospective cohort study.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      This alternative Brigham and Women's Hospital (BWH) system classifies tumor categories on the basis of presence of several clinical and pathologic risk factors, as summarized in Table II. The BWH system was validated by an expanded retrospective cohort from the same group, as well as by an independent systematic literature review.
      • Karia P.S.
      • Jambusaria-Pahlajani A.
      • Harrington D.P.
      • Murphy G.F.
      • Qureshi A.A.
      • Schmults C.D.
      Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma.
      • Schmitt A.R.
      • Brewer J.D.
      • Bordeaux J.S.
      • Baum C.L.
      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.
      Although the BWH system does not address nodal and metastasis classifications and advanced stage groups as the AJCC staging system does, it appears to provide superior prognostication for patients with localized cSCC. Further validation by independent cohorts, as well as clinical trials regarding nodal staging and adjuvant therapy, will be needed to determine the clinical utility of the proposed staging system.
      Table IIBrigham and Women's Hospital tumor classification system
      Reprinted with permission.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      Copyright ©2013 American Medical Association. All rights reserved.
      CategoryDefinition
      T0In situ SCC
      T10 risk factors
      Risk factors include tumor diameter 2 cm or larger, poorly differentiated histology, perineural invasion, and tumor invasion beyond the subcutaneous fat (excluding bone, which automatically upgrades to T3).
      T2a1 risk factor
      T2b2-3 risk factors
      T34 risk factors or bone invasion
      SCC, Squamous cell carcinoma.
      Risk factors include tumor diameter 2 cm or larger, poorly differentiated histology, perineural invasion, and tumor invasion beyond the subcutaneous fat (excluding bone, which automatically upgrades to T3).
      Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for cSCC provide an approach to stratifying high-risk and low-risk tumors, similar to that used for BCC.

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2017). Available at: www.nccn.org. Accessed October 3, 2016.

      This stratification, summarized in Table III, takes both clinical and pathologic parameters into account and is based on a combination of available evidence and expert opinion. The NCCN risk stratification is primarily intended to provide health care providers with practical clinical guidance on how to treat cSCC rather than to provide accurate prognostication and assess outcome as the BWH system does. For this reason, treatment recommendations throughout the currently presented guidelines are based on the NCCN risk stratification (for the recommendations, see Table IV; for the level of evidence/strength of the recommendations, see Table V
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Brunner M.
      • Veness M.J.
      • Ch'ng S.
      • Elliott M.
      • Clark J.R.
      Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV.
      • Brunner M.
      • Ng B.C.
      • Veness M.J.
      • Clark J.R.
      Comparison of the AJCC N staging system in mucosal and cutaneous squamous head and neck cancer.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Karia P.S.
      • Jambusaria-Pahlajani A.
      • Harrington D.P.
      • Murphy G.F.
      • Qureshi A.A.
      • Schmults C.D.
      Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma.
      • Schmitt A.R.
      • Brewer J.D.
      • Bordeaux J.S.
      • Baum C.L.
      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.
      • Roozeboom M.H.
      • Mosterd K.
      • Winnepenninckx V.J.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Agreement between histological subtype on punch biopsy and surgical excision in primary basal cell carcinoma.
      • Haws A.L.
      • Rojano R.
      • Tahan S.R.
      • Phung T.L.
      Accuracy of biopsy sampling for subtyping basal cell carcinoma.
      • Mosterd K.
      • Thissen M.R.
      • van Marion A.M.
      • et al.
      Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma.
      • Smith L.C.
      • Cox N.H.
      • Dawn G.
      Shave biopsy without local anaesthetic to diagnose basal cell carcinoma and other skin tumours prior to definitive treatment: analysis of 109 lesions.
      • Russell E.B.
      • Carrington P.R.
      • Smoller B.R.
      Basal cell carcinoma: a comparison of shave biopsy versus punch biopsy techniques in subtype diagnosis.
      • Kadouch D.J.
      • van Haersma de With A.
      • Limpens J.
      • et al.
      Is a punch biopsy reliable in subtyping basal cell carcinoma? A systematic review.
      • Westers-Attema A.
      • Joosten V.M.
      • Roozeboom M.H.
      • et al.
      Correlation between histological findings on punch biopsy specimens and subsequent excision specimens in cutaneous squamous cell carcinoma.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Rieger K.E.
      • Linos E.
      • Egbert B.M.
      • Swetter S.M.
      Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
      • Brandt M.G.
      • Moore C.C.
      • Jordan K.
      Randomized control trial of fluorescence-guided surgical excision of nonmelanotic cutaneous malignancies.
      • Campoli M.
      • Brodland D.G.
      • Zitelli J.
      A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma.
      • Lott D.G.
      • Manz R.
      • Koch C.
      • Lorenz R.R.
      Aggressive behavior of nonmelanotic skin cancers in solid organ transplant recipients.
      • Carter J.B.
      • Johnson M.M.
      • Chua T.L.
      • Karia P.S.
      • Schmults C.D.
      Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study.
      • Ross A.S.
      • Whalen F.M.
      • Elenitsas R.
      • Xu X.
      • Troxel A.B.
      • Schmults C.D.
      Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study.
      ).
      Table IIINational Comprehensive Cancer Network stratification of low versus high risk cSCC
      Reprinted with permission.

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2017). Available at: www.nccn.org. Accessed October 3, 2016.

      ParametersLow riskHigh risk
      Clinical
       Location
      Area L consists of trunk and extremities (excluding hands, feet, nail units, pretibia, and ankles); area M consists of cheeks, forehead, scalp, neck, and pretibia; and area H consists of central face, eyelids, eyebrows, periorbital skin, nose, lips, chin, mandible, preauricular and postauricular skin/sulci, temple, ear, genitalia, hands, and feet.
      /size
      Greatest tumor diameter, including peripheral rim of erythema.
      Area L <20 mmArea L ≥20 mm
      Area M
      Location independent of size may constitute high risk.
      <10 mm
      Area M ≥10 mm
      Area H
      Area H constitutes high-risk on the basis of location, independent of size.
       BordersWell definedPoorly defined
       Primary vs recurrentPrimaryRecurrent
       ImmunosuppressionNoYes
       Site of prior radiation therapy or chronic inflammatory processNoYes
       Rapidly growing tumorNoYes
       Neurologic symptomsNoYes
      Pathologic
       Degree of differentiationWell to moderately differentiatedPoorly differentiated
       High-risk histologic subtype
      Adenoid (acantholytic), adenosquamous (showing mucin production), desmoplastic, or metaplastic (carcinosarcomatous) subtypes.
      NoYes
       Depth (thickness or Clark level)
      A modified Breslow measurement should exclude parakeratosis or scale/crust and should be made from base of the ulcer is present. If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, consider narrow-margin excisional biopsy.
      <2 mm, or I, II, III≥2 mm or IV, V
       Perineural, lymphatic, or vascular involvementNoYes
      cSCC, Cutaneous squamous cell carcinoma.
      Area L consists of trunk and extremities (excluding hands, feet, nail units, pretibia, and ankles); area M consists of cheeks, forehead, scalp, neck, and pretibia; and area H consists of central face, eyelids, eyebrows, periorbital skin, nose, lips, chin, mandible, preauricular and postauricular skin/sulci, temple, ear, genitalia, hands, and feet.
      Greatest tumor diameter, including peripheral rim of erythema.
      Location independent of size may constitute high risk.
      § Area H constitutes high-risk on the basis of location, independent of size.
      Adenoid (acantholytic), adenosquamous (showing mucin production), desmoplastic, or metaplastic (carcinosarcomatous) subtypes.
      A modified Breslow measurement should exclude parakeratosis or scale/crust and should be made from base of the ulcer is present. If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, consider narrow-margin excisional biopsy.
      Table IVRecommendations for grading and staging of cSCC
      Stratification of localized SCCs using the NCCN guideline framework is recommended for clinical practice.
      Clinicians should refer to the BWH tumor classification system to obtain the most accurate prognostication of patients with localized cSCC.
      BWH, Brigham and Women's Hospital; cSCC, cutaneous squamous cell carcinoma; NCCN, National Comprehensive Cancer Network; SCC, squamous cell carcinoma.
      Table VLevel of evidence and strength of recommendations for grading and staging, biopsy, clinical information, and pathology report for the treatment of cSCC
      RecommendationStrength of recommendationLevel of evidenceReferences
      Grading and staging
       AJCCBII
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Brunner M.
      • Veness M.J.
      • Ch'ng S.
      • Elliott M.
      • Clark J.R.
      Distant metastases from cutaneous squamous cell carcinoma—analysis of AJCC stage IV.
      • Brunner M.
      • Ng B.C.
      • Veness M.J.
      • Clark J.R.
      Comparison of the AJCC N staging system in mucosal and cutaneous squamous head and neck cancer.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Karia P.S.
      • Jambusaria-Pahlajani A.
      • Harrington D.P.
      • Murphy G.F.
      • Qureshi A.A.
      • Schmults C.D.
      Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma.
      • Schmitt A.R.
      • Brewer J.D.
      • Bordeaux J.S.
      • Baum C.L.
      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.
       BWHBII
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Karia P.S.
      • Jambusaria-Pahlajani A.
      • Harrington D.P.
      • Murphy G.F.
      • Qureshi A.A.
      • Schmults C.D.
      Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma.
      • Schmitt A.R.
      • Brewer J.D.
      • Bordeaux J.S.
      • Baum C.L.
      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.
       NCNNCIII

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2015). Available at: www.nccn.org. Accessed April 1, 2015.

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2017). Available at: www.nccn.org. Accessed October 3, 2016.

      BiopsyCII, III
      • Roozeboom M.H.
      • Mosterd K.
      • Winnepenninckx V.J.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Agreement between histological subtype on punch biopsy and surgical excision in primary basal cell carcinoma.
      • Haws A.L.
      • Rojano R.
      • Tahan S.R.
      • Phung T.L.
      Accuracy of biopsy sampling for subtyping basal cell carcinoma.
      • Mosterd K.
      • Thissen M.R.
      • van Marion A.M.
      • et al.
      Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma.
      • Smith L.C.
      • Cox N.H.
      • Dawn G.
      Shave biopsy without local anaesthetic to diagnose basal cell carcinoma and other skin tumours prior to definitive treatment: analysis of 109 lesions.
      • Russell E.B.
      • Carrington P.R.
      • Smoller B.R.
      Basal cell carcinoma: a comparison of shave biopsy versus punch biopsy techniques in subtype diagnosis.
      • Kadouch D.J.
      • van Haersma de With A.
      • Limpens J.
      • et al.
      Is a punch biopsy reliable in subtyping basal cell carcinoma? A systematic review.
      • Westers-Attema A.
      • Joosten V.M.
      • Roozeboom M.H.
      • et al.
      Correlation between histological findings on punch biopsy specimens and subsequent excision specimens in cutaneous squamous cell carcinoma.
      Clinical information provided to pathologist
       AgeAI, II
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
       SexBII
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
       Anatomic locationBI, II
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Rieger K.E.
      • Linos E.
      • Egbert B.M.
      • Swetter S.M.
      Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
       Recurrent lesionAI, II
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
       Size of lesionAI, II
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Rieger K.E.
      • Linos E.
      • Egbert B.M.
      • Swetter S.M.
      Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
       ImmunosuppressionBI, II
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Brandt M.G.
      • Moore C.C.
      • Jordan K.
      Randomized control trial of fluorescence-guided surgical excision of nonmelanotic cutaneous malignancies.
       History, especially radiation, burn, organ transplantBII
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Campoli M.
      • Brodland D.G.
      • Zitelli J.
      A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma.
      • Lott D.G.
      • Manz R.
      • Koch C.
      • Lorenz R.R.
      Aggressive behavior of nonmelanotic skin cancers in solid organ transplant recipients.
      Pathology report elements
       Degree of differentiation
      Well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
      BI, II
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
       Presence of aggressive histologic subtype
      Acantholytic, adenosquamous, or carcinosarcomatous subtypes.
      BI, II
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
       Depth of invasion, mmAI, II
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
       Clark level of invasionBII
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
       Perineural invasionAI, II
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
       Lymphovascular invasionAI, II
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
       Invasion of fascia, muscle, or boneAI, II
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
       No. of high-risk features
      High-risk features include thickness greater than 2 mm, Clark level IV or V, poorly differentiated/undifferentiated, site on mucosa lip or ear, perineural invasion, and lymphovascular invasion.
      CIIIExpert opinion
       Margin statusBII
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
       TNM stage (AJCC)AI
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
       InflammationAI
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
       Infiltrative strands, single cells, small nestsBII
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
       Diameter of largest involved nerveBII
      • Carter J.B.
      • Johnson M.M.
      • Chua T.L.
      • Karia P.S.
      • Schmults C.D.
      Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study.
      • Ross A.S.
      • Whalen F.M.
      • Elenitsas R.
      • Xu X.
      • Troxel A.B.
      • Schmults C.D.
      Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study.
      AJCC, American Joint Committee on Cancer; BWH, Brigham and Women's Hospital; cSCC, cutaneous squamous cell cancer; NCCN, National Comprehensive Cancer Network; TNM, tumor, node, metastasis.
      Well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
      Acantholytic, adenosquamous, or carcinosarcomatous subtypes.
      High-risk features include thickness greater than 2 mm, Clark level IV or V, poorly differentiated/undifferentiated, site on mucosa lip or ear, perineural invasion, and lymphovascular invasion.
      On the basis of the low overall risk for nodal and distant metastases in cSCC, staging imaging studies are rarely indicated. Although very limited data are available on the value of such studies in cSCC, imaging to evaluate for nodal metastasis (eg, computed tomography, F-fluorodeoxyglucose positron emission tomography/computed tomography, or ultrasound) may be considered for high-risk tumors (eg, BWH category ≥T2b). Imaging may also be considered to assess for deep structural involvement with extensive localized disease.
      • Veness M.J.
      • Morgan G.J.
      • Palme C.E.
      • 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.
      A thorough clinical examination of the regional lymph node basins should always be performed.
      The value of sentinel lymph node biopsy (SLNB) in cSCC is currently unknown. Tumor size and thickness, as well as angiolymphatic and perineural invasion, have been proposed as risk factors for sentinel lymph node positivity, but small study sizes limit the assessment of prognostic parameters. Retrospective and prospective case series have demonstrated successful detection of occult nodal metastases and suggested a prognostic role in patients with high-risk tumors.
      • Ross A.S.
      • Schmults C.D.
      Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature.
      • Navarrete-Dechent C.
      • Veness M.J.
      • Droppelmann N.
      • Uribe P.
      High-risk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: a literature review.
      However, the effect of SLNB on management and outcome of patients with cSCC is unknown; enrollment of high-risk patients in clinical trials is encouraged, when available.

      Biopsy

      The available literature does not identify a single optimal biopsy technique for sampling lesions suspected of being cSCC. Recommended biopsy techniques for cSCC include punch biopsy, shave (eg, by tangential technique) biopsy,
      Shave biopsies are not necessarily superficial, tangential shaves of tissue. We use the term shave for biopsies that are saucerize or scoop techniques that may penetrate deep into the dermis.
      and excisional biopsy. Excisional biopsy is distinguished from excision with margins in that the intent of the former is to determine and/or confirm diagnosis, whereas the intent of the latter is to remove the tumor. For all techniques, the biopsy specimen size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy, including by identifying an aggressive growth pattern if present. Repeat biopsy may be considered if the initial biopsy specimen is inadequate for accurate diagnosis. The recommendations for biopsy of suspected cSCC are shown in Table VI, and the level of evidence/strength of the recommendation is presented in Table V.
      Table VIRecommendations for the biopsy of suspected cSCC
      The recommended biopsy techniques for cSCC are punch biopsy, shave biopsy, and excisional biopsy. The biopsy technique used will depend on the characteristics of the suspected malignancy (morphology, location, etc) and the judgment of the physician.
      The biopsy size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy.
      Repeat biopsy may be considered if the initial biopsy specimen is inadequate for accurate diagnosis.
      cSCC, Cutaneous squamous cell cancer.
      Selection of the specific biopsy technique is contingent on the clinical characteristics of the suspected tumor, including morphology, expected histologic subtype and depth, natural history, and anatomic location; patient-specific factors, such as bleeding and wound healing diatheses; and patient preference and physician judgment. Most investigations that have compared biopsy methods for detection of NMSC have studied BCC rather than cSCC.
      • Roozeboom M.H.
      • Mosterd K.
      • Winnepenninckx V.J.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Agreement between histological subtype on punch biopsy and surgical excision in primary basal cell carcinoma.
      • Haws A.L.
      • Rojano R.
      • Tahan S.R.
      • Phung T.L.
      Accuracy of biopsy sampling for subtyping basal cell carcinoma.
      • Mosterd K.
      • Thissen M.R.
      • van Marion A.M.
      • et al.
      Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma.
      • Smith L.C.
      • Cox N.H.
      • Dawn G.
      Shave biopsy without local anaesthetic to diagnose basal cell carcinoma and other skin tumours prior to definitive treatment: analysis of 109 lesions.
      • Russell E.B.
      • Carrington P.R.
      • Smoller B.R.
      Basal cell carcinoma: a comparison of shave biopsy versus punch biopsy techniques in subtype diagnosis.
      • Kadouch D.J.
      • van Haersma de With A.
      • Limpens J.
      • et al.
      Is a punch biopsy reliable in subtyping basal cell carcinoma? A systematic review.
      • Westers-Attema A.
      • Joosten V.M.
      • Roozeboom M.H.
      • et al.
      Correlation between histological findings on punch biopsy specimens and subsequent excision specimens in cutaneous squamous cell carcinoma.
      However, given the similarity in the depth and anatomic distribution of many BCC and cSCC tumors, the findings of these studies are likely applicable also to biopsy of cSCC. Specifically, it is likely that initial punch or shave biopsies can detect the relevant histologic characteristics for the vast majority of sampled cSCC tumors. When recurrent tumor, deep invasion, or other aggressive features are suspected, more extensive tissue resection or multiple scouting biopsies may be needed to detect these features if more superficial methods are insufficient. The need to obtain information through biopsy is counterbalanced by the patient and physician preferences to minimize biopsy-associated discomfort, trauma, risk for wound infection or dehiscence, scar, or loss of function, particularly on the head, neck, and other vital, functional, sensory, or cosmetically sensitive sites.

       Clinical and pathologic information

      A presumptive diagnosis of cSCC is based on the physician's interpretation of clinical information, including appearance and morphology, anatomic location, and patient-reported history. Clinical diagnosis is routinely confirmed by biopsy findings before treatment. When the clinician is submitting biopsy tissue for histopathologic diagnosis, and when possible and appropriate, key elements of the patient demographics, clinical presentation, and history should be provided to the pathologist (Table VII; for level of evidence/strength of recommendations, see Table V). These include patient age and biologic sex,
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
      anatomic location of the tumor,
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Rieger K.E.
      • Linos E.
      • Egbert B.M.
      • Swetter S.M.
      Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      and any history of treatment at the same anatomic site.
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Rieger K.E.
      • Linos E.
      • Egbert B.M.
      • Swetter S.M.
      Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      Additional desirable relevant information may include the clinical size of the lesion
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Rieger K.E.
      • Linos E.
      • Egbert B.M.
      • Swetter S.M.
      Recurrence rates associated with incompletely excised low-risk nonmelanoma skin cancer.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
      and whether the patient currently has, or in years past had, additional risk factors, such as immunosuppression,
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Brandt M.G.
      • Moore C.C.
      • Jordan K.
      Randomized control trial of fluorescence-guided surgical excision of nonmelanotic cutaneous malignancies.
      radiation treatment, or solid organ transplantation.
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Campoli M.
      • Brodland D.G.
      • Zitelli J.
      A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma.
      • Lott D.G.
      • Manz R.
      • Koch C.
      • Lorenz R.R.
      Aggressive behavior of nonmelanotic skin cancers in solid organ transplant recipients.
      Although not prognostically relevant, information regarding ongoing treatment that may or may not contribute to cSCC pathogenesis (eg, kinase or hedgehog pathway inhibitor) may be diagnostically useful.
      Table VIIRecommendations for clinical information and pathology report for suspected cSCC
      • Clinical information provided to pathologist
        • Strongly recommended
          • Age
          • Sex
          • Anatomic location
          • Recurrent lesion
        • Recommended
          • Size of lesion
          • Immunosuppression
          • History (especially radiation, burn, organ transplant)
      • Elements to be included in final pathology report (excision specimens)
        • Strongly recommended
          • Degree of differentiation
            Well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
          • Presence of aggressive histologic subtype
            Acantholytic, adenosquamous, or carcinosarcomatous subtypes.
          • Depth of invasion, mm
          • Clark level of invasion
          • Perineural invasion
          • Lymphovascular invasion
          • Invasion of fascia, muscle, or bone
          • Number of high-risk features
            High-risk features include thickness greater than 2 mm, Clark level IV or V, poorly differentiated/undifferentiated, site on mucosa lip or ear, perineural invasion, and lymphovascular invasion.
          • Margin status
          • TNM stage (AJCC)
        • Recommended
          • Inflammation
          • Infiltrative strands, single cells, small nests
          • Diameter of largest involved nerve
      AJCC, American Joint Committee on Cancer; cSCC, cutaneous squamous cell carcinoma; TNM, tumor, node, metastasis.
      Well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
      Acantholytic, adenosquamous, or carcinosarcomatous subtypes.
      High-risk features include thickness greater than 2 mm, Clark level IV or V, poorly differentiated/undifferentiated, site on mucosa lip or ear, perineural invasion, and lymphovascular invasion.
      The principal purpose of the biopsy pathology report is to provide the clinician with an accurate diagnosis of the presence (or absence) of cSCC. If cSCC is detected, additional features that are reported include degree of differentiation and, when possible and appropriate, any features that would classify the lesion as high risk, including aggressive histologic subtypes (acantholytic, adenosquamous, and carcinosarcomatous), depth greater than 2 mm (measured from the granular layer of the adjacent intact epidermis), Clark level IV or greater, and presence of perineural and/or angiolymphatic invasion. The presence of prognostically favorable features, such as histopathologic subtype, including verrucous carcinoma and keratoacanthomatous SCC, may be clinically useful.
      For excision specimens, the extent of the reported detail depends on whether it represents a primary excisional biopsy or re-excision of a biopsy-confirmed tumor. Any new prognostically relevant findings should be noted. It is recommended that the following items be reported, if possible and appropriate: the degree of cellular differentiation
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Eroglu A.
      • Berberoglu U.
      • Berreroglu S.
      Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      ; presence of any aggressive histologic subtypes
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      ; depth of invasion in millimeters
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Brantsch K.D.
      • Meisner C.
      • Schonfisch B.
      • et al.
      Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
      ; anatomic (Clark) level of invasion
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      ; presence of any perineural invasion
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Schmults C.D.
      • Karia P.S.
      • Carter J.B.
      • Han J.
      • Qureshi A.A.
      Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study.
      • Thompson A.K.
      • Kelley B.F.
      • Prokop L.J.
      • Murad M.H.
      • Baum C.L.
      Risk factors for cutaneous squamous cell carcinoma recurrence, metastasis, and disease-specific death: a systematic review and meta-analysis.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
      ; presence of any lymphovascular invasion
      • Brougham N.D.
      • Dennett E.R.
      • Cameron R.
      • Tan S.T.
      The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      ; description of any invasion of fascia, muscle, or bone
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      • Clayman G.L.
      • Lee J.J.
      • Holsinger F.C.
      • et al.
      Mortality risk from squamous cell skin cancer.
      ; margin status (involved or not involved by tumor)
      • Clark J.R.
      • Rumcheva P.
      • Veness M.J.
      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.
      • Hansen C.
      • Wilkinson D.
      • Hansen M.
      • Soyer H.P.
      Factors contributing to incomplete excision of nonmelanoma skin cancer by Australian general practitioners.
      • Talbot S.
      • Hitchcock B.
      Incomplete primary excision of cutaneous basal and squamous cell carcinomas in the Bay of Plenty.
      ; the number of high-risk features present and the relevant TNM (tumor, node, and metastasis) stage based on current AJCC criteria (Table VII) (for level of evidence/strength of recommendations, see Table V).
      • Edge S.B.
      American Joint Committee on Cancer, American Cancer Society. AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual.
      • Jambusaria-Pahlajani A.
      • Kanetsky P.A.
      • Karia P.S.
      • et al.
      Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system.
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      In selected cases, other elements that have been shown to have prognostic significance for clinical care may additionally be reported; they include the presence of inflammation
      • Kyrgidis A.
      • Tzellos T.G.
      • Kechagias N.
      • et al.
      Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.
      • Moore B.A.
      • Weber R.S.
      • Prieto V.
      • et al.
      Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.
      or infiltrative strands, single cells, or small nests of tumor.
      • Cherpelis B.S.
      • Marcusen C.
      • Lang P.G.
      Prognostic factors for metastasis in squamous cell carcinoma of the skin.
      When perineural invasion is observed, the diameter of the largest affected nerve (eg, when ≥ 0.1 mm) may be reported, if this is deemed to be clinically significant.
      • Carter J.B.
      • Johnson M.M.
      • Chua T.L.
      • Karia P.S.
      • Schmults C.D.
      Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study.
      • Ross A.S.
      • Whalen F.M.
      • Elenitsas R.
      • Xu X.
      • Troxel A.B.
      • Schmults C.D.
      Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study.
      With regard to margin status, if a cSCC with aggressive features extends close to a margin, it should be reported.
      Pathologic evaluation of skin biopsy specimens is ideally performed by a dermatologist or pathologist who is experienced in interpreting cutaneous neoplasms. Such a physician is most able to collectively interpret the clinical tumor findings and the histologic features (ie, clinicopathologic correlation) to provide the most precise and accurate biopsy diagnosis.

      Surgical treatment

      It is generally accepted that the majority of cSCCs are successfully treated with standard treatment modalities, such as surgical excision. However, there is a subset of tumors with increased risk for local recurrence, perineural spread, and even nodal or distant metastasis, particularly in immunocompromised individuals. Unfortunately, a systematic review of the literature reveals a complete absence of RCTs and a general paucity of prospective trials assessing the effectiveness of primary surgical interventions for cSCC.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      Treatment recommendations are generally based on retrospective data, consensus opinion, and extrapolation from data on BCC or non-cSCC of the head and neck. When the most appropriate therapy is being chosen, recurrence rate, preservation of function, patient expectations, and potential adverse effects must be taken into consideration.
      • Chren M.M.
      • Sahay A.P.
      • Bertenthal D.S.
      • Sen S.
      • Landefeld C.S.
      Quality-of-life outcomes of treatments for cutaneous basal cell carcinoma and squamous cell carcinoma.
      In this section, the available data on the most commonly used surgical treatment modalities for cSCC, including standard excision, MMS, and C&E, will be reviewed. Nonsurgical therapies will be addressed separately.

       Standard excision

      cSCC, similar to BCC, is characterized by asymmetric subclinical extension of the tumor beyond the clinically visible lesion. To ensure complete removal with histologically negative margins, standard excision with “bread loaf” histopathologic sectioning must include a margin of clinically normal–appearing skin around the tumor and surrounding erythema. To our knowledge, no RCT comparing different excision margins for cSCC has been performed. An extensive systematic review of observational studies on interventions for cSCC by Lansbury et al identified 12 studies addressing standard excision of cSCC, mostly retrospective case series of limited quality and with variable follow-up periods.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      The authors reported an average local recurrence rate of 5.4% (95% confidence interval, 2.5-9.1 [n = 1144]) among all studies, with excision margins ranging from 2 to 10 mm. Incomplete excisions were reported in 8.8% of all cases, although the definitions of an incomplete excision varied widely. In 1992, Brodland and Zitelli reported that 4-mm margins were required to achieve at least 95% clearance rates when excising cSCC using MMS.
      • Brodland D.G.
      • Zitelli J.A.
      Surgical margins for excision of primary cutaneous squamous cell carcinoma.
      In the same study, for high-risk lesions larger than 2 cm in clinical diameter or with higher histologic grade, at least 6-mm margins were required to achieve 95% clearance rates. On the basis of the limited available data and consensus opinion, NCCN guidelines recommend 4- to 6-mm clinical margins for standard excision of low-risk cSCC (Table III).

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2017). Available at: www.nccn.org. Accessed October 3, 2016.

      Given the limited available data, the work group recommends standard excision with a 4- to 6-mm margin of uninvolved skin around the tumor and/or biopsy site to a depth of the mid-subcutaneous adipose tissue with histologic margin assessment for low-risk primary cSCC (on the basis of NCCN risk stratification [Table III]). Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality without complete margin assessment for high-risk cSCC. The insufficient data preclude recommendation of defined peripheral and deep margins for excision of high-risk tumors with standard excision. When standard excision is performed for high-risk tumors, a linear repair, skin graft, or healing by second intention are recommended. If a repair requiring significant tissue rearrangement is indicated, closure should be delayed until negative histologic margins are confirmed. Recommendations for standard excision of cSCC are summarized in Table VIII. The strength of these recommendations is shown in Table IX.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Chren M.M.
      • Sahay A.P.
      • Bertenthal D.S.
      • Sen S.
      • Landefeld C.S.
      Quality-of-life outcomes of treatments for cutaneous basal cell carcinoma and squamous cell carcinoma.
      • Leibovitch I.
      • Huilgol S.C.
      • Selva D.
      • Hill D.
      • Richards S.
      • Paver R.
      Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years.
      • van Loo E.
      • Mosterd K.
      • Krekels G.A.
      • et al.
      Surgical excision versus Mohs' micrographic surgery for basal cell carcinoma of the face: a randomised clinical trial with 10 year follow-up.
      Table VIIIRecommendations for the surgical treatment of cSCC
      A treatment plan that considers recurrence rate, preservation of function, patient expectations, and potential adverse effects is recommended.
      C&E may be considered for low-risk, primary cSCC in non–terminal hair–bearing locations.
      For low-risk primary cSCC, standard excision with a 4- to 6-mm margin to a depth of the mid-subcutaneous adipose tissue with histologic margin assessment is recommended.
      Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality for high-risk tumors without a complete margin assessment.
      MMS is recommended for high-risk cSCC.
      C&E, Curettage and electrodessication; cSCC, cutaneous squamous cell carcinoma; MMS, Mohs micrographic surgery.
      Table IXLevel of evidence and strength of recommendations for the surgical treatment of cSCC
      RecommendationStrength of recommendationLevel of evidenceReferences
      Treatment planAII
      • Chren M.M.
      • Sahay A.P.
      • Bertenthal D.S.
      • Sen S.
      • Landefeld C.S.
      Quality-of-life outcomes of treatments for cutaneous basal cell carcinoma and squamous cell carcinoma.
      Standard excision with 4- to 6-mm margins for low-risk primary SCC
      As defined by the National Comprehensive Cancer Network.
      BII
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      Standard excision for high-risk SCCBII
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      C&E for low-risk primary SCC
      As defined by the National Comprehensive Cancer Network.
      BII, III
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      MMS for high-risk SCC
      As defined by the National Comprehensive Cancer Network.
      BII, III
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Leibovitch I.
      • Huilgol S.C.
      • Selva D.
      • Hill D.
      • Richards S.
      • Paver R.
      Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years.
      • van Loo E.
      • Mosterd K.
      • Krekels G.A.
      • et al.
      Surgical excision versus Mohs' micrographic surgery for basal cell carcinoma of the face: a randomised clinical trial with 10 year follow-up.
      C&E, Curettage and electrodessication; cSCC, cutaneous squamous cell carcinoma; MMS, Mohs micrographic surgery; SCC, cutaneous squamous cell carcinoma.
      As defined by the National Comprehensive Cancer Network.

       MMS

      Dr Frederic Mohs first described the use of chemosurgery for the removal of difficult or recurrent cutaneous tumors in the 1940s.
      • Mohs F.E.
      Chemosurgery: a microscopically controlled method of cancer excision.
      • Mohs F.E.
      Chemosurgical treatment of cancer of the nose; a microscopically controlled method.
      Three decades later, the concept of en face horizontal sectioning for complete peripheral and deep margin control pioneered by Mohs to achieve optimal cure rates and maximum tissue conservation was adapted to the “fresh tissue” technique by Tromovitch and Stegman.
      • Tromovitch T.A.
      • Stegeman S.J.
      Microscopically controlled excision of skin tumors.
      This modification eliminated the pain from in vivo fixation with zinc chloride paste, shortened the time required to perform surgery and allowed immediate repair of a fresh surgical wound. Microscopic controlled excision, later referred to as MMS, was recommended for all recurrent or poorly defined tumors, for sclerosing BCC, and for all primary cutaneous carcinomas in areas with a predilection for recurrence.
      • Tromovitch T.A.
      • Stegman S.J.
      Microscopie-controlled excision of cutaneous tumors: chemosurgery, fresh tissue technique.
      Since that time, the use of MMS has significantly increased and indications have expanded to include many other cutaneous malignancies, including cSCC. In 2012, a combined task force of the AAD, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery developed appropriate use criteria for MMS.
      • Connolly S.M.
      • Baker D.R.
      • Coldiron B.M.
      • 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.
      However, to date, no RCTs or prospective cohort studies comparing MMS with other treatment modalities for the treatment of cSCC have been performed. In a systematic review of the literature since 1940, Rowe et al, reported a 5-year local recurrence rate of 3.1% (n = 2065) for primary cSCC treated with MMS.
      • Rowe D.E.
      • Carroll R.J.
      • Day Jr., C.L.
      Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.
      In comparison, the 5-year recurrence rates for C&E, standard excision, and radiation therapy were 3.7% (n = 82), 8.1% (n = 124), and 10.0% (n = 160), respectively. When high-risk factors were taken into account, MMS showed lower recurrence rates compared with standard excision and other non-MMS treatment modalities: 25.2% versus 41.7% for tumors 2 cm or larger, 32.6% versus 53.6% for poorly-differentiated cSCC, and 0% versus 47% for neurotropic cSCC. For recurrent cSCC, the meta-analysis by Rowe et al revealed a 5-year recurrence rate after MMS of 10.0% (n = 151) compared with 23.3% (n = 34) following standard excision. Similar 5-year recurrence rates for recurrent cSCC treated with MMS (ranging between 6% and 11%) were reported by others.
      • Leibovitch I.
      • Huilgol S.C.
      • Selva D.
      • Hill D.
      • Richards S.
      • Paver R.
      Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years.
      • Lawrence N.
      • Cottel W.I.
      Squamous cell carcinoma of skin with perineural invasion.
      In the absence of high-level data, extrapolation from a recent RCT demonstrating the benefit of MMS for primary and recurrent facial BCC may be justified to support the use of MMS for high-risk cSCC.
      • van Loo E.
      • Mosterd K.
      • Krekels G.A.
      • et al.
      Surgical excision versus Mohs' micrographic surgery for basal cell carcinoma of the face: a randomised clinical trial with 10 year follow-up.
      A large percentage of cSCCs are located on the head and neck, where tissue conservation is important. Similar to BCC, cSCC is characterized histologically by asymmetric subclinical extension beyond the clinically visible tumor, but it presents with perineural involvement more frequently than BCC does.
      • Goepfert H.
      • Dichtel W.J.
      • Medina J.E.
      • Lindberg R.D.
      • Luna M.D.
      Perineural invasion in squamous cell skin carcinoma of the head and neck.
      Both histopathologic features would support the importance of meticulous and complete margin assessment with MMS. However, aggressive histopathologic growth patterns poorly visualized with frozen sections (eg, sarcomatoid/spindle cell or single cell infiltrative cSCC) may limit the utility of MMS under certain circumstances. An additional limitation is that tissue blocks from MMS layers are not available for molecular testing or further evaluation of high-risk or unusual features by using paraffin sections.
      • Ebede T.L.
      • Lee E.H.
      • Dusza S.W.
      • Busam K.J.
      • Nehal K.S.
      Clinical value of paraffin sections in association with Mohs micrographic surgery for nonmelanoma skin cancers.
      To overcome this challenge, the tumor debulk specimen may be submitted for paraffin sections to document high-risk features and obtain ancillary molecular studies, if indicated, without compromising the integrity of the MMS procedure.

      American Academy of Dermatology. Appropriate uses of paraffin sections in association with Mohs micrographic surgery. 2014; Available at: https://www.aad.org/Forms/Policies/Uploads/PS/PS%20Appropriate%20Uses%20of%20Paraffin%20Sections%20in%20Association%20with%20Mohs%20Mircographic%20Surgery.pdf. Accessed February 1, 2017.

      Alternatively, key pathologic high risk features can be documented in the Mohs report to facilitate prognostic assessment and guide postoperative management when indicated. Careful selection, on the basis of initial biopsy results, of tumors appropriate for treatment with MMS and evaluation by frozen sections will minimize these limitations.
      On the basis of the best available data, the work group recommends MMS for the treatment of high-risk cSCC (on the basis of NCCN risk stratification [Table VIII]; for level of evidence/strength of recommendation, see Table IX).

       C&E

      C&E is regularly used in daily practice for the treatment of low-risk cSCC. However, no RCTs have been performed and no prospective data are available to compare C&E with other treatment modalities. In the aforementioned systematic review by Lansbury et al, 8 retrospective series of variable follow-up periods that addressed C&E were identified.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      A pooled analysis revealed a recurrence rate of 1.7% (95% confidence interval, 0.5-3.4 [n = 1131]). Small, individual studies suggested higher recurrence rates for lesions greater than 2 cm in diameter or located on the ear and treated with C&E.
      The limited available data suggest that C&E is an effective treatment modality for properly selected tumors, although results are highly operator dependent.
      • Goldman G.
      The current status of curettage and electrodesiccation.
      It is the work group's opinion that C&E may be considered for small, low-risk primary cSCC (on the basis of NCCN risk stratification [Table VIII]; for level of evidence/strength of recommendation, see Table IX). Lesions on terminal hair–bearing skin (the scalp, pubic, axillary regions, and the beard area in men) should be excluded from treatment with C&E because of potential follicular extension of tumor.

      National Comprehensive Cancer Center. NCCN clinical practice guidelines in oncology; squamous cell carcinoma (V1.2017). Available at: www.nccn.org. Accessed October 3, 2016.

      Moreover, C&E may be associated with a longer healing time and inferior cosmetic outcome compared with standard excision and is best avoided in cosmetically sensitive areas.
      • Rodriguez-Vigil T.
      • Vazquez-Lopez F.
      • Perez-Oliva N.
      Recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation.

      Nonsurgical treatment

      In general, treatment of cSCC is most effectively accomplished by surgical therapy. There are relatively few exceptions to this guiding principle, especially for high-risk cSCC, because of the potential for recurrence and metastasis. If surgical therapy is not feasible or elected, nonsurgical approaches may be considered when tumors are low risk, with the understanding that the cure rate may be lower. Further research is needed to better establish the comparative safety and effectiveness of nonsurgical therapies for cSCC. The recommendations for nonsurgical treatments are shown in Table X. The level of evidence/strength of the recommendations is listed in Table XI.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Ashby M.A.
      • Smith J.
      • Ainslie J.
      • McEwan L.
      Treatment of nonmelanoma skin cancer at a large Australian center.
      • Hernandez-Machin B.
      • Borrego L.
      • Gil-Garcia M.
      • Hernandez B.H.
      Office-based radiation therapy for cutaneous carcinoma: evaluation of 710 treatments.
      • Grossi Marconi D.
      • da Costa Resende B.
      • Rauber E.
      • et al.
      Head and neck non-melanoma skin cancer treated by superficial x-ray therapy: an analysis of 1021 cases.
      • Finizio L.
      • Vidali C.
      • Calacione R.
      • Beorchia A.
      • Trevisan G.
      What is the current role of radiation therapy in the treatment of skin carcinomas?.
      • Schulte K.W.
      • Lippold A.
      • Auras C.
      • et al.
      Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas.
      • Cognetta A.B.
      • Howard B.M.
      • Heaton H.P.
      • Stoddard E.R.
      • Hong H.G.
      • Green W.H.
      Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients.
      • Bhatnagar A.
      Nonmelanoma skin cancer treated with electronic brachytherapy: results at 1 year.
      • Paravati A.J.
      • Hawkins P.G.
      • Martin A.N.
      • et al.
      Clinical and cosmetic outcomes in patients treated with high-dose-rate electronic brachytherapy for nonmelanoma skin cancer.
      • Tiodorovic-Zivkovic D.
      • Zalaudek I.
      • Longo C.
      • De Pace B.
      • Albertini G.
      • Argenziano G.
      Successful treatment of two invasive squamous cell carcinomas with topical 5% imiquimod cream in elderly patients.
      • Dirschka T.
      • Schmitz L.
      • Bartha A.
      Clinical and histological resolution of invasive squamous cell carcinoma by topical imiquimod 3.75%: a case report.
      Table XRecommendations for the nonsurgical therapy of cSCC
      If surgical therapy is not feasible or preferred, radiation therapy (eg, superficial radiation therapy, brachytherapy, external electron beam therapy, and other traditional radiotherapy forms) can be considered when tumors are low risk, with the understanding that the cure rate may be lower.
      Cryosurgery may be considered for low-risk cSCC when more effective therapies are contraindicated or impractical.
      Topical therapies (imiquimod or 5-FU) and PDT are not recommended for the treatment of cSCC on the basis of available data.
      There is insufficient evidence available to make a recommendation on the use laser therapies or electronic surface brachytherapy in the treatment of cSCC.
      cSCC, Cutaneous squamous cell carcinoma; 5-FU, 5-fluorouracil; PDT, photodynamic therapy.
      Table XILevel of evidence and strength of recommendations for the nonsurgical treatment of cSCC
      RecommendationStrength of recommendationLevel of evidenceReferences
      CryosurgeryBII
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Radiation therapy
        • Traditional radiotherapies and modern superficial radiation therapy
        • Electronic surface brachytherapy


      B

      C


      II, III

      III


      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Ashby M.A.
      • Smith J.
      • Ainslie J.
      • McEwan L.
      Treatment of nonmelanoma skin cancer at a large Australian center.
      • Hernandez-Machin B.
      • Borrego L.
      • Gil-Garcia M.
      • Hernandez B.H.
      Office-based radiation therapy for cutaneous carcinoma: evaluation of 710 treatments.
      • Grossi Marconi D.
      • da Costa Resende B.
      • Rauber E.
      • et al.
      Head and neck non-melanoma skin cancer treated by superficial x-ray therapy: an analysis of 1021 cases.
      • Finizio L.
      • Vidali C.
      • Calacione R.
      • Beorchia A.
      • Trevisan G.
      What is the current role of radiation therapy in the treatment of skin carcinomas?.
      • Schulte K.W.
      • Lippold A.
      • Auras C.
      • et al.
      Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas.
      • Cognetta A.B.
      • Howard B.M.
      • Heaton H.P.
      • Stoddard E.R.
      • Hong H.G.
      • Green W.H.
      Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients.


      • Bhatnagar A.
      Nonmelanoma skin cancer treated with electronic brachytherapy: results at 1 year.
      • Paravati A.J.
      • Hawkins P.G.
      • Martin A.N.
      • et al.
      Clinical and cosmetic outcomes in patients treated with high-dose-rate electronic brachytherapy for nonmelanoma skin cancer.
      • Against topical therapy alone
        • Imiquimod
        • 5-FU


      C

      C


      III

      III


      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Tiodorovic-Zivkovic D.
      • Zalaudek I.
      • Longo C.
      • De Pace B.
      • Albertini G.
      • Argenziano G.
      Successful treatment of two invasive squamous cell carcinomas with topical 5% imiquimod cream in elderly patients.
      • Dirschka T.
      • Schmitz L.
      • Bartha A.
      Clinical and histological resolution of invasive squamous cell carcinoma by topical imiquimod 3.75%: a case report.


      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      Against photodynamic therapy aloneBII
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      Laser therapyCIII
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      cSCC, Cutaneous squamous cell carcinoma; 5-FU, 5-fluorouracil.

       PDT

      Photodynamic therapy (PDT) is a 2-part treatment consisting of topical application of a photosensitizer, either 5-aminolevulinic acid (ALA) or methylaminolevulinate (MAL), followed by 1 to several hours of incubation by light irradiation, typically with a blue, red, or broadband light source.
      • Roozeboom M.H.
      • Aardoom M.A.
      • Nelemans P.J.
      • et al.
      Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up.
      • Roozeboom M.H.
      • Arits A.H.
      • Mosterd K.
      • et al.
      Three-year follow-up results of photodynamic therapy vs. imiquimod vs. fluorouracil for treatment of superficial basal cell carcinoma: a single-blind, noninferiority, randomized controlled trial.
      • Roozeboom M.H.
      • Arits A.H.
      • Nelemans P.J.
      • Kelleners-Smeets N.W.
      Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
      • Wang H.
      • Xu Y.
      • Shi J.
      • Gao X.
      • Geng L.
      Photodynamic therapy in the treatment of basal cell carcinoma: a systematic review and meta-analysis.
      • Foley P.
      • Freeman M.
      • Menter A.
      • et al.
      Photodynamic therapy with methyl aminolevulinate for primary nodular basal cell carcinoma: results of two randomized studies.
      • Berroeta L.
      • Clark C.
      • Dawe R.S.
      • Ibbotson S.H.
      • Fleming C.J.
      A randomized study of minimal curettage followed by topical photodynamic therapy compared with surgical excision for low-risk nodular basal cell carcinoma.
      • Rhodes L.E.
      • de Rie M.A.
      • Leifsdottir R.
      • et al.
      Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma.
      • Kuijpers D.I.
      • Thissen M.R.
      • Thissen C.A.
      • Neumann M.H.
      Similar effectiveness of methyl aminolevulinate and 5-aminolevulinate in topical photodynamic therapy for nodular basal cell carcinoma.
      • Soler A.M.
      • Angell-Petersen E.
      • Warloe T.
      • et al.
      Photodynamic therapy of superficial basal cell carcinoma with 5-aminolevulinic acid with dimethylsulfoxide and ethylendiaminetetraacetic acid: a comparison of two light sources.
      • Osiecka B.
      • Jurczyszyn K.
      • Ziolkowski P.
      The application of Levulan-based photodynamic therapy with imiquimod in the treatment of recurrent basal cell carcinoma.
      • de Vijlder H.C.
      • Sterenborg H.J.
      • Neumann H.A.
      • Robinson D.J.
      • de Haas E.R.
      Light fractionation significantly improves the response of superficial basal cell carcinoma to aminolaevulinic acid photodynamic therapy: five-year follow-up of a randomized, prospective trial.
      • Arits A.H.
      • Mosterd K.
      • Essers B.A.
      • et al.
      Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.
      Available data for PDT and laser therapy do not currently support the efficacy of either modality in the treatment of cSCC.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      Limited case report and case series data suggest that PDT may be used as an adjuvant modality in combination with curettage
      • Jambusaria-Pahlajani A.
      • Ortman S.
      • Schmults C.D.
      • Liang C.
      Sequential curettage, 5-fluorouracil, and photodynamic therapy for field cancerization of the scalp and face in solid organ transplant recipients.
      and surgery
      • Wang Y.
      • Yang Y.
      • Yang Y.
      • Lu Y.
      Surgery combined with topical photodynamic therapy for the treatment of squamous cell carcinoma of the lip.
      for invasive cSCC in high-risk patients such as solid organ transplant recipients (SOTRs) and potentially to spare tissue, but the specific contribution of PDT to observed outcomes in such combination approaches is uncertain.
      When PDT is combined with surgery, multiple PDT treatments may be used. Exacerbation or induction of well-differentiated cSCC or keratoacanthoma after PDT has however been reported.
      • Kwiek B.
      • Schwartz R.A.
      Keratoacanthoma (KA): an update and review.

       Topical therapies

      The available data do not currently support the use of topical modalities for the treatment of cSCC. Published studies investigating the use of topical imiquimod or 5-fluorouracil (5-FU) for cSCC (excluding SCC in situ) are limited to case reports for imiquimod and 2 small case series for 5-FU.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Tiodorovic-Zivkovic D.
      • Zalaudek I.
      • Longo C.
      • De Pace B.
      • Albertini G.
      • Argenziano G.
      Successful treatment of two invasive squamous cell carcinomas with topical 5% imiquimod cream in elderly patients.
      • Dirschka T.
      • Schmitz L.
      • Bartha A.
      Clinical and histological resolution of invasive squamous cell carcinoma by topical imiquimod 3.75%: a case report.
      Variable lengths of follow-up and histologic clearance limit the strength of these data.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      Because use of 5-FU typically results in marked erythema, erosions, and crust lasting for a month or longer, decreased patient compliance with treatment regimens may result in diminished effectiveness. Similarly, imiquimod dosing for cSCC is complicated by the resultant tissue effects, including erythema, edema and erosions, ulceration and crust, that are not consistent from one individual to the next. In addition, imiquimod use for larger surface areas may be associated with systemic symptoms, including fatigue, influenza-like symptoms, myalgia, and headache.

       Radiation therapy

      Although surgery remains the first-line, and most effective, treatment for cSCC, primary radiation therapy can be used in special situations in which surgery is not feasible, contraindicated, or not preferred by the patient after a discussion of risks and benefits. Several different types of radiotherapy can be used to treat cSCC, including superficial radiation therapy, isotope-based brachytherapy (interstitial or topical contact), or external electron beam radiation.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.
      • Ashby M.A.
      • Smith J.
      • Ainslie J.
      • McEwan L.
      Treatment of nonmelanoma skin cancer at a large Australian center.
      • Hernandez-Machin B.
      • Borrego L.
      • Gil-Garcia M.
      • Hernandez B.H.
      Office-based radiation therapy for cutaneous carcinoma: evaluation of 710 treatments.
      • Grossi Marconi D.
      • da Costa Resende B.
      • Rauber E.
      • et al.
      Head and neck non-melanoma skin cancer treated by superficial x-ray therapy: an analysis of 1021 cases.
      • Finizio L.
      • Vidali C.
      • Calacione R.
      • Beorchia A.
      • Trevisan G.
      What is the current role of radiation therapy in the treatment of skin carcinomas?.
      • Schulte K.W.
      • Lippold A.
      • Auras C.
      • et al.
      Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas.
      • Locke J.
      • Karimpour S.
      • Young G.
      • Lockett M.A.
      • Perez C.A.
      Radiotherapy for epithelial skin cancer.
      Primary or adjuvant radiation therapy is an effective treatment option for selected patients with cSCC, resulting in good tumor control and cosmesis,
      • Mendenhall W.M.
      • Amdur R.J.
      • Hinerman R.W.
      • Cognetta A.B.
      • Mendenhall N.P.
      Radiotherapy for cutaneous squamous and basal cell carcinomas of the head and neck.
      with the understanding that the cure rates may be lower.

      American Academy of Dermatology. Position statement on superficial radiation therapy for basal cell carcinoma (bcc) and squamous cell carcinomas (SCC) https://www.aad.org/Forms/Policies/Uploads/PS/PS-Superficial%20Radiation%20Therapy.pdf. Accessed November 5, 2016.

      American Academy of Dermatology. Position statement on electronic surface brachytherapy for basal cell carcinoma (bcc) and squamous cell carcinomas (SCC). https://www.aad.org/Forms/Policies/Uploads/PS/PS%20-%20Electronic%20Surface%20Brachytherapy.pdf. Accessed November 5, 2016.

      Smaller and thinner tumors may be more responsive to radiation therapy.
      • Lansbury L.
      • Bath-Hextall F.
      • Perkins W.
      • Stanton W.
      • Leonardi-Bee J.
      Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies.