Comparative Analysis of US Guidelines for the Management of Cutaneous Squamous Cell and Basal Cell Carcinoma

Background This study presents a comparative analysis of recently published guidelines to manage cutaneous squamous cell carcinoma (cSCC) and cutaneous basal cell carcinoma (cBCC) within the United States (US). Methods A PubMed database search was performed for the time period between June 1, 2016, and December 1, 2022. A comprehensive comparison was performed in the following clinical interest areas: staging and risk stratification, management of primary tumor and regional nodes with curative intent, and palliative treatment. Results Guidelines from 3 organizations were analyzed: the American Academy of Dermatology (AAD), the National Comprehensive Cancer Network (NCCN), and the American Society for Radiation Oncology (ASTRO). The guidelines used different methodologies to grade evidence, making comparison difficult. There was agreement that surgery is the preferred treatment for curative cBCC and cSCC. For patients ineligible for surgery, there was a consensus to recommend definitive radiation. AAD and NCCN recommended consideration of other topical modalities in selected low-risk cBCC. Postoperative radiation therapy (PORT) was uniformly recommended in patients with positive margins that could not be cleared with surgery and in patients with nerve invasion. The definition and extent of nerve invasion varied. All guidelines recommended surgery as the primary treatment in patients with lymph node metastases in a curative setting. The criteria used for PORT varied; NCCN and ASTRO used lymph node size, number of nodes, and extracapsular extension for recommending PORT. Both NCCN and ASTRO recommend consideration of systemic treatment along with PORT in patients with extracapsular extension. Conclusion: US guidelines provide contemporary and complementary information on the management of cBCC and cSCC. There are opportunities for research, particularly in the areas of staging, indications for adjuvant treatment in curative settings, extent of nerve invasion and prognosis, and the role of systemic treatments in curative and palliative settings.


Introduction
Skin cancer is the most common malignancy in the United States (US).Te most common skin malignancies are cutaneous basal cell carcinoma (cBCC) and cutaneous squamous cell carcinoma (cSCC) [1].Although they have excellent local control and survival rates, there is wide variation in the management of these tumors, with few randomized trials comparing the diferent treatment modalities [2][3][4].To provide recommendations based on the best available evidence and expert opinion, several international and US organizations have published guidelines to manage these tumors [5][6][7][8][9][10][11][12].
In the US, the National Comprehensive Cancer Network (NCCN) was the frst organization to publish consensusbased guidelines in 1999 for the management of skin malignancies.Tese were recently updated in 2022 [12].In 2018, the American Academy of Dermatology (AAD) published their guidelines to manage cBCC and cSCC [9,10].In 2019, the American Society for Radiation Oncology (ASTRO) published guidelines with an emphasis on indications for radiation therapy [11].
A comparative analysis of International and US guidelines in patients with high risk and advanced cSCC has been published [13], but no such comparison has been performed amongst US guidelines.Te aim of this review is to compare recently published US guidelines for the management of cBCC and cSCC and point out future opportunities for research.

Materials and Methods
We developed search strategies in PubMed that combined and incorporated medical subject headings and text words.Te frst search incorporated terms for the NCCN, squamous cell carcinoma, and basal cell carcinoma.Te second search combined terms for guidelines, squamous cell carcinoma, basal cell carcinoma, and diagnosis and management.Te search terms included cutaneous, skin, basal, squamous, cancer, carcinoma, and guidelines.We limited the search to studies published between June 1, 2016, and December 1, 2022.
To compare various US guidelines, the following areas of clinical interest were reviewed and compared: methodology of guideline development, staging and risk stratifcation, management of primary tumors and regional nodes with curative intent, and palliative treatment.

Results
A total of 25 published articles were identifed relevant to our study (Figure 1).Following abstract review, 11 articles underwent full review.Of these, 7 articles were excluded; 1 was Spanish guidelines for the management of cBCC [14], 1 was Swiss guidelines for the management of cBCC [15], 2 were British guidelines for the management of adults with cSCC and cBCC [16,17], 1 was on consensus management of actinic keratosis [18], 1 described guidelines for the followup of patients treated with hedgehog inhibitors [19], and 1 presented US preventive service task force recommendation for screening skin cancer [20].Te remaining 4 US guidelines, 2 from the AAD, 1 from the NCCN, and 1 from the ASTRO, form the basis of this report [9][10][11][12].

Panel Expertise.
Te specialties represented on the expert panel could potentially bias treatment recommendations in the absence of high-level evidence.Table 1 lists the specialties represented on the AAD, NCCN, and ASTRO panels.

Methodology of Guideline Development.
US guidelines used diferent methodologies to evaluate available evidence and give recommendations, making interguideline comparisons difcult.Te AAD evaluated the evidence using a unifed system called the Strength of Recommendation Taxonomy (SORT).Treatment recommendations were developed based upon the quality of evidence and expert opinion (Table 2).Te ASTRO guidelines were developed in accordance with the National Academy of Medicine standards.Te available evidence for key questions was assessed using the Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) framework.Te Delphi approach was used to develop consensus (Table 2).NCCN guidelines are a statement of consensus of the panel members regarding their views of currently accepted approaches to cancer treatment (Table 2).

Staging and Risk Stratifcation.
Several staging and risk stratifcation systems were discussed, including NCCN risk stratifcation [12], the American Joint Committee on Cancer (AJCC) Staging Manual-8 th edition [21], and Brigham and Women's Hospital (BWH) tumor classifcation [22,23].AAD and NCCN used low-and high-risk criteria as defned by NCCN to give their recommendations.In addition, NCCN categorized the cSCC high-risk group into high and very high-risk groups; the high-risk group has elevated risk of local recurrence, and the very high-risk group has elevated risk of local recurrence and metastasis [12].NCCN used AJCC criteria for the management of neck nodes.ASTRO advocated the use of AJCC staging for their recommendations.Tere was moderate overlap between the guidelines.

Management of Primary Tumors with Curative Intent.
Tere is general agreement that due to the paucity of data from well-designed randomized trials, most of the recommendations are based upon observational studies, expert opinion, and consensus of the panel members.Tere is consensus that the recommended treatments should take into consideration the best tumor control, cosmesis, function preservation, and patients' expectations.

Surgical Management.
All of the guidelines advocated surgery as the preferred treatment (Table 3).Details of surgical procedures were beyond the scope of the ASTRO guidelines.Te indications for standard excision with "bread loaf" histopathologic sectioning with a 4-6 mm margin were the same in the AAD and NCCN guidelines, though the SOR varied from A to C in AAD, while the category of evidence and consensus was the same throughout the NCCN guidelines.Te selection of patients for Mohs surgery and curettage and electrodessication (C & E) was the same between AAD and NCCN guidelines.Te only diference was that in the NCCN guidelines, other forms of peripheral and deep enface margin assessment (PDEMA) were recommended along with Mohs for the treatment of high-risk tumors.C & E was recommended in both AAD and NCCN guidelines for lowrisk tumors, excluding tumors of terminal hair-bearing areas.[9,11]), NCCN: National Comprehensive Cancer Network (Reference # [13]), and ASTRO: American Society of Radiation Oncology (Reference # [12]).5).Discussion of these modalities was beyond the scope of ASTRO guidelines.For cBCC, there was agreement between the AAD and NCCN guidelines that these modalities can be used only for low-risk superfcial cBCC where other more efective treatments are contraindicated.In the AAD guidelines, the level of evidence and SOR was high due to available data from randomized trials comparing a variety of treatment modalities.

Management of Metastatic Regional Nodes with Curative
Intent.Tere was agreement between the AAD and NCCN guidelines in managing cBCC with lymph node metastases, both recommended surgery ± PORT and hedgehog inhibitors as indicated (Table 6).For cSCC, surgery ± PORT was recommended by both the AAD and NCCN in patients with regional lymph node metastases.However, in the NCCN guidelines, the use of PORT was dependent on the size and the number of nodes and presence of extracapsular extension (ECE).Any patients with a lymph node >3 cm, ≥2 regional nodes, and ECE were recommended to have PORT.Patients with ECE were advised to consider systemic therapy in addition to PORT.In the ASTRO guidelines, cBCC and cSCC were addressed together.Tere were similarities between the NCCN and ASTRO guidelines for PORT recommendations to patients with nodes >3 cm and/or ECE.ASTRO guidelines also conditionally recommended elective nodal radiation to patients with SCC at a high risk of regional nodal metastases.

Management of Distant Metastases and Advanced Disease
with Palliative Intent.All guidelines encouraged clinical trials, multidisciplinary consultation, and management with supportive care.Tere was uniformity in recommending various combinations of surgery, radiation, platinum-based chemotherapy, epidermal growth factor receptor inhibitors, and immunomodulators, depending on the clinical scenario.All guidelines recommended hedgehog inhibitors in patients with cBCC with distant metastases.

Discussion
We present a comparative analysis of recently published US guidelines to manage cBCC and cSCC.Te diferences in methodology, grading for quality of evidence, staging, and risk stratifcation make comparison between guidelines challenging.Tere was agreement between guidelines that, due to limited data from randomized trials, most of the recommendations are based upon retrospective studies, expert opinions, and consensus of the panel members.Te expertise represented on the panels could potentially bias recommendations, particularly in the absence of high-level evidence.
In 2013, Brigham and Women's Hospital's (BWH) tumor classifcation system was proposed and later validated [22,23] for the management of cSCC due to the poor prognostic value of AJCC staging.However, BWH classifcation lacks the inclusion of lymph node and distant metastases, which are included in the AJCC classifcation.NCCN risk stratifcation has been widely adopted and was used in both the AAD and NCCN guidelines.Currently, there is no consensus on which staging or risk stratifcation system is optimum in managing and predicting the outcome for cSCC and it is an area of active research.
Heppt et al. [13] recently published a comparative analysis of guidelines for managing high-risk and advanced cSCC from the US, Canada, the United Kingdom, the European Union, and Italy.Te authors noted that there was consensus on several treatment strategies; however, there were diferences in the management recommendations, SOR related to surgical margins, indications for sentinel node biopsy, use of PORT, and the treatment of metastatic disease.
Our analysis mirrors the observations made by Heppt et al. [13].We observed signifcant points of agreement between guidelines, but there were diferences also.Tere was general agreement on the use of surgery, surgical margins of 4-6 mm, and surgery as the preferred curative treatment for primary sites.Te AAD recommended Mohs to treat high-risk tumors, while NCCN categorized high-risk into high and very high-risk groups and added other forms of peripheral and deep enface margin assessment (PDEMA) to Mohs to manage these tumors.Te randomized data to support use of MMS are from van Loo et al., who reported a 5-year cumulative probability of recurrence of 12.2% vs. 4.4% in patients treated with surgical excision vs. MMS, respectively [3].Details of reconstruction of surgical defect, though beyond the scope of this manuscript, are important in order to achieve an optimum treatment outcome.Guidelines for reconstruction after resection of skin cancer are published by Chen et al. [24].
Te role of radiation was discussed more comprehensively in ASTRO and NCCN guidelines.Tere was agreement between guidelines to use defnitive radiation if surgery is not possible or advisable.Efectiveness of radiation as the primary management is based largely on observation studies [25,26].Te indications of PORT for primary management varied between guidelines.Tere was general agreement to use PORT in patients with perineural invasion (PNI) and positive margins only if the margin cannot be corrected with additional surgery.In addition, ASTRO guidelines strongly recommend PORT in patients with tumors invading bones or tumors >4 cm in the largest dimension.Te defnition and extent of nerve invasion for PORT varied from gross perineural spread that is clinically or radiographically apparent (ASTRO) to PNI without further characterization (AAD) and extensive PNI spread to large or named nerves (>0.1 mm in diameter; NCCN).Te SOR for PORT was strong in the ASTRO guidelines.Retrospective studies have shown that local control is much higher in patients with incidental PNI compared to clinical PNI [27], minimal to moderate PNI compared to central or macroscopic PNI [28], and microscopic focal PNI (involvement of 1-2 nerves <0.1 mm ), ASTRO: American Society of Radiation Oncology (Reference # [12]), LOE: level of evidence, QOE: quality of evidence, SOR: strength of recommendation, and COE: category of evidence.

Journal of Skin Cancer
8 Journal of Skin Cancer diameter) compared to macroscopic extensive PNI (involvement of >2 nerves) [29].Tere was no universal agreement on the risk category based on the extent of PNI.Tis is a potential area for future research.In order to reduce variations among clinicians, a group of experts published international radiation treatment contouring guidelines in the postoperative setting to treat patients with complex cSCC of the head and neck area [30].
In the AAD and NCCN guidelines, treatment modalities such as imiquimod, 5-fuorouracil, cryosurgery, and photodynamic therapy are contraindicated for cSCC but can be used in selected low-risk superfcial cBCC if other treatment modalities are contraindicated.Te level of evidence and SOR was high in AAD guidelines due to available data from randomized trials [31][32][33].
Te risk for regional nodal metastases is uncommon but higher in immunocompromised patients.Both ASTRO and NCCN guidelines were aligned and used the AJCC Staging Manual-8 th Edition criteria to recommend PORTdepending on the nodal size, number of positive nodes, and ECE.AAD guidelines suggest considering PORT in patients with neck metastases without further clarifcation.All guidelines suggest considering adjuvant chemotherapy or participation in a clinical trial.However, in a phase III trial of high-risk cSCC of the head and neck, there was no beneft of adding chemotherapy to radiation treatment [4].Elective treatment of regional nodes is an area of controversy.Wilkie et al. [34] published a contemporary perspective in the management of regional nodal basin in patients with cSCC.Te management of regional nodes is another potential area for research.
For patients treated with palliative intent, clinical trial participation, and multidisciplinary consultation was uniformly recommended.Tere was general agreement on the use of hedgehog inhibitors in cBCC.Use of surgery, radiation, platinum-based chemotherapy, epidermal growth factor receptor inhibitors, and immunomodulators were recommended depending on the clinical scenario.
Recent advances in the understanding of cancer biology and the mechanism by which cancer creates an immunologically privileged microenvironment for the malignant cells to survive aford an opportunity for ongoing and future research.cSCC is an immunogenic tumor with a high mutational burden [35,36].Checkpoint inhibitors such as pembrolizumab and cemiplimab have shown clinically meaningful activity against recurrent or metastatic and unresectable cSCC [37][38][39].Recently published results from a phase II trial confrmed that neoadjuvant cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cSCC [40].Integration of 40-gene expression profling (40-GEP) in the management of cSCC and advances in artifcial intelligence and data science will create additional opportunities in the diagnosis and management of cBCC and cSCC [41][42][43][44][45].

Conclusion
US guidelines provide contemporary and complementary information on the management of cBCC and cSCC.Tere are signifcant points of agreement and few disagreements between the guidelines.In spite of diferent criteria used for grading the evidence and potential bias introduced by experts on the panels, the guidelines are useful in clinical practice by reducing variability and maintaining quality care.Te discordance in treatment recommendations can be harmonized by creating a national task force of stakeholders.Due to limited data from randomized trials, there are signifcant opportunities for future research.

Figure 1 :
Figure 1: Preferred reporting items for systematic review and meta-analysis (PRISMA) fowchart used for identifcation of articles.

Table 1 :
Specialties represented on expert panels.
AAD: American Academy of Dermatology (Reference #

Table 2 :
Quality of evidence.

Table 3 :
Management of primary tumor with curative intent: surgical management.

Table 4 :
Management of primary tumor with curative intent: radiation therapy.Amongst the AAD and NCCN guidelines, there was consensus that these modalities have no role in the defnitive treatment of SCC, except that AAD recommended cryosurgery for the treatment of low-risk SCC only if other more efective therapies are contraindicated (Table [12]1]merican Academy of Dermatology (Reference #[9,11]), NCCN: National Comprehensive Cancer Network (Reference #[13]), ASTRO: American Society of Radiation Oncology (Reference #[12]), LOE: level of evidence, QOE: quality of evidence, SOR: strength of recommendation, COE: category of evidence, and PORT: postoperative radiation therapy.