NCCN临床实践指南：皮肤鳞状细胞癌（2026.V1）

指南综合与多学科· 未分类与其他 · 2026

STRATIFICATION TO DETERMINE TREATMENT OPTIONS FOR LOCAL CSCB BASED ON RISK FACTORS FOR LOCAL RECURRENCE, METASTASES, OR DEATH

|Risk Group|Low Risk|High Risk|Very High Risk| |---|---|---|---| |Treatment options|SCC-4|SCC-5|SCC-5 and SCC-6| |H&P|H&P|H&P|H&P| |Location/diameter(cm)|Trunk, extremities <2cm|Trunk, extremities 2 cm -≤4cm|>4 cm (any location)| |Location/diameter(cm)||Head,neck, hands,feet, pretibia, and anogenital area (any size)n|| |Clinical borders|Well-defined|Poorly-defined|| |Primary vs. recurrent|Primary|Recurrent|| |Immunosuppression|(-)|(+)|| |Site of prior RT or chronic inflammation|(-)|(+)|| |Rapid growth tumor|(-)|(+)|| |Neurologic symptoms|(-)|(+)|| |Pathology (SCC-A)|Pathology (SCC-A)|Pathology (SCC-A)|Pathology (SCC-A)| |Degree of differentiation|Well or moderately differentiated||Poorly differentiated| |Histologic subtype|(-)|(+)|(+)| |Depth l,m: Thickness or level of invasion|<2 mm thick and no invasion beyond subcutaneous fat|2-6 mm depth and no invasion beyond subcutaneous fat|>6 mm or invasion beyond subcutaneous fat| |Perineural involvement|(-)|(+)|Tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm| |Lymphatic or vascular involvement|(-)|(-)|(+)|

j Risk category assignment should be based on the highest risk factor present. The high-risk group has elevated risk of local recurrence; the very-high-risk group has elevated risk of local recurrence and elevated risk of metastasis.

k Adenosquamous or sarcomatoid subtypes in any portion of the tumor.

If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, consider narrow margin excisional biopsy.

m Deep invasion is defined as invasion beyond the subcutaneous fat OR>6 mm(as measured from the granular layer of adjacent normal epidermis to the base of the tumor, consistent with the AJCC Cancer Staging Manual, 8th Edition).

n Narrow excision margins due to anatomic and functional constraints are associated with increased recurrence rates with standard histologic processing. Complete margin assessment with Mohs/PDEMA is recommended. For tumors< 6 mm in size, without other high-risk or very-high-risk features, other treatment modalities may be considered if at least 4-mm clinically tumor-free margins can be obtained without significant anatomic or functional distortions.

Note:All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

FIELD CANCERIZATION/CONFLUENT EPIDERMAL DYSPLASIA

![Field cancerization/h/ Confluent epidermal dysplasia\n\n Prevention:□p,Lq,r-dir\n ▲\nNecin\nCancerization/h/ Confluent epidermal dysplasia\n\nA.\nNational\nNCCN Guidelines Version 1.2026\nNCCN Guidelines Version 1.2026\nUniquoacil(pferred)\nImiquimod\nTirbanibulin\nDiclofenac(category 2B)\nDestructive\nAblative laser vermioinctomy or electrosurgical destruction(may be of value in the treatment of extensive actinic cheilitis)\nAblative skin resurfacing(eg, laser, dermatasion)\nChemical peels\nRycotherapy\nCurettage and electrodesiccation(C&E)\nOther modalities that may be considered:\nCapecitabiner\n v(for severe refractory disease that has progressed on oral retinoids)\n\nFlield cancer\nRegental\nRegental\nRegental\nRegental\nSystemic therapy\nS. All557.25\ncitlin.}\n9.54\ntinial.19.25\ntinial.19.25\ntinal.19.25\ntidal.19.25\ntodal.19.25\ntodernal\nRegental\nRerextrom\nRegental\nRerextrom\nRegental\n19.25\ntodernal\n19.25\ntodernal\n19.25\ntodernal\n19.25\ntodernal\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodalcrenin\n19.25\ntodromal\nStympacilone\n19.25\ntodromin\n19.25\ntodrominal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19.25\ntodromal\n19\n](2/aj0YEe4oUhYkBdfpda0fYP/figure25cdbdcb3184418d8cf407dd3c32be13_0_6.png) h Field cancerization defined as UV induced confluent dysplasia clinically manifested as diffuse actinic keratoses and superficial (in situ) SCC.Willenbrink TJ,et al.J Am Acad Dermatol 2020;83:709-717.

○Principles of Systemic Therapy.

P Actinic keratoses that have an atypical clinical appearance or do not respond to appropriate therapy should be biopsied for histologic evaluation.

q Actinic keratoses should be treated at first development.

r Cornejo CM,et al.J Am Acad Dermatol 2020;83:719-730.

s Green AC,et al.J Clin Oncol 2011;29:257-263.

t Oral Nicotinamide may be effective in reducing the development of CSCCs, Chen AC,et al. N Engl J Med 2015;373:1618-1626; Allen NC,et al. N Engl J Med 2023;388:804-812; Mainville L,et al. J Cutan Med Surg 2022;26:297-308; Chen AC,et al. Br J Dermatol 2016;175:1073-1075.

uThe longest duration of prophylaxis against SCC has been demonstrated with topical Fluorouracil plus Calcipotriol.Cunningham TJ,et al.J Clin Invest 2017;127:106-116;Jansen MHE,et al.N Engl J Med 2019;380:935-946.

v Endrizi B, et al. Dermatol Surg 2013;39:634-645.

w Use of oral retinoids(eg, Acitretin, Isretinoin) is a therapeutic option used to reduce the development of actinic keratoses. Side effects of oral retinoids may be significant, especially in patients of childbearing potential, and therapeutic benefits are limited to the duration of the regimen. Topical retinoids were shown not to reduce development of actinic keratosis. Badri O, et al. Dermatol Surg 2021;47:125-126.

NCCN

National Comprehensive Cancer Network

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

![LOW-RISK CSCC\nPRIMARY TREATMENTX\n·C&Ey or\n·Shave removalzaa\nor\n·Standard excision with 4- to 6-mm clinical margins and postoperative margin assessment. Tissue rearrangement(eg, flap reconstruction,extensive undermining) should not be undertaken until clear margins are identified (second intention healing, linear repair, or skin graft are acceptable)\n·Mohsbb,cc,dd or other forms of PDEMAee\nor\n·Re-excision if clinically feasible\nor\n·RTff,gg for nonsurgical candidates\n·SCC-11\n·R\n·Follow-up(SCC-11)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6f88a63a6af242ada12d405add8495f6_0_5.png) a Principles of Pathology(SCC-A).

b Risk Factors for Local Recurrence. Metastases, or Death(SCC-2) and Identification and Management of Patients at High Risk for Multiple Primary CSCCs(SCC-B).

xPrinciples of Treatment(SCC-C).

yC&E may have a lower cure rate than excision.

z Shave removal(shaving of epidermal or dermal lesion) is a sharp removal by transverse bowl-shaped slicing to remove epidermal and dermal lesions(without including fat) and does not require suture closure. Emmett AJ,et al. Plast Reconstr Surg 1987;80:47-54.

aa If tumor appears to extend beyond the dermis, surgical excision should generally be performed rather than C&E or shave removal.

bb When Mohs is being performed and the preoperative biopsy is considered insufficient for providing all the staging information required to properly treat the tumor, submission of the central specimen for vertical paraffin-embedded permanent sections or documentation of staging parameters in Mohs report is recommended.

${ }^{cc}$ As per other appropriate use Guidelines. Task Force/Committee Members, Vidal CI, Armbrect EA, et al.J Am Acad Dermatol 2019;80:189-207.e11.

dd Mohs surgery should be performed by dermatologic surgeons who have specialized training and experience in this procedure.

ee PDEMA with permanent section analysis or intraoperative frozen section analysis is an alternative to Mohms. See Principles of PDEMA Technique (SCC-D).

ff Principles of Radiation Therapy(SCC-D).

99 Determination of the appropriateness of RT should be performed together with a radiation oncologist.

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure52dde6e86e244ee5a16e36b9c3fb74be_0_1.png) National Comprehensive Cancer Network

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

HIGH-RISK/VERY-HIGH-RISK CSCC

TREATMENT PLANNING

PRIMARY TREATMENTX

ADDITIONAL TREATMENTX

![High-risk/very-high-risk CSCC\nTREATMENT\n PRIMARY TREATMENT^\n· Mohsbb,cc.dd or other forms of PDEMA(pferred for very high risk)ee,jj,kk,ll\nconsultation at center with specialized discuss options\n● Multidisciplinary\nconsultation at center with specialized specialized discuss options\n● Consider\nsentinel lymph of node biopsy\n(SLNB)hh,ii in\ncases that are recurrent or with multiple high-risk features\n● For nonsurgical candidates, consider definitive RTff,gg\n● For nonsurgical variants\n● If surgery and/or RTgg\n● are not curative\n● ADITIONAL TREATMENT^\n+Re-resect,\nif feasible\n+RTff,gg\n● Follow-up(RSCC disease)\n● If expensive perineural, large\nor named nerve involvement,\n● or other poor prognostic\n● features,a,nn consider\n● Adjuvant RTff,gg,oo\nFollow-up(SCC-11)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2f9ff3ae255a42e2be018e70eaf2758a_0_9.png) NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

Version 1.2026, 09/02/2025 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

SCC-5A

FOOTNOTES

performance status, then consider radiation therapy. Following neck dissection, refer to SCC-6 for additional recommendations.

jj In patients with very-high-risk CSCC and normal exam of nodal basin, discuss and consider radiologic imaging of nodal basin.kk If invasion to parotid fascia, superficial parotidectomy may be indicated.ll For tumors being considered for SLNB, delay reconstruction if not able to close primarily with minimal undermining.mm Appropriate margins should be determined case by case based on tumor and patient-specific factors.nn Large nerve involvement is defined by the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition for CSCC of the head and neck as ≥0.1 mm or nerve involvement deeper than the dermis. Most nerves deep to the dermis are >0.1 mm. oo Adjuvant RT can be considered for CSCCs with gross clinical radiologic perineural invasion (PNI), multifocal histologic nerve invasion, ≥6 cm tumor diameter, recurrent tumors, high risk for regional or distant metastasis, close surgical margins where further surgery cannot be performed, and desmoplastic or infiltrative tumors in patients who are chronically immunosuppressed. Ruiz ES, et al. J Am Acad Dermatol 2022;87:87-94.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

VERY-HIGH-RISK CSCG

TREATMENT PLANNING

PRIMARY TREATMENTX

ADDITIONAL TREATMENT*

![Very-high-risk CSCC with significant risk of extensive local recurrence, nodal, or in-transit metastasis,a,b\nor\n· Consider SNLBh,ii in cases that are recurrent or with multiple high-risk features\n· Consider neoadjuvant therapy with Cemiplimab-rwc° if: keratoacanthomatous rapid growth tumors\n· For nonsurgical candidates, consider definitive functional limitation\n· Mohs b,cc,dd or other forms of PDEMD (preferred for very high risk) ee,jk, ll"\n●Resident SNLBh,ii in cases that are recurrent or with multiple high-risk features\n· Consider neoadjuvant therapy with Cemiplimab-rwc° if: Nonreactive non-keratoacanthomatous rapid growth tumors\n· For nonsurgical candidates, consider definitive functional limitation\n· Standard excision with wider surgical margins mmms and posterior images and intention\nand second intention healing, linear repair, or skin graft\n·For nonsurgical candidates, consider definitive or Tff,gg\n·Re-resect, if feasible or RTff, gg-gll\n· Follow-up(SCC-11)\n· Follow-up (SCC-7)\n· In patients with extremely high risk nodal and non-nodal features, consider Cemiplimab-rwc' following adjuvant RT(category 1 preferred)PP\n·For nonsurgical variants, consider definitive or Tff,gg, h\n](2/aj0YEe4oUhYkBdfpda0fYP/figure46ab867e48ef4b079489c6edee4e71c9_0_9.png) PP Cemiplimab-rwc was studied in CSCC with very-high-risk for recurrence due to nodal features (extracapsular extension with largest node ≥20 mm in diameter or ≥3 involved nodes) or non-nodal features (in-transit metastases, T4 lesion [with bone invasion], PNI, or locally recurrent tumor with ≥1 additional risk feature). Rischin D, Porcedus D, S day F, et al. Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2025;393:774-785.

Note:All recommendations are category 2A unless otherwise indicated.

Footnotes on SCC-6A

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

a Principles of Pathology (SCC-A).b Risk Factors for Local Recurrence, Metastases, or Death (SCC-2) and Identification and Management of Patients at High Risk for Multiple Primary CSCCs (SCC-B).d Extensive disease includes deep involvement such as bone, named nerves, and deep soft tissue. If disease of named nerve(s) is suspected, MRI with and without

contrast is preferred. If bone disease is suspected, CT with contrast is preferred unless contraindicated.

f Imaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease (ie, local, regional, metastatic). Histologic confirmation is sufficient to diagnose local recurrence, but MRI with and without contrast can be considered to assess extent of local disease. For nodal or distant

metastases, histologic analysis and/or other imaging modalities can be used for confirmation and to gauge extent of disease.

g MRI with and without contrast of the brain may be considered to rule out subclinical cortical involvement in cases with bone invasion.o Principles of Systemic Therapy.x Principles of Treatment (SCC-C).bb When Mohs is being performed and the preoperative biopsy is considered insufficient for providing all the staging information required to properly treat the tumor,submission of the central specimen for vertical paraffin-embedded permanent sections or documentation of staging parameters in Mohs report is recommended.cc As per other appropriate use Guidelines. Task Force/Committee Members, Vidal CI, Armbrect EA, et al. J Am Acad Dermatol 2019;80:189-207.e11.dd Mohs surgery should be performed by dermatologic surgeons who have specialized training and experience in this procedure.ee PDEMA with permanent section analysis or intraoperative frozen section analysis is an alternative to Mohs. See Principles of PDEMA Technique (SCC-F).ff Principles of Radiation Therapy (SCC-D).gg Determination of the appropriateness of RT should be performed together with a radiation oncologist. hh Discuss and consider SLNB prior to or at time of PDEMA for patients with very-high-risk CSCCs that are recurrent or have multiple risk factors placing them in the very-high-risk group and have normal exam of draining nodal basin (category 2B). ii For positive SLNB: Recommend multidisciplinary discussion after obtaining radiologic staging of the neck, chest, abdomen, and pelvis if not yet completed. In the absence of metastatic disease, consider completion lymphadenectomy of the affected nodal basin. If surgery is not an option due to patient preference or poor performance status, then consider radiation therapy. Following neck dissection, refer to SCC-6 for additional recommendations.jj In patients with very-high-risk CSCC and normal exam of nodal basin, discuss and consider radiologic imaging of nodal basin.kk If invasion to parotid fascia, superficial parotidectomy may be indicated.ll For tumors being considered for SLNB, delay reconstruction if not able to close primarily with minimal undermining.mm Appropriate margins should be determined case by case based on tumor and patient-specific factors.nn Large nerve involvement is defined by the AJCC Cancer Staging Manual, 8th Edition for CSCC of the head and neck as ≥0.1 mm or nerve involvement deeper than the dermis. Most nerves deep to the dermis are >0.1 mm. oo Adjuvant RT can be considered for CSCCs with gross clinical radiologic PNI, multifocal histologic nerve invasion, ≥6 cm tumor diameter, recurrent tumors, high risk for regional or distant metastasis, close surgical margins where further surgery cannot be performed, and desmoplastic or infiltrative tumors in patients who are chronically immunosuppressed. Ruiz ES, et al. J Am Acad Dermatol 2022;87:87-94.

FOOTNOTES

Note: All recommendations are category 2A unless otherwise indicated.

SCC-6A

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

PRIMARY TREATMENTX

![laCSC (Primary or recurrent extensive disease and/or where surgery and/or RT may not result in a cure or would possibly produce a significant functional impairment.9q Multidisciplinary discussion\nfor nonsurgical candidates, due to comorbidities, extent of disease, risk of functional or cosmetic defects,isability to clear disease with surgery: RTf,99± systemic therapy of Systemic therapyif curative RT99 is not feasible\nRe-resect, if feasible or RTff,ggt± systemic therapyor or Systemic therapyif curative RT99 is not feasible\nStandard excision with wider surgical margins and postoperative margin and assessment"If extensive perineural, large or named nerve involvement,or other poor prognostic features,a,nn consider: ● Adjuvant RTff,gg,oo\nfor nonsurgical candidates, due to comorbidities, extent of disease, risk of functional or cosmetic defects,isability to clear disease with surgery: RTff,99± systemic therapy of Systemic therapyof curative RT99 is not feasible\nFor nonsurgical candidates, due to comorbidities, extent of disease, risk of functional or cosmetic defects,isability to clear disease with surgery: RTff,99± systemic therapy of systemic solver for scientificly.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure81d0776fa9134b7597843379c909a94e_0_5.png) NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

SCC-7A

FOOTNOTES

a Principles of Pathology (SCC-A).b Risk Factors for Local Recurrence, Metastases, or Death (SCC-2) and Identification and Management of Patients at High Risk for Multiple Primary CSCCs (SCC-B).o Principles of Systemic Therapy.x Principles of Treatment (SCC-C).bb When Mohs is being performed and the preoperative biopsy is considered insufficient for providing all the staging information required to properly treat the tumor,submission of the central specimen for vertical paraffin-embedded permanent sections or documentation of staging parameters in Mohs report is recommended.cc As per other appropriate use Guidelines. Task Force/Committee Members, Vidal CI, Armbrect EA, et al. J Am Acad Dermatol 2019;80:189-207.e11.dd Mohs surgery should be performed by dermatologic surgeons who have specialized training and experience in this procedure.ee PDEMA with permanent section analysis or intraoperative frozen section analysis is an alternative to Mohs. See Principles of PDEMA Technique (SCC-F).ff Principles of Radiation Therapy (SCC-D).gg Determination of the appropriateness of RT should be performed together with a radiation oncologist. kk If invasion to parotid fascia, superficial parotidectomy may be indicated.ll For tumors being considered for SLNB, delay reconstruction if not able to close primarily with minimal undermining.mm Appropriate margins should be determined case by case based on tumor and patient-specific factors.nn Large nerve involvement is defined by the AJCC Cancer Staging Manual, 8th Edition for CSCC of the head and neck as ≥0.1 mm or nerve involvement deeper than the dermis. Most nerves deep to the dermis are >0.1 mm. oo Adjuvant RT can be considered for CSCCs with gross clinical radiologic PNI, multifocal histologic nerve invasion, ≥6 cm tumor diameter, recurrent tumors, high risk for regional or distant metastasis, close surgical margins where further surgery cannot be performed, and desmoplastic or infiltrative tumors in patients who are chronically immunosuppressed. Ruiz ES, et al. J Am Acad Dermatol 2022;87:87-94.qq Bertrand N, et al. eClinicalMedicine 2021;5:100844. rr If patient is immunosuppressed, consider modification or reduction of immunosuppression as appropriate.ss Consider neoadjuvant therapy with Cemiplimab-rwlc, after multidisciplinary discussion, if the tumor has very rapid growth, in-transit metastasis, lymphovascular invasion, is borderline resectable, or surgery alone may not be curative or may result in significant functional limitation.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL STAGING AND PREOPERATIVE ASSESSMENT\nConsider re-evaluation:\cdot Clinical exam\n· CT with contrast of the nodal basin\n· Fast neither of the clinical trial, or excisional biopsy\nV\nPositive\nFNA or lymph nodes identified by imaging studies\nTurbital biopsy\nPositive\n\nControl evaluation:· Clinical exam\n· CT with contrast of the nodal basin\n· CT with contrast of the end of the nodal basin to determine size, number, and location of nodes\nSurgical and clinical trial evaluation ww\n Positive\nTrunk\ndeadis ex\nTrunst and extremities\nrelax\ntumor\nderect of a clinical diduse $xx\%$\nHead and neck\nExcision of primary tumor and regional\ndeventious\nrelaxual\ninoretable\nMultidisciplinary consultation to discuss options:\cdot RTff,gg.yt\pm systemictherapy^{\circ}.\nResubsequent resected disease^{\text{xx}}\nRT99 not feasible\n](2/aj0YEe4oUhYkBdfpda0fYP/figure70fd459498824b14b9e991582a8f27f9_0_5.png) 9MRI with and without contrast of the brain may be considered to rule out subclinical cortical involvement in cases with bone invasion.

° Principles of Systemic Therapy.

x Principles of Treatment(SCC-C).

ff.Principles of Radiation Therapy(SCC-D).

99 Determination of the appropriateness of RT should be performed together with a radiation oncologist.

"If the patient is immunosuppressed, consider modification or reduction of immunosuppression as appropriate.It identification and Management of Patients at High Risk for Multiple Primary CSCCs (SCC-B).

$u^{u}$ Ultrasound-guided biopsy by a center or physician with expertise is recommended. Core biopsy may be preferred over FNA in cases where primary tumor histology is uncertain or if a larger tissue sample is required for further genetic or other testing.

$w^{\prime}$ An excisional biopsy may be considered to confirm a negative initial FNA or core lymph node biopsy if clinical suspicion remains high.

ww Regional lymph node dissection is preferred unless the patient is not a surgical candidate.

$xx$ Cemiplimab-rwlc, in one study of 79 patients with CSCC, showed a 51% complete histologic response in the neoadjuvant setting.There it may be considered in patients who are considered borderline resectable, unresectable, or for whom surgery may carry a high morbidity.

yY Consider palliative RT/surgery for symptomatic sites. Stereotactic body RT(SBRT) may also be considered in select patients.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

SATELLITOSIS/IN-TRANSIT METASTASIS(S-ITM)

TREATMENT PLANNING

PRIMARY TREATMENTX

![Tissue sampling\nconfirmed S-ITM\n· Imaging of the anatomic region (ie, CT with contrast) capturing S-ITM to determine geographic footprint\nCT with contrast or FDG-PET/CT as clinically indicated to rule out distant disease\nMultidisciplinary discussion\nUnresectable or incompletely resected disease\n with consideration of adjuvant therapy zz,aaa\n· Imaging of the anatomic region (ie, CT with contrast) capturing S-ITM to determine geographic footprint\nCT with contrast or FDG-PET/CT as clinically indicated to rule out distant disease\n● Unresectable or incompletely disease\n with Melphalan-based regimens\· Attenuative Index\nUnresectable or R is not not not not discovered in the RMB 342036\n● Isolated limb infusion/perfusion (ILI/ILP)with Melphalan-based regimens'bb (Useful in certain circumstances)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2b531c5a8bca4ae5bb6b07f101a2fc4c_0_8.png) NCCN授权医脉通提供NCCN指南全文下载。wmlsyy于2025/09/06,21:21在医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。

National Comprehensive NCCN Guidelines Version 1.2026 NCCN Guidelines Conference Table of Contents Regional LYMPH NODE:

![REGIONAL LYMPH NODES\nTREATMENT OF HEAD AND NECK ${}^{X}$(FINDINGS\nOne positive node\nRTff,gg\nor\nObservation\nIncompletely excised on nodal disease\nRTff,gg\nObservation\nFollow-up\nSCC-11)\nPrartid nodes\nParotid nodes\ninvolvedccc\nExcision of primary tumor and generally superficial parotidectomy and ellipsoidal neck dissection if clinically indicated\nNCCN Guidelines Version 1.2026\nNCCN Guidelines Version 1.2026\nA few nodes\nRTff,gg\nObservation\nFollow-up(SCC-11)\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figuredc3fe0c9492347598ddfaf26e911c347_0_2.png) ° Principles of Systemic Therapy.

× Principles of Treatment(SCC-C).

$^{99}$ Determination of the appropriateness of RT should be performed together with a radiation oncologist.

99 Determination of the appropriateness of RT should be performed together with a radiation oncologist.

ddd Multidisciplinary consultation recommended.

Note:All recommendations are category 2A unless otherwise indicated.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

FOLLOW-UP

Local disease:

●H&Pee,fff,ggg

For patients who are low risk:

Every 3-12 mo for 2 y, then every 6-12 mo for 3 y, then annually for lifeb

For patients who are high risk:

Every 3-6 mo for 2 y, then every 6-12 mo for 3 y, then annually for lifeb

For patients who are very high risk:

Every 3-6 mo for 2 y, then every 6 mo for 3 y, then every 6-12 mo for lifeb

●Consider imaging:

If clinical exam is insufficient for following disease

If there is appreciable risk of subclinical local or nodal recurrencef

● Patient education

Sun protection

Self examination of skin

Regional/S-ITM disease:

●H&Pee,fff,ggg

Every 2-3 mo for 1 y,

then every 2-4 mo for 1 y,

then every 4-6 mo for 3 y,

then every 6-12 mo for life

●Consider imaging:

If clinical exam is insufficient for following disease

If there is appreciable risk of subclinical local or nodal recurrencef,hhh

● Patient education

Sun protection

Self examination of skin and lymph nodes

b Risk Factors for Local Recurrence, Metastases, or Death (SCC-2) and Identification and Management of Patients at High Risk for Multiple Primary CSCCs (SCC-B).

fImaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease (ie, local, regional, metastatic). Histologic confirmation is sufficient to diagnose local recurrence, but MRI with and without contrast can be considered to assess extent of local disease. For nodal or distant metastases, histologic analysis and/or other imaging modalities can be used for confirmation and to gauge extent of disease.

° Principles of Systemic Therapy.

y Consider palliative RT/surgery for symptomatic sites. SBRT may also be considered in select patients.

![Local recurrencef\nSCC-5 and SCC-6\nLocally advanced (laCSCC) recurrencef\nSSC-7\nNew or recurrent S-ITM\nSCC-9\nNew regional disease\nSCC-8 and SCC-10\nRegional recurrence or distant metastases\nmultidisciplinary consultationo,yy,iii\n](2/aj0YEe4oUhYkBdfpda0fYP/figure17a211a2a3b84ec0868d30337633108e_0_36.png) eee Including complete skin and regional lymph node exam.

fff Frequency of follow-up should be adjusted based on risk.

gg99 Follow-up with a dermatologist is strongly recommended if any of the following criteria are met: past or imminent solid organ, marrow, or stem cell transplant, one or more cutaneous melanomas in the past 5 years, or four or more non-melanoma skin cancers in the past 5 years.

hh Surveillance imaging of regional nodal basin and to evaluate for distant metastatic disease, ideally based on multidisciplinary board recommendation, or as clinically indicated.

iii Under highly selective circumstances, in the context of multidisciplinary consultation,resection of limited metastases can be considered.

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

Principles of Biopsy Reporting• Pathologic evaluation of skin biopsies is ideally performed by a dermatologist, pathologist, or dermatopathologist experienced ininterpreting cutaneous neoplasms. Reporting of margins and the elements below is not required for biopsy specimens.

Principles of Excision Reporting (including Mohs excisions)• Specimens from intended complete surgical removal (eg, shave excisions) should be labeled as such so that margin status is reported.• Since depth of invasion (in mm) may not be ascertained on tangentially cut Mohs specimens, anatomic level of invasion should be reported.Frozen or permanent section analysis of the clinical tumor specimen may be undertaken if needed for complete reporting of the featuresbelow to enable AJCC tumor staging.1,2• Immunohistochemistry may be utilized as needed to help identify lymphovascular or nerve invasion, or to identify single tumor cells or smallaggregates.

Recommended Elements for Pathology Reporting of Excisional Specimens (including Mohs excisions)• NOTE: Tumors less than 2 cm in diameter without perineural invasion (as defined below) that are superficial (<6 mm in depth or confinedto skin and fat) are AJCC T1 and do not require specific reporting of the histologic findings below with the exception of grade. However,reporting the presence of any of the prognostic features below is strongly encouraged.

• Elements reported (on requisition form) by the clinician submitting the tissue:

Anatomic location

Clinical pre-excision diameter in cm

Primary or recurrent tumor

Clinical or radiologic nerve invasion, including name of nerve

Other risk factors (optional) (eg, immunosuppression, prior radiation at site)

• Elements reported by the physician reporting the histologic findings:

Margin status (whether or not tumor is present at margins)

Well, moderate, or poor differentiation

Depth of invasion (either Breslow depth [in mm] measured from granular layer of adjacent normal epidermis to the base of the tumor OR

tissue plane of deepest invasion (eg, dermis, fat, fascia, muscle, perichondrium/periosteum, cartilage bone, other)

Perineural invasion defined as tumor cells within the nerve sheath of a nerve deep to dermis or with a caliber 0.1 mm or larger

Lymphovascular invasion

High-risk histology (eg, adenosquamous, or sarcomatoid)

Low-risk histology (optional) (eg, verrucous)

Other useful reportable histologic features (eg, acantholytic, infiltrative, and spindle cell)

PRINCIPLES OF PATHOLOGY

1 Kim JYS, Kozlow JH, Mittal B, et al; Invited Reviewers; Work Group. Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad

Dermatol 2018;78:560-578.

2 Califano JA, Lydiatt WM, Nehal KS, et al. Cutaneous squamous cell carcinoma of the head and neck. In: Amin MB, Edge S, Greene F, et al, eds. AJCC Cancer Staging Manual (Eighth Edition). New York: Springer International Publishing; 2017:171-181.

Note: All recommendations are category 2A unless otherwise indicated.

SCC-A

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Note: All recommendations are category 2A unless otherwise indicated.

SCC-B 1 OF 2

IDENTIFICATION AND MANAGEMENT OF PATIENTS AT HIGH RISK FOR MULTIPLE PRIMARY CSCCs

Definition

• Certain patient groups are at high risk for developing multiple CSCCs and tumors that can behave aggressively.

These include:

Organ transplant recipients

Other settings of immunosuppression (eg, lymphoma, chronic lymphocytic leukemia [CLL], drug-induced, HIV)

Genetic syndromes predisposing to CSCC formationa

• Within these high-risk groups, individual patients who are high risk should be identified for closer follow-up.

• Important individual risk factors include:

Total number of tumors

Frequency of development

Occurrence of aggressive tumors (eg, extension beyond cutaneous structures, perineural involvement, large and poorly differentiated,

having ≥3 risk factors for recurrence) (See Stratification to Determine Treatment Options for Local CSCC Based on Risk Factors for Local

Recurrence, Metastases, or Death [SCC-2]).

Diagnosis

• Skin lesions in these high-risk populations may be difficult to assess clinically. Therefore, a low threshold for performing skin biopsies of suspect lesions is necessary.

• In these patients, urgent diagnosis and treatment of lesions are important, and nodal staging (CT with contrast and/or ultrasound or

pathologic evaluation) may be considered in those with significant risk of nodal metastases.

a Examples include xeroderma pigmentosum, generalized eruptive keratoacanthoma of Grzybowski, Rothmund-Thomson syndrome, dyskeratosis congenita,

epidermodysplasia verruciformis, recessive dystrophic epidermolysis bullosa, severe generalized junctional epidermolysis bullosa, KID syndrome (keratitis, ichthyosis, deafness), and Ferguson-Smith disease.

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Treatment of Skin Cancers• Because patients in high-risk groups may develop multiple lesions in short periods of time, destructive therapy (eg, C&E, cryotherapy) maybe a preferred treatment for clinically low-risk tumors because of the ability to treat multiple lesions at a single patient visit. If C&E has beenperformed based solely on the clinical appearance of a low-risk tumor, the pathology from the biopsy taken at the time of C&E should bereviewed to make sure there are no high-risk pathologic features that would suggest the need for further therapy beyond C&E.• In patients who develop multiple adjacent tumors in close proximity, surgical excision of invasive disease sometimes doesnot include surrounding in situ disease, and tissue rearrangement should be minimized. In situ disease may then be treated with topicalapproaches similar to actinic keratoses/field cancerization.• Compared to the low-risk population, RT is used more frequently as an adjuvant therapy in patients who are high risk and for perineuraldisease.• Satellite lesions and in-transit cutaneous metastases may occur more frequently in this population. They must be treated aggressively withmultidisciplinary consultation.• In organ transplant recipients and other patients undergoing immunosuppressive therapy, decreasing the level of immunosuppressivetherapy and/or incorporating mTOR inhibitors may be considered in cases of life-threatening skin cancer or the rapid development ofmultiple tumors.

Follow-Up• Follow-up schedules should be titrated to the frequency of tumor development.

Patient Education• Individual risk assessment is necessary and should be discussed.• Both extensive and repetitive patient education regarding sun avoidance and protection is required.• Sun avoidance and protection methods must be stringent.• Monthly self examination of all skin surfaces is recommended. If a patient has a history of invasive skin cancer, self examination of thelymph nodes should be taught and performed.• Rapid entrance into the health care delivery system at the onset of tumor development is critical.• Patient education should begin, in the case of recipients of organ transplant, at transplantation, and in the case of xeroderma pigmentosum,at birth or diagnosis.

Prevention• Regular sunscreen use prevents CSCC long term.1• Use of oral retinoids (eg, acitretin, isotretinoin) is effective in reducing the development of CSCC in some patients who are high risk. Sideeffects of oral retinoids may be significant. Therapeutic effects disappear shortly after cessation of the drug. Oral retinoids are teratogenicand must be used with extreme caution in patients of childbearing potential. Topical retinoids have been shown not to reduce developmentof CSCC. (See SCC-3)• Use of nicotinamide may be effective in reducing the development of CSCCs. Therapeutic effects disappear shortly after cessation of thedrug.• Aggressive treatment of precancers can prevent the development of subsequent invasive tumors.

Note: All recommendations are category 2A unless otherwise indicated.

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IDENTIFICATION AND MANAGEMENT OF PATIENTS AT HIGH RISK FOR MULTIPLE PRIMARY CSCCs

1 Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol 2011;29:257-263.

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PRINCIPLES OF TREATMENT

Note: All recommendations are category 2A unless otherwise indicated.

SCC-C

• The primary goals of treatment of CSCCs are the complete removal of the tumor and the maximal preservation of function and cosmesis.

All treatment decisions should be customized to account for the particular factors present in the individual case and for the patient’s

preference.

• Surgical approaches often offer the most effective and efficient means for accomplishing cure, but considerations of function, cosmesis,

and patient preference may lead to choosing RT/topical therapy/systemic therapy as primary treatment in order to achieve optimal overall results.

• In certain patients at high risk for multiple primary tumors, increased surveillance and consideration of prophylactic measures may be

indicated. (See Identification and Management of Patients at High Risk for Multiple Primary CSCCs [SCC-B]).

• Epidermally limited CSCC may be treated with nonsurgical options. (See SCC-3 and Principles of Systemic Therapy SCC-E).

• When Mohs with margin assessment is being performed and the preoperative biopsy is considered insufficient for providing all the staging information required to properly treat the tumor, submission of the central specimen for vertical paraffin-embedded permanent sections ordocumentation of staging parameters in Mohs report is recommended.

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PRINCIPLES OF RADIATION THERAPY

General Principles

●Refer to the ASTRO Guideline on Definitive and Postoperative Radiation Therapy for Basal and Squamous Cell Cancers of the Skin1 for general indications and dose recommendations.

●Protracted fractionation is associated with improved cosmetic results and should be utilized for poorly vascularized or cartilaginous areas.

●For extensive perineural invasion(PNI) or involvement of named nerves(particularly in the head and neck region), consider including the course of the cranial nerve proximally.

●Perineural tumor spread (PNTS), defined as clinically or radiographically apparent macroscopic spread along nerves, is considered higher risk and warrants comprehensive coverage of the involved, and potentially interconnected, cranial nerve pathways.2,3

●For patients with very-high-risk CSCC such as those with PNTS, consider referral to a high-volume center given potential for severe toxicity when irradiating cranial nerves adjacent to critical optic and neurologic structures.

●RT is contraindicated for genetic conditions predisposing to skin cancer(eg, basal cell nevus syndrome[Gorlin syndrome]) and relatively contraindicated for patients with connective tissue diseases(eg, scleroderma).

●Given higher complication rates, reirradiation should not be routinely utilized for recurrent disease within a prior radiation field.

●Consider elective nodal irradiation (ENI) in cases of multiple high-risk pathologic features (SCC-2), especially in patients who are immunocompromised.

●Recommendations for external beam RT(EBRT) apply to both photons and electrons.

●Image-guided radiation therapy (IGRT) is considered best practice when treating with intensity-modulated radiation therapy (IMRT),proton beam radiotherapy, or 3D conformal radiation. The use of IGRT for other types of radiotherapy to treat skin cancer is considered unnecessary.a

●Application of bolus over the primary tumor should be considered to ensure full dose to the surface. Use of surface dosimeters should be considered to verify delivered dose.

●Radiation treatments should be given by a practicing radiation oncologist with radiation physics support to meet established quality assurance and dosimetric constraints.

Primary Tumor and Regional Disease RT Dosing Table on SCC-D(2 of 4)

Brachytherapy RT Dosing Table on SCC-D(3 of 4)

a See Discussion.

Note: All recommendations are category 2A unless otherwise indicated.

References on SCC-D(4 of 4)

SCC-D 1 OF 4

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PRIMARY TUMOR, REGIONAL DISEASE, AND S-ITM

|Primary Tumor|RT Dosing|Common examples| |---|---|---| |Adjuvant RT2|Adjuvant RT2|| |●Conventional fractionation (1.8-2 Gy/fraction)|BED10 of 60-79 Gy|●60-66 Gy in 2 Gy/fraction4 ●60-66 Gy in 1.8 Gy/fraction (reserved for areas with poor wound healing [eg, lower extremity])| |●Hypofractionation|BED10 of 48-70 Gy|●2.5 Gy x 20 fractions5 ●3 Gy x 15-17 fractions to 45-51 Gy ●6 Gy x 5 fractions (non-consecutive days)| |Definitive EBRT|Definitive EBRT|Definitive EBRT| |●Conventional fractionation (1.8-2 Gy/fraction)|BED10 of 70-84 Gy|●60 Gy (for small tumors in cosmetically sensitive areas) ●66-70 Gy (for locally advanced tumors involving bone or cartilage)| |●Hypofractionation|BED10 of 48-72 Gyc|●Tumors <2 cm: 2.5 Gy x 20 fractions ●Tumors≥2 cm: 2.5-3 Gy x 20-22 fractions ●3 Gy x 17-18 fractions to 51-54 Gy ●4.4 Gy x 10 fractions, 4 fractions per week7 ●6 -7 Gy x 5 fractions, 2 treatments per weekd, 7, 8| |Regional Disease|Regional Disease|Regional Disease| |●Conventional fractionation (1.8-2 Gy/fraction) Macroscopic/gross residual lymph nodes Lymph node + dissected nodal basins PNTsb.3|66-70 Gy 60 Gy 50-66 Gy|| |●Undissected at-risk nodal basins|1.8-2 Gy x 25-30 fractions|| |Satellitosis/ln-Transit Metastasis (S-ITM)||| |●Resected ●Unresected|50-60 Gy over 5 to 6 weeks 60-70 Gy over 6 to 7 weeks||

●Conventionally fractionated radiotherapy consists of five daily treatments per week.

●Hypofractionated radiotherapy consists of fewer treatments with larger fraction size.

b Track involved cranial nerve to base of skull and at-risk nerve interconnections.

c Given lack of randomized data, the optimal dose/fractionation is not established, but generally, a goal BED10 of 48-72 Gy is recommended.

d Generally reserved for patients who are older or unable to come for protracted course.

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PRINCIPLES OF RADIATION THERAPY BRACHYTERAPY

General Principles-Brachytherapy

●Isotope-based brachytherapy can be an effective treatment for certain sites of disease, particularly on the head and neck.a

●There are insufficient long-term efficacy and safety data to support the routine use of electronic surface brachytherapy.a

●Consider longer courses of RT (ie, 16 fractions) for sensitive areas such as ears, nose, or near eyes.

●Consider a higher total dose for immunocompromised patients (ie, 3 Gy x 16 fractions).

●Consider a lower dose for low risk, small tumors when using a single channel applicator (ie, 3 Gy x 16 fractions).

●Consider BID fraction if performing interstitial brachytherapy.

●Consider shielding normal structures when possible (ie, eye shields, internal nose shields).

●Start adjuvant radiation within 4-8 weeks of surgery after incision has healed.

●Surface applicators should only be used for superficial tumors(<5 mm depth).

●If deeper than 5 mm, consider interstitial brachytherapy or EBRT techniques.

●Consider referral to a center with expertise with brachytherapy.

|Primary Tumor|RT Dosing|Common Examples| |---|---|---| |Definitive or Adjuvant Skin Brachytherapy||| |●Custom surface mold applicators: Prescription depth≤5 mm|GOAL BED10 at least 60 Gy|●3 Gy x 16 fractions (daily) ●5 Gy x 8 fractions (2 times per week [for non- cosmetically sensitive areas])| |●Interstitial Brachytherapy: Prescription depth＞5 mm|GOAL BED10 at least 60 Gy|●4.4 Gy x 10 fractions (BID [6 hours minimum between fractions])| |●Shielded single channel surface applicators(Leipzig or Valencia): Prescription depth≤3 mm|GOAL BED10 at least 60 Gy|●3 Gy x 12-16 fractions (daily)|

Note: All recommendations are category 2A unless otherwise indicated.

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1 Likhacheva A, Awan M, Barker CA, et al. Definitive and postoperative radiation therapy for basal and squamous cell cancers of the skin: Executive summary of an

American Society for Radiation Oncology Clinical Practice Guideline. Pract Radiat Oncol 2020;10:8-20.

2 Porceddu SV, Daniels C, Yom SS, et al. Head and Neck Cancer International Group (HNCIG) Consensus Guidelines for the Delivery of Postoperative Radiation

Therapy in Complex Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN). Int J Radiat Oncol Biol Phys 2020;107:641-651.

3 Bakst RL, Glastonbury CM, Parvathaneni U, et al. Perineural invasion and perineural tumor spread in head and neck cancer. Int J Radiat Oncol Biol Phys

2019;103:1109-1124.

4 McDowell L, Yom SS. Locally advanced non-melanomatous skin cancer: Contemporary radiotherapeutic management. Oral Oncol 2019;99:104443.5 Hu M, Liu H, Bernard A, et al. Hypofractionated adjuvant radiotherapy in cutaneous squamous cell and basal cell carcinoma of the head and neck: 50(Gy) in 20 study. Oral Oncol Rep 2025;13:100732.

6 van Hezewijk M, Creutzberg CL, Putter H, et al. Efficacy of a hypofractionated schedule in electron beam radiotherapy for epithelial skin cancer: Analysis of 434 cases. Radiother Oncol 2010;95:245-249.

7 Veness M. Hypofractionated radiotherapy in older patients with non-melanoma skin cancer: Less is better. Australas J Dermatol 2018;59:124-127.8 Dundar Y, Cannon RB, Hunt JP, et al. Radiotherapy regimens in patients with nonmelanoma head and neck skin cancers. Int J Dermatol 2018;57:441-448.9 Gauden R, Pracy M, Avery AM, et al. HDR brachytherapy for superficial non-melanoma skin cancers. J Med Imaging Radiat Oncol 2013;57:212-217.

REFERENCES

Note: All recommendations are category 2A unless otherwise indicated.

SCC-D 4 OF 4

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PRINCIPLES OF SYSTEMIC THERAPY

Field Cancerization/Confluent Epidermal Dysplasia (SCC-E 2 of 5)Very-High-Risk Disease (SCC-E 3 of 5)

Primary and Recurrent laCSCC Disease (SCC-E 3 of 5)

S-ITM (SCC-E 3 of 5)

New Regional Disease (SCC-E 3 of 5)

Regional Recurrence or Distant Metastatic Disease (SCC-E 3 of 5)

Note: All recommendations are category 2A unless otherwise indicated.

SCC-E 1 OF 5

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PRINCIPLES OF SYSTEMIC THERAPY

Field Cancerization/Confluent Epidermal Dysplasia (SCC-3)1

●Actinic keratoses should be treated at first development.

Accepted treatment modalities(in addition to SCC-3) include topical Imiquimod and topical Tirbanibulin. For hyperkeratotic actinic keratoses, pretreatment with topical Tazarotene,curettage, or topical keratalytics(topical Urea, Lactic acid, and Salicylic acid) prior to above therapies and select therapies listed in Table 1 may be considered. Another modality that may be considered is topical Clofenac

●Actinic keratoses that have an atypical clinical appearance or do not respond to appropriate therapy should be biopsied for histologic evaluation.

●Use of oral retinoids(eg, Acitretin, Isotretinoin) is a therapeutic option used to reduce the development of actinic keratoses. Side effects of oral retinoids may be significant, especially in patients of childbearing potential, and therapeutic benefits are limited to the duration of the regimen. Topical retinoids were shown not to reduce development of actinic keratosis.

●In patients with CSC in situ(Bowen disease), therapies such as topical Fluorouracil, topical Imiquimod, and photodynamic therapy(eg,ALA, Porfimer sodium) may be considered.a

●Vigorous cryotherapy2 may be considered for discrete lesions(not field cancerization).

●Focal squamous cell carcinoma in situ arising within actinic keratosis is not appropriate for surgery and should be treated topically.

|Table 1: Therapy Options for Field Cancerization/Confluent Epermal Dysplasia||| |---|---|---| |Preferred|Other Recommended|Useful in Certain Circumstances| |●Topical Calcipotriene/Fluorouracil,b,3,4 ●Topical Fluorouracil|● Topical Aminolevulinic acid (in conjunction with PDT)|● Acitretin$^5$ ● Capecitabine$^1,6$ (for severe refractory disease that has progressed on oral retinoids) ● Isotretinoin ● Porimer sodium(in conjunction with PDT)|

NCCN Guidelines Index Table of Contents Discussion

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PRINCIPLES OF SYSTEMIC THERAPY

Very-High-Risk Disease (SCC-6)

S-ITM (SCC-9)

●In patients with extremely high risk nodal and non-nodal features and postoperative negative margins, following adjuvant RT d,e,f Cemiplimab-rwlc is category 1 preferred.

●For S-ITM, multidisciplinary team to discuss systemic therapy alone (Table 3)or in combination with local therapies such as RT or surgery (Table 2).

●For tumors with nonreactive non-keratoacanthomatous rapid growth, in-transit metastasis, are borderline resectable, or where surgery alone may not be curative or may result in significant functional limitation, neoadjuvant Cemlimab-rwlc is an option.

New Regional Disease (SCC-8 and SCC-10)

●For most cases of fully resected regional disease, adjuvant systemic therapy is not recommended, unless within a clinical trial.

●For resected high-risk regional disease of head and neck, RT± systemic therapy (Table 2).

●For unresectable, inoperable, or incompletely resected disease,multidisciplinary consultation is needed to discuss:

Primary and Recurrent laCSCC Disease9(SCC-7)

●If surgery is not feasible, recommend RT, and multidisciplinary teams to discuss concurrent systemic therapy in select cases (Table 2).

.RT± systemic therapy(Table 2)

▶Systemic therapy alone if curative RTf is not feasible(Table 3).

●If curative surgery and curative RTf are not feasible,recommend multidisciplinary consultation to discuss systemic therapy alone(Table 3).

Regional Recurrence or Distant Metastatic Disease (SCC-11)For the regional recurrence or distant metastases, multidisciplinary team to discuss systemic therapy alone (Table 3) or in combination with RT (Table 2).

|Table 2: Systemic Therapy Options for Use with RT (or Surgery for Regional Recurrence Following Systemic Treatment)||| |---|---|---| |Preferred|Other Recommended|Useful in Certain Circumstances| |●Cisplatin,9 ● Clinical trial|●Carboplatin ●Carboplatin/Paclitaxelh,13,14 ● EGFR inhibitors (eg, Cetuximab)h,15|●Cisplatin/Fluorouracilh,22| |Table 3: Options for Systemic Therapy Alone||| |Preferred|Other Recommended|Useful in Certain Circumstances| |●Cemiplimab-rwcli,j (if curative RTf or surgery is not feasible for locally advanced, recurrent, or metastatic disease)10,11 ●Pemblizumab1j (if curative RTf or surgery is not feasible for locally advanced, recurrent, or metastatic disease)12 ● Clinical trial|●Cosibelimab-iplif (if curative RTf or surgery is not feasible for locally advanced [category 2B] or metastatic disease)16 ● Nivolumabk ● If ineligible for or progressed on immune checkpoint inhibitors and clinical trials, consider: ● Carboplatin/Paclitaxelh17 ● Carboplatin/Paclitaxel+ Cetuximab18-21 ● EGFR inhibitors (eg, Cetuximab)h,15|●Neoadjuvant Cemiplimab-rwcl,10 ● If ineligible for or progressed on immune checkpoint inhibitors and clinical trials, consider: ● Capecitabine 23,24 ●Cisplatinh,i1 ● Cisplatin/Fluorouracilh,24|

Cemiplimab-rwlc was studied in CSCC with very-high-risk for recurrence due to nodal features (extracapsular extension with largest node ≥20 mm in diameter or ≥3 involved nodes) or non-nodal features (in-transit metastases, T4 lesion [with bone invasion], PNI, or locally recurrent tumor with ≥1 additional risk feature). Rischin D,Porcedu S,Day F,et al.Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2025;393:774-785.

Note:All recommendations are category 2A unless otherwise indicated.

Footnotes on SCC-E(4 of 5)

References on SCC-E(5 of 5)

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d Principles of Radiation Therapy (SCC-D).e Adjuvant RT can be considered for CSCCs with gross clinical radiologic PNI, multifocal histologic nerve invasion, ≥6 cm tumor diameter, recurrent tumors, high risk for regional or distant metastasis, close surgical margins where further surgery cannot be performed, and desmoplastic or infiltrative tumors in patients who are chronically immunosuppressed. Ruiz ES, et al. J Am Acad Dermatol 2022;87:87-94.

f Assessment of feasibility of RT should be made by a radiation oncologist.g A cure is unlikely to result from surgery and/or RT or there are concerns of significant functional impairment. Multidisciplinary discussion and multimodality treatment

(including neoadjuvant and adjuvant therapy) merits consideration.

h These options have occasionally produced useful responses, but data supporting efficacy are limited.i Recent published phase II trial data support the efficacy and safety of Cemiplimab-rwlc and Pembrolizumab in patients with laCSCC, recurrent, and metastatic CSCC. Migden MR, et al. Lancet Oncol 2020;21:294-305. Rischin D, et al. J Immunother Cancer 2020;8:e000775. Hughes BGM, et al. Ann Oncol 2021;32:1276-1285.

j In solid organ transplant recipients, potential benefit from immune checkpoint inhibitor therapy has to be weighed against a significant risk of organ rejection. For

patients receiving immunosuppressive therapy, in consultation with their treating physician, consider dose reduction of the immunosuppressive agent(s) and/or

minimizing the doses of calcineurin inhibitors and/or antimetabolites in favor of mTOR inhibitors where appropriate. Patients with underlying immunodeficiencies,

including CLL, were excluded from the phase I–II Cemiplimab-rwlc trial, so the efficacy of Cemiplimab-rwlc in this population is unclear.

k Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV Nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and

administration instructions compared to IV Nivolumab.

Note: All recommendations are category 2A unless otherwise indicated.

SCC-E 4 OF 5

FOOTNOTES

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REFERENCES

1 Cornejo CM,Jambusaria-Pahlajani A, Willenbrink TJ, et al. Field cancerization:Treatment.J Am Acad Dermatol 2020;83:719-730.

2Afsar FS,Erkan CD, Karaca S. Clinical practice trends in cryosurgery:a retrospective study of cutaneous lesions. Postepy Dermatol Aergol 2015;32:88-93.

3 Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipitrol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest 2017;127:106-116.

4 Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med 2019;380:935-946.

5 Badri O, Schmults CD, Karia PS, Ruiz ES. Efficacy and cost analysis for acitretin for basal and squamous cell carcinoma prophylaxis in renal transplant recipients. Dermatol Surg 2021;47:125-126.

6 Endrizzi B,Ahmed RL,Ray T,et al. Capecitabine to reduce nonmelanoma skin carcinoma burden in solid organ transplant recipients. Dermatol Surg 2013;39:634-645.

7 Jansen MHE, Mosterd K, Arits AHMM, et al. Five-year results of a randomized controlled trial comparing effectiveness of photodynamic therapy, topical imiquimod, and topical 5-Fluouracil in patients with superficial basal cell carcinoma. J Invest Dermatol 2018;138:527-533.

8 Drew BA, Karia PS, Mora AN, et al. Treatment patterns, outcomes, and patient satisfaction of primary epidermally limited nonmelanoma skin cancer. Dermatol Surg 2017;43:1423-1430.

9 Guthrie TH Jr, Porubresky ES, Luxenberg MN, et al. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin:results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol 1990;8:342-346.

10 Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma. N Engl J Med 2022;387:1557-1568.

11 Rischin D, Migden MR, Lim AM,et al. Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing. J Immunother Cancer 2020;8:e000775.

12 Hughes BGM, Munoz-Couselo E, Mortier L, et al. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma(KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial[published correction appears in Ann Oncol 2022;33:853]. Ann Oncol 2021;32:1276-1285.

13 Maring S,Elsayad K,Stenner M,et al.Efficacy of carboplatin/paclitaxel-based radiochemistry in locally advanced squamous cell carcinoma of head and neck.Oncol Res Treat 2018;41:736-743.

14 Vlacich G,Diaz R,Thorpe SW,et al.Intensity-modulated radiation therapy with concurrent carbloplatin and paclitaxel for locally advanced head and neck cancer:toxicities and efficacy. Oncologist 2012;17:673-681.

15 Maubec E,Petrov S,Chere-Senyarich I,et al.Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011;29:3419-3426.

16 Clingan P, Ladwa R, Brungs D, et al. Efficacy and safety of cosibelabim, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma. J Immunother Cancer.2023;11:e007637.

17 Ferrari D,Fiore J,Codeca C,et al.A phase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancer. Anticancer Drugs 2009;20:185-190.

18 Carinato H, Burgy M, Ferry R, et al. Weekly Paclitaxel, Carbollatin, and Cetuximab as First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma for Patients Ineligible to Cisplatin-Based Chemotherapy: A Retrospective Monocentric Study in 60 Patients. Front Oncol 2021;11:714551.

19 Botticelli A, Pomati G, Cirillo A, et al. Weekly chemotherapy as first line treatment in frail head and neck cancer patients in the immunotherapy era. J Transl Med 2021;19:303.

20 Tahara M, Kiyota N, Yokota T, et al. Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab(PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck(CSPOR-HN02). Ann Oncol 2018;29:1004-1009.

21 Geraghty L, Schultz TE, Hoffman SE, et al. Weekly vs. 3-weekly capacitaxel,carboplatin, and cetuximab(PCC) in recurrent/metastatic head and neck cancer. Mol Clin Oncol 2021;15:240.

22 Khansur T,Kennedy A.Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin. Cancer 1991;67:2030-2032.

23 Peron J, Poupart M, Ceruse P, et al. Efficacy and safety of capecitabine in heavily pretreated recurrent/metastatic head and neck squamous cell carcinoma. Anticancer Drugs 2012;23:1107-1111.

24 Martinez-Truero J, Isla D, Adansa JC, et al. Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment. Br J Cancer 2010;102:1687-1691.

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NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

SCC-F 1 OF 4

PRINCIPLES OF PDEMA TECHNIQUE

• PDEMA, also known as complete margin assessment, is a descriptive term for surgical techniques that allow high-quality histologic

visualization and interpretation of the entire marginal surface of surgically excised tissue. The NCCN Guidelines Panel recognizes that a

variety of surgical methods may achieve complete margin assessment. This NCCN appendix is intended to be inclusive of this diversity,

while defining the features that are essential to the superior cure rates achieved by these techniques.1

• The most commonly used form of PDEMA is Mohs. When anatomic structures at the deep margin (eg, major vessels, nerves, bone) preclude complete histologic evaluation of the marginal surface via Mohs or other forms of PDEMA, Mohs or other forms of PDEMA should be

used to evaluate as much of the marginal surface as feasible. Treatment considerations for non-visualized areas may be the subject of

multidisciplinary discussion.

• A surgical procedure can be described as PDEMA if and only if all of the following criteria are met:

1. The entire marginal surface of the surgical specimen is microscopically visualized and histopathologically analyzed for the presence of cancer. The marginal surface includes the complete deep and peripheral margin.

2. The surgical specimen is oriented with respect to the surgical site and marked in a manner such that any positive margin identified in

histopathologic analysis can be accurately located and re-excised.

3. The surgical margin of any re-excised tissue is again entirely visualized and oriented as above. This process is repeated until no further cancer is identified at the surgical margin or until further excision is not anatomically possible or not in the best interest of the patient.

4. The time interval between the steps of this process is rapid enough to prevent significant size or shape changes in the wound bed (ie,

granulation, contraction) that would decrease the accuracy of orientation.

1 Curtis KK, Fakult NJ, Strunck JL, et al. Establishing Consensus for Mohs Micrographic Surgical Techniques in the Treatment of Melanoma in Situ for Future Clinical Trials: A Modified Delphi Study. J Natl Compr Canc Netw 2024;22:e247036.

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PRINCIPLES OF PDEMA TECHNIQUE

●Visualization of the entire marginal surface of an irregular surgical specimen may be challenging, but is critical to the success of PDEMA methods. Typically, this visualization is achieved by flattening topographically complex surfaces onto a single plane and sectioning the specimen paralle/ to this plane(see Figure 1 below or Figure 2). Sampling methods such as perpendicular sectioning, also known as“breadloafing,” do not achieve direct visualization of the entire surgical margin and would prevent a procedure from achieving PDEMA.

●PDEMA can be achieved with either frozen sections or formalin fixation and paraffin embedding. Although it is often helpful for the surgeon to examine the specimen histologically, the surgeon is not required to examine the specimen histopathologically to achieve PDEMA; a trained pathologist or dermatopathologist may communicate results to the surgeon. If a pathologist or dermatopathologist analyzes the specimen, a consistent communication system must be in place to designate the marginal surfaces for examination and to ensure that the three-dimensional orientation of marginal surfaces and of tissue blocks relative to the wound bed are maintained and communicated to the surgeon to enable accurate localization of residual tumor within the wound bed. The use of multiple operating settings and surgeons is also consistent with PDEMA as long as the orientation of the tissue and wound bed are accurately communicated and complete margin assessment is maintained.2

Figure 1

Tubingen muffin technique

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF PDEMA TECHNIQUE

Figure 2

Tubingen torte technique

Courtesy of Dr. Brooke Walls, DO, FAAD, Aspen Center for Cosmetic Medicine & Dermatology

![](2/aj0YEe4oUhYkBdfpda0fYP/figure5be3d0668e2c4032a36f48c4af6e3cab_0_9.png) Note:All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF PDEMA TECHNIQUE

● Published examples of PDEMA include:

Mohs ${}^{3,4}$

Tubingen muffin technique5,6

Tubingen torte technique(see https://esms-mohs.eu/tuebingen/)

●Examples of techniques that do not achieve PDEMA include:

Wide local excision with“breadloafing”(perpendicular section prevents visualization of the entire margin)

Square procedure,4 quadrant technique, moat technique, and perimeter technique8(wherein the deep margin is assessed with vertical sections so complete visualization of the deep margin is absent). As compared to"breadloafing," these techniques provide more complete peripheral margin evaluation for superficial tumors(eg, melanoma in situ and extramammary Paget disease) that do not involve subcutaneous tissues. However, these techniques do not provide complete deep margin evaluation so are not PDEMA.

|PDEMA Checklist|Yes|No| |---|---|---| |Is the entire peripheral margin of the surgical specimen microscopically visualized?||| |Is the entire deep margin of the surgical specimen microscopically visualized?||| |Is the surgical specimen oriented to the wound bed and marked such that any positive margin identified in histopathologic analysis can be accurately located and re-excised?||| |Is the process of excision and complete histologic examination repeated until no further cancer is identified or until further excision is no longer in the best interest of the patient?||| |Is the process rapid enough to prevent distortion of the wound bed that would decrease accuracy of tissue orientation?|||

All of the above categories must be marked Yes to achieve PDEMA. If any of the above are marked No, the procedure does not achieve PDEMA.

3 Tromovitch TA, Stegeman SJ. Microscopically controlled excision of skin tumors. Arch Dermatol 1974;110:231-232.

4 Behshad R. Mohs Micrographic Surgery. In: Kantor J, ed. Dermatologic Surgery. McGraw-Hill Education; 2018:388-413.

5 Mohrle M, Breuninger H.[The Muffin technique--an alternative to Mohs' micrographic.]. J Dtsch Dermatol Ges 2006;4:1080-1084.

6Farma JM.Ammori JB,Zager JS,et al. Dermatofibrosarcoma protuberans: How wide should we resect? Ann Surg Oncol 2010;17:2112-2118.

7 Johnson TM, Headingon JT, Baker SR, Lowe L. Usefulness of the staged excision for lentigo maligna and lentigo maligna: The“square” procedure. J Am Acad Dermatol 1997;37:758-764.

8 Moehrle M, Breuninger H, Rocken M. A confusing world: what to call histology of three-dimensional tumour margins? J Eur Acad Dermatol Venereol 2007; 21:591-595.

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NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING

• The decision to offer genetic testing involves three related stages:

1) Pre-test counseling prior to ordering testing;

2) Consideration of the most appropriate testing strategy; and

3) Testing result disclosure and post-test counseling.

• There are rare genetic syndromes that can markedly predispose patients to aggressive CSCC formations. These include xeroderma

pigmentosum (XP) and recessive dystrophic epidermolysis bullosa (RDEB). Patients with these conditions should be referred to a cancer

center with particular expertise in CSCC prevention and prophylaxis.

• It is recommended that a genetic counselor, medical geneticist, endocrinologist, oncologist, surgeon, oncology nurse, or other health

professional with expertise and experience in cancer genetics be involved at each stage whenever possible. Clinicians without direct referral access to the appropriate expertise should be aware of the telehealth genetic counseling options available. These resources can be found

through the National Society of Genetic Counselors (NSGC) “Find a Genetic Counselor” tool (www.nsgc.org).

See the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate for the following:

• Principles of Cancer Risk Assessment and Counseling (EVAL-A)

• Pedigree: First-, Second-, and Third-Degree Relatives of Proband (EVAL-B)

Note: All recommendations are category 2A unless otherwise indicated.

SCC-G

NCCN Guidelines Index Table of Contents Discussion

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American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Cutaneous Carcinoma of the Head and Neck (8th ed., 2017)^{1,2}

Table 1. Definitions for T,N, M

Clinical N(cN)

T Primary Tumor

cN Regional Lymph Nodes

TX Primary tumor cannot be assessed

NX Regional lymph nodes cannot be assessed

Tis Carcinoma in situ

NO regional lymph node metastasis

T1 Tumor smaller than or equal to 2 cm in greatest dimension

N1 Metastasis in a single ipsilateral lymph node,3cm or smaller in greatest dimension and ENE(-)

T2 Tumor larger than 2cm, but smaller than or equal to 4cm in greatest dimension

N2 Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-);

T3 Tumor larger than 4 cm in maximum dimension or minor bone erosion or perineural invasion or deep invasion*

or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-);

T4 Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion

or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-)

T4a T4b T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a T4a

N2a Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-)

T4b T4b T4um with skull base invasion and/or skull base foramen involvement

N2b Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-)

*Deep invasion is defined as invasion beyond the subcutaneous fat or>6 mm(as measured from the granular layer of adjacent normal epidermis to the base of the tumor); preineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.

N2c Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-)

N33 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-);

or metastasis in any node(s) and clinically overt ENE[ENE(+)]

N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-)

N3b Metastasis in any node(s) and ENE(+)

Note: A designation of "U" or "L" may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological extranodal extension (ENE)should be recorded as ENE(-) or ENE(+)

1 These staging tables are for cutaneous squamous cell carcinoma, cutaneous carcinoma, basal cell carcinoma of the head and neck, and all other nonmelanoma skin carcinomas of the head and neck(except Merkel cell carcinoma). Anatomic site of external verimilion lip is included because it has a more similar embryologic origin to skin,and its etiology-which is often based on ultraviolet exposure-is more similar to other nonmelanoma skin cancers. The AJCC Staging Manual, Eighth Edition does not include staging for cutaneous carcinoma outside the head and neck.

2©2021,American College of Surgeons,All Rights Reserved. Used with the permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging System.

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National NCCm Comprehensive Cancer Network®

American Joint Committee on Cancer (AJCC)

TNM Staging Classification for Cutaneous Carcinoma of the Head and Neck (8th ed., 2017)1,2

Pathological N(pN)

pN Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-)

N2 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(+);or larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(-);or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(-);

N2a Metastasis in single ipsilateral node 3 cm or smaller in greatest dimension and ENE();or a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest dimension, ENE(-)

N2b Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-)

N2c Metastases in bilateral or bilateral temporal lymph node(s), none larger than 6 cm in greatest dimension and ENE(-)

N3 Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE( -);or in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+);or a single ipsilateral, contralateral, or bilateral nodes,any with ENE(+);or a single contralateral node of any size and ENE(+)

N3a Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(+)

N3b Metastasis in a single ipsilateral node larger than 3 cm in greatest dimension and ENE(+)or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+)or a single contralateral node of any size and ENE(+)

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

G Histologic Grade

GX Grade cannot be assessed

G1 Well differentiated

G2 Moderately differentiated

G3 Poorly differentiated

G4 Undifferentiated

Table 2. AJCC Prognostic Stage Groups

|T|N|M| |---|---|---| |Stage 0|Tis|N0| |Stage I|T1|N0| |Stage III|T2|N0| |Stage III|T3|N0| |T1|N1|N0| |T2|N1|M0| |T3|N1|M0| |Stage IV|T1|N2|

Stage IV T1 N2 N2 MO

T2 N2 N3 MO

T3 N2 M0

Any T N3 MO

T4 Any N

Any T Any N M1

1 These staging tables are for cutaneous squamous cell carcinoma, cutaneous carcinoma, basal cell carcinoma of the head and neck, and all other nonmelanoma skin carcinomas of the head and neck(except Merkel cell carcinoma). Anatomic site of external vermiol lip is included because it has a more similar embryologic origin to skin,and its etiology-which is often based on ultraviolet exposure-is more similar to other nonmelanoma skin cancers. The AJCC Staging Manual, Eighth Edition does not include staging for cutaneous carcinoma outside the head and neck.

2©,2021,American College of Surgeons, All Rights Reserved. Used with the permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging System.

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NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

NCCN Guidelines Index Table of Contents Discussion

|||ABBREVIATIONS| |---|---|---| |ALA|aminolevulinic acid|laCSCC locally advanced cutaneous squamous cell carcinoma| |BED|biologically effective dose|NSGC NSGC National Society of Genetic Counselor| |C&E|curettage and electrodesiccation|| |CLL|chronic lymphocytic leukemia|PDEMA peripheral and deep en face margin assessment| |CSCC|cutaneous squamous cell carcinoma|assessment| |EBRT|external beam RT|PNTS perineural invasion| |ENE|extranodal extension|PNTS perineural tumor spread| |ENI|elective nodal irradiation|RDEB recessive dystrophic epidermolysis bullosa| |FDG|fluorodeoxyglucose|| |FNA|fine-needle aspiration|| |H&P|history and physical|SBRT stereotactic body radiation therapy| |HIV|human immunodeficiency virus|S-ITM satellitis/in-transit metastasis SLNB| |IGRT|image-guided radiation therapy|| |ILI|isolated limb infusion|UV ultraviolet| |ILP|isolated limb perfusion|| |IMRT|intensity-modulated radiation therapy|XP xeroderma pigmentosum| |KID|keratitis, ichthyosis, deafness||

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NCCN Guidelines Index Table of Contents Discussion

|NCCN Categories of Evidence and Consensus|| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is isNCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

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NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

Discussion

This discussion corresponds to the NCCN Guidelines for Squamous Cell Skin Cancer. Last updated February 07, 2025.

Treatment of SCC in Patients at High Risk.

Overview $\ldots$ MS-2

Prevention in Patients at High Risk. $\ldots$ MS-20

Guidelines Update Methodology. MS-2

Patient Education for Patients at High Risk $\ldots$ MS-20

Literature Search Criteria and Guidelines Update Methodology .MS-2

References.MS-24

Sensitive/inclusive Language .MS-2

Risk Factors for SCC. $\ldots$ MS-2

Clinical Presentation and Workup .MS-3

Risk Stratification of Local CSC Based on Risk Factors for Local Recurrence, Metastases, or Death. $\ldots$ MS-4

History & Physical .MS-4

Pathology $\ldots$ MS-5

Field Cancerization/Confluent Epidermal Dysplasia

Prevention of Actinic Keratoses..MS-7

Treatment of Actinic Keratoses$\longdots$MS-7

Treatment Modalities for Local SCC

Curettag and Electrodescence .MS-9

Mohs Micrographic Surgery or Excision with Peripheral and Deep En Face Margin Assessment..MS-9

Shave Removal.. MS-10

Standard Excision with Postoperative Margin Assessment .MS-11

Radiation Therapy $\ldots$ MS-11

Sentinel Lymph Node Biopsy..MS-14

Regional Lymph Node Involvement in SCC.MS-14

Workup for Suspicion of Regional Lymph Node Involvement......MS-14

Treatment of SCC with Regional Lymph Node Involvement......MS-15

Satellitosis/In-transit Metastasis..MS-16

Recurrence and Metastasis..MS-16

Systemic Therapy for Distant Metastatic Disease $\ldots$ MS-16

Systemic Therapy Options $\ldots$ MS-17

Follow-up $\ldots$ MS-19

Care for Patients at High Risk of Developing Multiple SCCs.....MS-19

Treatment of SCC in Patients at High Risk.

Prevention in Patients at High Risk. $\ldots$ MS-20

Patient Education for Patients at High Risk $\ldots$ MS-20

References.MS-24

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

Overview

Cutaneous squamous cell carcinoma (SCC or CSCC) is the second most common skin cancer.1-3 Numerous population-based studies have demonstrated that the incidence of SCC is rising.1,4-8 Some studies show that SCC incidence rates are rising more rapidly than basal cell carcinoma(BCC), reducing the difference in incidence between these two skin cancers.2,3,9 Current estimates by the American Cancer Society indicate that 3.3 million individuals in the United States have≥1 basal or squamous cell skin cancers where approximately 20% are SCCs. ${ }^{10}$ Although rarely metastatic, SCC can produce substantial local destruction along with disfigurement and may involve extensive areas of soft tissue, cartilage,and bone. SCCs generally have a good prognosis, with 5-year survival of about 98%.1,11-13 However, the treatment landscape continues to evolve to improve a patient's quality of life and minimize disease recurrence.

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria and Guidelines Update Methodology

Prior to the update of this version of the NCCN Guidelines® for Squamous Cell Skin Cancer, an electronic search of the PubMed database was performed to obtain key literature published since the previous Guidelines update, using the search term: cutaneous squamous cell carcinoma. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.14

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:Clinical Trial, Phase 2; Clinical Trial, Phase 3; Clinical Trial, Phase 4;

Guideline; Meta-Analysis; Practice Guideline; Randomized Controlled Trial; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language

NCCN Guidelines strive to use language that advances the goals of equity,inclusion, and representation.15 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misognist, anti-ageist, anti-ableist, and anti-weight biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently.If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Risk Factors for SCC

A number of risk factors are associated with the development of SCC.The most recognized environmental carcinogen is sunlight. Evidence reveals that chronic sun exposure, total site-specific exposure, and number of site-

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National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

specific sunburns are strongly correlated with development of SCC.16-19 Due to the link with chronic and cumulative sun exposure, SCC rates are higher in occupations involving outdoor work20-22 and increase with age,particularly in sun-exposed sites.2,9,18 Indoor tanning is also significantly associated with SCC. According to two large meta-analyses, any exposure to indoor tanning increases the risk of SCC by 67%,23 with the prevalence of indoor tanning much higher than previously thought among U.S. adults and college students.24

Individuals with light skin, hair, and eye color who have received too much sun exposure are at the greatest risk for SCC.25-27 The incidence of ultraviolet(UV)-induced SCCs is very low in non-white populations and has been poorly quantified in people of mixed ethnicities. Most of SCCs develop on sun-exposed skin sites, especially the head and neck area.5,17,28 Actinic keratoses(AKs) and Bowen's disease, if left untreated,can also progress to invasive SCC with the potential for metastasis. 21,29-31 Furthermore, SCCs are also known to develop in association with scars or chronic wounds (Marjolin's ulcer). 32,33 These types of SCCs occur at similar rates in people of all racial and ethnic groups. Such SCC lesions tend to be difficult to treat and have higher risk of recurrence.34-36

Lastly, certain genetic syndromes greatly predispose affected individuals to SCC formation, such as albinism 37-39 and xeroderma pigmentosum. 40-42 Certain settings of immunosuppression(eg, organ transplantation,lymphoma, chronic lymphocytic leukemia, drug-induced immunosuppression, and HIV) also predispose affected individuals to UV-induced SCC.43-50 Most notably, analyses of transplant registries have reported a 5-fold to 113-fold increase in incidence of SCC in patients with transplants compared to the general population.45,51-53 These patient groups are also at high risk of developing multiple CSCCs and tumors that can behave aggressively. 42,54-61 Within these high-risk groups, individual patients should be identified for closer follow-up(See Identification and

Management of Patients at High Risk for Multiple Primary CSCCs in the algorithm).

Clinical Presentation and Workup

On clinical presentation of a suspicious lesion, workup for SCC begins with a history and physical examination. A skin biopsy is then performed on any suspicious lesion. The biopsy should include deep reticular demis if the lesion is suspected to be more than a superficial process. This procedure is preferred because an infiltrative histology may sometimes be present only at the deeper, advancing margins of a tumor and superficial biopsies will frequently miss this component.62,63 Skin lesions in high-risk populations may be difficult to assess clinically; therefore, a low threshold for performing skin biopsies in these patients is necessary.

Imaging studies of the area of interest should be done when locally,extensive or metastatic disease is suspected, which includes deep structural involvement such as bone, perineural disease, and deep soft tissue.67,68 Due to its higher sensitivity, MRI with and without contrast is preferred for perineural disease or deep soft tissue involvement.69-71 Bone disease is suspected, CT with contrast is preferred unless contraindicated. Imaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease(ie, local, regional, metastatic). Histologic confirmation is sufficient to diagnose local recurrence, but MRI with and without contrast can be considered to assess extent of local disease. For nodal or distant metastases, histologic analysis and/or other imaging modalities can be used for confirmation and to gauge extent of disease. For rare instances that present with distant metastatic disease at diagnosis, the distant metastases pathway should be followed.(See Follow-up in the algorithm).After a CSCC diagnosis is confirmed, additional workup includes a complete skin and regional lymph node (LN) examination. A full skin

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examination is recommended because individuals with a skin cancer often have additional, concurrent precancers or cancers located at other, usually sun-exposed skin sites. These individuals are also at increased risk of developing cutaneous melanoma.60,72,73

Risk Stratification of Local CSCC Based on Risk Factors for Local Recurrence, Metastases, or Death

After the additional workup, a risk assessment of the primary tumor should be performed (See Stratification to Determine Treatment Options and Follow-up for Local CSCC Based on Risk Factors for Local Recurrence,Metastases, or Death in Disease in the algorithm). Risk category assignment should be based on the highest risk factor present. The high-risk group has elevated risk of local recurrence while the very-high-risk group has elevated risks of local recurrence and metastasis. Other staging systems, including the AJCC 8th edition staging system of CSCC, have been formulated and independently tested to define high-risk groups of among patients with localized disease, and can act as additional sources of reference. ${ }^{11,54,55,60,74-81}$

History& Physical

Location and Diameter

Anatomic location has been known to be a risk factor for SCC recurrence and metastasis for many years. ${ }^{34,55,82}$ In general, SCCs that develop in the head and neck area, particularly the ears and vermillion lips, are more likely to recur and metastasize than those developing on the trunk and extremities. ${ }^{11,34,54,55,75,82-85}$ Besides the head and neck, SCCs that develop on the hands, feet, pretibial, and anogenital areas are also at greater risk of local recurrence and nodal metastasis, independent of diameter. ${ }^{11,86,87}$

Tumor diameter has also been shown to be a risk factor for SCC recurrence and metastasis.34,55,85,88,89 Although different divisions have been used, robust data support that tumors>2 cm are at higher risk of

recurrence, metastasis, and poor disease-specific survival (DSS).11,34-36,54,55,74,90,91 Taken together, the NCCN Panel recommends that low-risk location (trunk, extremities) and $≤2 cm$ constitute low-risk CSCL. Low-risk location (trunk, extremities) and size >2 cm (but ≤4 cm), or high-risk locations (head, neck, hands, feet, pretibia, and anogenital area), constitute high-risk CSCC.

Regardless of location, the NCCN Panel recommends that a tumor diameter of>4 cm warrants the very-high designation. This is based on data from a large, prospective study, which demonstrate that lesion<4 cm and≥4 cm are associated with 3-year DSS of 93% and 67%(P=.0003),respectively.88 Studies have also reported that mean lesion diameter of 4.2 cm(±3.4)92 and>5 cm85 as significantly associated with LN metastases.

Clinical Borders

The risk factor of well-defined versus poorly-defined clinical tumor borders has been reported in the context of BCC and extrapolated to the SCC population based on clinical experience of the NCCN Panel. ${ }^{93-95}$ The NCCN Panel considers well-defined clinical borders as a low-risk SCC feature.

Primary Versus Recurrent Disease

The higher risk of recurrence and metastasis for recurrent versus primary disease has been extensively documented in the literature.34,88,90,92,96,97 The NCCN Panel notes that primary disease is a low-risk of recurrence feature.

Immunosuppression

In addition to increasing the risk of SCC development,immunosuppression has been shown to be associated with recurrence,metastasis, and death in multiple reports.34,54,55,58-60,74,98,99 Studies from the organ transplant literature have further elucidated features linked with

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SCCs in this unique population of patients who are immunocompromised.58,77,100,101 A retrospective review confirmed that patients with transplants with CSCC had more primary tumors and were more likely to have deep tissue spread and perineural and lymphatic invasion.58 Other studies found diffuse/focal spindle cell morphology,evidence of human papillomavirus(HPV) infection, and aggressive subclinical extension to be more likely in SCCs from patients with transplants.100,102 Two large retrospective studies reported high rates of SCC recurrence and metastasis among patients with transplants despite the fact that most SCCs were stage l/Il at presentation.77,101

Site of Prior Radiotherapy or Chronic Inflammation

Tumors developing in sites of prior radiotherapy(RT) refer to primary CSCCs arising in areas previously irradiated for unrelated conditions. All recurrent tumors are defined as high risk irrespective of prior therapy. Data support that prior RT for unrelated(frequently benign) conditions is a risk factor for SCC recurrence or metastasis.90.103 Retrospective studies and meta-analyses have also documented increased rates of metastasis for SCC arising from sites of chronic scarring or inflammation.34,35,92,96,104-106

Rapidly Growing Tumor

The evidence for growth rate and prognosis is lacking in CSCC. Based on clinical experience, the NCCN Panel included rapid growth rate as a high-risk factor. A Japanese study reported tumor size and rapid growth as prognostic factor for SCC.107 In a small retrospective series, tumor growth rate of>4 mm/month exhibits a higher risk of nodal progression and a shorter progression time to LN metastasis.108 There is also evidence that CSCC in immunosuppressed individuals are often characterized by aggressive behavior and rapid growth.109,110

Neurologic Symptoms

In tumors with perineural involvement (PNI), clinical symptoms suggesting possible involvement of sensory or motor nerves are commonly absent but

may occur.Symptoms include pain, burning,stinging, anesthesia,paresthesia, facial paralysis, diplopia, and blurred vision.111,112 Any suggestion of neurologic involvement in the region of a CSCC should place that tumor in a high-risk category, as PNI is associated with recurrence,metastasis,and poor outcomes.11,34,54,74,82,88,90,106,113-115 Poorer outcomes are associated with the presence of clinical symptoms and extent of neuronal involvement.74,116-119

Pathology

Degree of Differentiation

Although Broders originally divided CSCC histologically into four grades in 1920, the NCCN Panel has adopted the current trend to reduce the divisions to two groups: 1) well or moderately differentiated; and 2) poorly differentiated.75,120 Many studies, including some very large retrospective studies(N> 1000) provide evidence that poor differentiation is correlated with CSCC recurrence, metastasis, DSS, and overall survival(OS).11,34,35,54,74,82,85,90,92,97,106,107,121

Histology

The histologic subtypes of acantholytic(adenoid), adenosquamous,metaplastic(carcinosarcomatous), and desmoplastic SCC are rare.122 Only case reports and case series document the outcomes of patients with these subtypes, and thus their prognostic significance is debated.123-128 Desmoplasia is associated with greatly increased risks of recurrence and metastasis.55,129 A retrospective study using the PALGA national registry of the Netherlands reported significantly higher rates of metastasis for desmoplastic versus non-desmoplastic CSCs: 89% versus 21%(P<.001).89 A 2011 review of 72 patients with desmoplastic SCC reported a rate of recurrence of 80%.130 Since these tumors may have a high risk of recurrence and likely would not be included in the high-risk category based on their degree of differentiation, the Panel decided to list them as separate risk factors.

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Depth

Data from many large studies support that risk of recurrence and metastasis increases with increasing lesion depth.11,34,54,74,75,85,89-91,97,131 CSCS lesion depth can be quantified as thickness in millimeters(mm)132 or by anatomic layer(s) invaded, both of which have been included in the T classification of the AJCC 7th and 8th Edition staging for CSCC.120,133

Prospective data from Brantsch and colleagues reported metastasis rates of 0% of tumors for 2.0 mm in thickness, 4% of tumors 2.1 to 6.0 mm in thickness, and 16% of tumors thicker than 6.0 mm, with depth measured as the greatest vertical distance from the top to the bottom of the tumor.55 Other studies show that the risk of recurrence and metastasis is significantly higher for lesions with thickness>2 mm.54,85,91 Meta-analyses have shown that 4-mm and 6-mm thickness cutoffs are prognostic for recurrence and metastasis, 34,54 and one retrospective study showed that risk for recurrence and metastasis increases significantly for every 1-mm increase in tumor depth.78 Regarding anatomic level of invasion, some studies showed significantly higher risk of recurrence or metastasis for CSCC lesions with Clark levels IV-V, corresponding to invasion of the deep reticular dermis or subcutaneous fat, respectively.34,89 Other studies have shown that lesions with invasion into the subcutaneous fat significantly increases rates of recurrence and metastasis.11,54,74,75,88,90,91

The NCCN Panel has chosen thickness<2 mm and no invasion beyond subcutaneous fat as low risk while>6 mm or invasion beyond subcutaneous fat is considered very high risk. If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, the Panel recommends considering narrow margin excisional biopsy to obtain accurate measurement of thickness and anatomic level of invasion.

Perineural Involvement

PNI is uncommon in any non-melanoma skin cancer(NMSC), but develops more frequently and is more aggressive in CSCC versus

BCC.117,118,134,135 PNI poses increased risks of recurrence, metastasis(nodal and distant), and death, is more common in recurrent versus primary tumors, and is associated with other risk factors, including larger lesion size, poor differentiation, and adenosquamous, desmoplastic, and metaplastic subtypes. ${}^{11,34,54,74,75,82,88,90,106,113-115,130,136-139}$ Specifically, PNI with tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring≥0.1 mm has been associated with metastasis and DSS.75,79,133 If large nerve involvement is suspected, MRI should be considered to evaluate extent and/or rule out skull involvement in those with head and neck tumors. ${}^{69,70,112,119,140}$

Lymphatic or Vascular Involvement

Significant association between lymphovascular invasion(LVI) and LN metastasis has been reported in prospective92,115 and retrospective studies.114 One retrospective study showed that in high-risk CSCC populations with PNI or neurotropism, LVI was significantly associated with DSS and all-cause death.79 Based on these data, the Panel considers lymphatic or vascular involvement an indication of very-high-risk SCC.

Field Cancerization/Confluent Epidermal Dysplasia

Field cancerization is defined as UV light induced confluent dysplasia clinically manifested as diffuse AKs and superficial (in situ) SCC.141 AKs should be treated at first development and biopsied for histologic evaluation if they have an atypical clinical appearance or do not respond to treatment.Treatment is particularly important in patients with diffuse AKs and/or field cancerization, as these patients are at high risk of developing multiple primary CSCCs.142 Given the limited penetration beyond the epidermis and lower cure rates than with surgical techniques,superficial therapies should be reserved for those patients with SCC in situ.143-146 The NCCN Panel's experience indicates that they may be effective for anatomically challenging locations, and recurrences are often small and manageable.

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Prevention of Actinic Keratoses

The regular use of sunscreen can significantly reduce the rate of development of new AKs and CSCCs, as well as increases remission rates of AKs.147-150 Application of sunscreen is particularly important to areas such as the head, neck, hands, and forearms. Oral nicotinamide may also be an effective way to reduce the development of CSCC.Nicotinamide is a form of vitamin B3 that enhances UV-induced DNA damage repair and reduces the UV-induced immunity suppression. 151 A phase III randomized control trial (N=386) concluded that the incidence of new AKs and CSCCs was 13% and 30% lower, respectively, compared to the control placebo group at 12 months. 152 While a meta-analysis by Mainville et al considers that oral nicotinamide is an effective preventative option for healthy patients and those with organ transplants, two other clinical trials concluded that AK rate was not significantly reduced in immunocompromised patients.153-155

Treatment of Actinic Keratoses

Cryotherapy has been used to treat AK for many decades, despite lack of prospective randomized trials comparing them with non-treatment. Large prospective randomized trials in patients with AKs(N> 100) have shown that each of the following therapies provides better complete clearance rates compared with placebo: topical 5-fluorouracil(5-FU) with or without calcipotriol,156-161 topical imiquimod,162-165 topical tiranibulin,166 and photodynamic therapy(PDT).167-175 Prospective randomized trials have reported pair-wise comparisons of the above treatments, but results are not consistent. These comparisons include PDT versus cryotherapy,167,169,172,176-178 imiquimod,179,180 5-FU,181-183 or ingenol mebutate184-186; cryotherapy versus 5-FU or imiquimod187-189; and 5-FU versus imiquimod190 or ingenol mebutate.191,192 Meta-analyses of randomized trials have attempted to determine an order of preference for these treatments.193-196

The NCCN Panel currently assigns a preference for 5-FU based on data from a randomized trial that reported the cumulative probability of remaining free from disease progression was significantly higher for 5-FU(74.7%) than imiquimod(53.9%), MAL-PDT(37.7%), or ingenol mebutate(28.9%).197 The longest duration for CSCC prophylaxis has been demonstrated with the combination of 5-FU and calcipotriol.161 It was demonstrated that more participants who received topical calcipotriol plus 5-FU for AK remained disease-free over the>1500-day period compared to those receiving petroleum jelly-based skin product plus 5-FU.198 Moreover, significantly fewer participants in the test cohort developed CSCC on the treated face and scalp within 3 years (7% vs. 28% in control group; hazard ratio, 0.215; P=.032).198

Topical irbanibulin is a recommended treatment for AK based on results from two identically designed double-blind phase III trials in which patients received either irbanibulin or vehicle ointment for the treatment of AKs on the face or scalp. In both trials, complete clearance by day 57 occurred in significantly more patients in the irbanibulin group compared to the vehicle group (trial 1:44% vs. 5%; $P<$ .001; trial 2: $54 \%$ vs. $13 \%$ ; $P<$ .001). $^{166}$

The utility of topical diclofenac is less clear, as efficacy results vary across large randomized trials, with some studies reporting no significant difference between diclofenac/hyaluronan and hyaluronan alone.160,199-201 Diclofenac/hyaluronan has also been shown to be inferior to MAL-PDT and to 5-FU for the treatment of AKs.202,203 The Panel therefore assigns category 2B for diclofenac in this setting.

Fewer high-quality data are available regarding the efficacy and safety of other treatments that are sometimes used and may be considered for treating AKs: chemical peels(trichloroacetic acid) and ablative skin resurfacing(eg,dermabrasion, laser).204-211 These studies have all confirmed that chemical peel or laser resurfacing significantly reduced

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AKs, although in some studies they were less effective than PDT or 5-FU.The use of chemical peels and ablative skin resurfacing varies widely across NCCN institutions.

AK on the lip, known as actinic cheilitis, may require a different approach.Prospective studies on the treatment of actinic cheilitis are limited.Therapies tested include surgical vermielionectomy, lip shave,electrodestication, laser vermiion ablation, laser resurfacing, 5-FU, laser+ 5-FU, trichloroacetic acid(TCA) chemical peel,PDT+ imiquimod,and diclofenac.212-223 The NCCN Panel considers ablative laser vermielectomy to be of value as a primary treatment option for extensive actinic cheilitis.

Retrospective studies, meta-analyses, and a small open-label phase II trial have shown that imiquimod was effective for treating patients with SCC in situ, with high rates of initial clearance(70%-100%) and low rates of recurrence.224-228 One small double-blind randomized trial showed that imiquimod led to the resolution of 73% of lesions compared to 0% with vehicle control(P<.001).229 Clearance rates with 5-FU tend to be lower than those for topical imiquimod and vary widely, ranging from 27% to 92%.225,228,230-232 Toxicities are similar between imiquimod and 5-FU, being primarily inflammatory skin reactions such as severe eczematous reactions, ulceration, and erosions.225,231,232

PDT with photosensitizing agents including methyl aminolevulinate(MAL)and 5-aminolevulinic acid(ALA) or porfimer sodium is another option for superficial SCC.MAL is no longer produced in the United States.For SCC in situ,rates of initial complete clearance following PDT range between 52% and 98%.231,233-244 Durable complete response rates range from 48%to 89%.231-236,238-242,244,245 It has been shown that differences in PDT techniques can cause significant differences in clearance rate for SCC in situ.234,242 Furthermore, results from randomized trials showed fewer treatments required for complete clearance and higher durable complete

response rates with PDT versus cryotherapy.232,246 Compared to 5-FU,PDT was also associated with higher rates of initial complete clearance and higher durable complete response rates.231,232 Data suggest that 5-FU may be associated with lower risk of adverse events compared with PDT or cryotherapy, but it is unclear whether risk of toxicity differs between cryotherapy and PDT.231,232,246

Hyperkeratotic AKs pretreatment may include topical tazarotene,curetage,or topical keratolytics such as topical ureal, lactic acid, and salicylic acid prior to treatment with 5-FU with or without calcipotri,imiquimod, or tiranibulin. The development of AKs may also be reduced by oral retinoid(eg acretin, isotretinoin) treatment; however, there are significant side effects especially in patients with childbearing potential and the benefits are limited to the time of treatment.247 Another treatment that may be considered for severe refractory disease after progression on oral retinoids is low-dose oral capecitabine, which was investigated in a small cohort of patients with transplants with varying side effects.248,249

Cryotherapy has been used for many years as a fast and cost-effective means for removal of SCCs. Prospective and retrospective studies,including large meta-analyses, have shown recurrence rates of 0% to 4%for invasive SCCs treated with cryotherapy. 34,250-253 For SCC in situ,recurrence rates range from 1% to 13% in retrospective studies 144,145,253,254 and 0% to 50% in prospective studies. 143,232,246,252,255 One prospective study reported that patients were much more likely to experience pain with cryotherapy compared with C&E, and time to complete healing was also significantly longer with cryotherapy. 143 Cryotherapy may also be associated with poorer cosmetic outcomes compared with topical 5-FU.232

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Treatment Modalities for Local SCC

Curetage and Electrodescence

Curettage and Electrodesiccation(C&E) is a fast and cost-effective technique for superficial lesions; however, it does not allow histologic margin assessment. Retrospective and observational data with long-term follow-up(>5 year) indicate that cure rates are between 95% to 100% for patients with primary CSCS lesions treated with C&E.34.256-258 These estimates are largely based on patients with low-risk SCC, and there is evidence to suggest that the cure rate is lower for tumors with risk factors.One study reported recurrence rates of 0.4% versus 11% for CSCCs with diameter less than versus greater than 2 cm, and another reported a recurrence rate of 19% for SCCs on the skin of the pinna that were treated with C&E.259,260

The NCCN Panel recommends this technique as a primary treatment option for low-risk CSCCs with three caveats. First, this technique should not be used to treat areas with terminal hair growth such as the scalp,public or axillary regions, or beard area in males due to the risk that a tumor extending down follicular structures might not be adequately removed. Second, if the subcutaneous layer is reached during the course of C&E, then surgical excision should generally be performed instead. This change in therapy is necessary as the effectiveness of the C&E technique rests on the ability of the clinician to distinguish between firm, normal dermis, and soft tumor tissue when using a sharp curette. Since subcutaneous adipose is even softer than tumor tissue, the ability of the curette to distinguish, and therefore to selectively and completely remove tumor cells, diminishes. Third, if C&E has been performed based only on the appearance of a low-risk tumor, biopsy results of the tissue taken at the time of C&E should be reviewed to make sure that there are no high-risk pathologic features that would require additional therapy.

Mohs Micrographic Surgery or Excision with Peripheral and Deep En Face Margin Assessment

Peripheral and deep en face margin assessment(PDEMA), or complete margin assessment, is a term used for a subset of surgical techniques for high-quality histologic visualization and interpretation of the margin surface or surgically excised tissue. Mohs micrographic surgery is the most common utilized PDEMA technique. Mohs procedures are particularly successful in non-metastatic basal and squamous cell skin cancers where tissue-sparing and precision microscopic control of margins is a priority and has been associated with lower recurrence rates.261,262 While PDEMA is a team procedure that requires the participation of physicians from multiple disciplines, Mohs physicians serve as both the surgeon and pathologist requiring highly specialized training. Efforts have been extended to generate consensus recommendations to offer Mohs surgeons guidance and promote standardization to make data aggregate from multicenter clinical trials possible.263

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Retrospective and prospective observational studies of localized primary SCCs treated with Mohs reported local recurrence rates of 1.2% to 4.1%and rates of metastases between 0% and 6.3%.256,257,266-279 Compared with primary tumors, rates of local recurrence or metastasis after Mohs are higher for recurrent tumors(previously treated with a non-Mohs modality).90.268 For recurrent CSCCs treated with Mohs, subsequent local reported recurrences occurred 5.9% to 7.7%; metastasis 0% to 10%.266-272 Other risk factors associated with recurrence after Mohs include larger subclinical extension and more Mohs stages required for clearance.268 CSCC with PNI is associated with elevated rates of recurrence(6.8%-32.3%) in studies that occasionally include BCC as well as treatment by RT.117,136,138,280-282 Risk factors associated with metastasis after Mohs include: size>2 cm, Clark's level(metastatic CSCC are more likely to be deeper-Clark level III-V), poor differentiation, location in areas of prior radiation, small tumor nests and infiltrative tumor strands, single-cell infiltration, PNI, and acantholysis.90

It is not uncommon to find discrepancies between pathology results from preoperative biopsy or initial debulking compared with frozen sections taken during Mohs.283-285 When Mohs with marginal assessment is being performed and the preoperative biopsy is considered insufficient for providing all the staging information required to properly treat the tumor,submission of the central specimen for pathologic evaluation with paraffin sections is recommended. If invasion to the parotid fascia is noted,superficial parotidectomy may be indicated.

Excision with PDEMA (via permanent or frozen section) is acceptable as an alternative to Mohs provided that it includes a complete margin assessment of en face peripheral and horizontal deep margins coupled with close communication between pathologists and surgeons regarding where within the tumor bed further resection is needed. These subsequent specimens must also be processed, and results communicated via the

PDEMA method. Low recurrence rates(0%-1%), and specifically lower recurrence rates when compared directly to standard excision,286 have been reported where histologically clear margins are achieved.287 It is important to note that truly histologically negative margins are not necessarily achieved by frozen sectioning alone, without PDEMA. Studies have reported that for CSCC tumors with negative margins upon frozen sectioning, permanent paraffin section analysis indicates positive margins in 10% to 20%.284.285.288-290 These discrepancies may be due to unrepresentative sampling of the margins, and instances of frozen sections in which permanent section showed positive margins have reported much higher recurrence rates.290 Overall, the descriptive term PDEMA underscores the Panel's belief that complete assessment of all tissue margins is the key to optimal tumor removal for high-risk tumors.Such effort at local control is particularly important in SCC because one third of deaths occur from local disease alone. Mohs or other forms of PDEMA are also recommended in case of positive margins after standard excision for low-risk CSC.

Shave Removal

Shave removal, the shaving of epidermal or dermal lesion, is a sharp removal by transverse bowl-shaped slicing to remove epidermal and dermal lesions, without including fat, and does not require suture closure.291 Like C&E, there is concern for inaccurate margin status assessment with shave removal.292 However, it is a recommended technique for low-risk BCCs located in the trunk or extremities. Shave removal studies have reported 0.5% to 30% rate of recurrence over a 3-to 5-year follow-up, multiple tumors treated in single visits, and a risk for misdiagnosis of only 1% of patients.291-294 Shave removal is a primary treatment option for low-risk CSCC when the tumor does not extend beyond the dermis.

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Standard Excision with Postoperative Margin Assessment

A common therapeutic option for CSCC is standard surgical excision followed by postoperative pathologic evaluation of margins. Retrospective analyses and prospective observational studies have reported rates of recurrence or metastasis ranging from 0% and 14%, with most studies reporting rates of 6% or lower.34,91,121,131,256,257,271,276,295-299 Distant metastasis was rarely observed, and rates of regional metastasis were highly variable across studies, ranging from 0% to 13.121,131,276,295,299,300 One large meta-analysis found that recurrence rates were lower for primary versus recurrent tumors, both with follow-up of<5 years(5.7% vs 17.3%) and with longer follow-up(8.1% vs. 23.3%).34 Incomplete excisions can depend on lesion location, thickness, PNI, invasion into the deep fascia, differentiation, surgeons' skills, and primary versus recurrent tumors,268,301-303 among other factors.276,295,304-311

The clinical margins chosen by the NCCN Panel for the primary treatment of low-risk CSCC are based on the work of Brodland and colleagues.312 Their analysis indicated that for well-circumscribed CSCC lesions<2 cm in diameter, excision with 4-mm clinical margins should result in complete removal in more than 95% of CSCCs. For low-risk lesions>2 cm in diameter, results indicated that 6-mm margins would be needed to achieve histologically clear margins in 95% of instances.

The NCCN Panel also recommends standard excision as the primary treatment for high-risk/very-high-risk CSCC when Mohs micrographic surgery(Mohs) and other forms of PDEMA are not available, however,wider surgical margins than those recommended for low-risk lesions must be taken and increased recurrence rates should be expected. Standard excision with wider margins is also a recommended treatment option for laCSCC following consideration of neoadjuvant cemiplimab and/or clinical trial after a multidisciplinary discussion to assess the most favorable treatment course.

According to Brodland et al, for CSCCs in high-risk locations(scalp, ears,eyelids, nose, lips) or with other high-risk features(histologic grade≥2,invasion of subcutaneous tissue), lesions with a diameter<1 cm,1 to 1.9 cm,and≥2cm would require margins of at least 4 mm,6mm,and 9mm,respectively.312 Other retrospective analyses of CSCCs removed with Mohs further support that larger excision margins are needed to consistently achieve clear margins as tumor diameter increases and when other risk factors are present. 268,272,301,313 Currently, European Guidelines recommend standard excisions with 6 to 10 mm peripheral clinical margins for high-risk to very-high-risk CSCCs.314-317 Appropriate margins should be determined case by case based on tumor- and patient-specific factors.

Whenever standard excision is utilized, any peripheral rim of erythema around a SCC must be included in what is assumed to be the tumor. For patients with positive margins from surgical excision and postoperative margin assessment, re-excision often yields clean margins, and in many instances, the re-excision specimen contains no tumor cells.121,131,296,318-320 Re-excision with postoperative margin assessment is therefore among the recommended treatment options for positive margins after standard excision of low-risk high-risk/very-high-risk, very-high-risk, and laCSCC. In any case, tissue rearrangement should not be undertaken until margins are identified.

Radiation Therapy

Radiation as Primary Therapy

Although surgery is the mainstay of local treatment for SCC, patient preference and other factors may lead to the choice of RT as primary therapy. The NCCN Panel noted that the determination of the appropriateness of RT should be performed together with a radiation oncologist. Patients may receive RT if they are considered nonsurgical candidates due to comorbidities, extent of disease, risk of functional or cosmetic defects, or inability to clear disease with surgery through a

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multidisciplinary discussion for low-risk, high-risk/very-high-risk, very-high-risk, and locally advanced CSCC. In the laCSCC setting, RT may be administered with or without additional systemic therapy. A large meta-analysis reported with 5-year recurrence rates of 6.7% and 10% after RT of primary and recurrent SCC, respectively.34 Subsequent retrospective analyses of patients with primary CSCCs have reported a large range of recurrence rates, from 2.8% to 42%, the latter for patients with locally advanced disease(size>2 cm or deeply invasive).⑤26,321-327 The risk of recurrence appears to increase with increasing lesion size and T-stage.324,326,328 A few small studies(n<20) have reported that for CSCCs that have been previously treated and recurred, treatment with RT results in 16.7% recurrence.323,326

Retrospective analyses have reported recurrence rates ranging from 0%to 10.5% in situ SCC lesions treated with RT as primary therapy, with most studies reporting local control rates near 100%.254,325,326,329-331

Adjuvant Radiation

For low-risk CSCC, the NCCN Panel recommends adjuvant RT for non-surgical candidates in case of positive margins after definitive surgery. For high-risk/very-high-risk and very-high-risk CSC, the NCCN Panel recommends adjuvant RT as a treatment option for patients with positive margins, if resection is not feasible, after a multidisciplinary consultation Adjuvant RT can also be considered for patients with negative margins and extensive hyperneural, large or named served involvement or if the CSCC has other poor prognostic features. Adjuvant RT may also be considered for patients with laCSCC and positive margins with or without systemic therapy. Similarly, it is a treatment that can be considered for high-risk/very-high-risk, very-high-risk, CSCC and laCSCC with negative margins if there is extensive perineural, large or named nerve involvement, or other poor prognostic features. 332

It has been shown that adjuvant RT improved locoregional control and survival outcomes for patients with positive margins after surgery or other high-risk features for recurrence.332-337 However, RT in the progressive disease is usually not curative so every effort should be taken to obtain a clear surgical margin prior to RT initiation.281 The outcome benefit of adjuvant RT following resection of CSCC with negative margins has been estimated to be approximately 50% reduction in local and nodal recurrence risks,338 despite older inconclusive data.337,339,340 Other retrospective studies combined results for patients treated with other modalities(eg,Mohs/standard excision alone,RT alone, chemotherapy),patients with other types of skin cancer(BCC and metatypical BCC),patients with LN metastases, and a mix of patients with primary and recurrent skin lesions, with and without positive margins.116,138,336,341-343 These studies suggest that postoperative RT for patients with high-staged CSCC may improve local and regional control and disease-free survival(DFS), but a survival benefit has not been demonstrated.

Radiotherapy Safety & Administration

The NCCN Panel previously cautioned that RT is often reserved for patients>60 years of age because of concerns about long-term sequelae,including secondary malignancies; however, this statement has been retracted. This is because age is no longer a major factor in determining treatment modality.

Large cohort and population-based studies(N> 1000) have shown that rates of NMSCs are significantly higher in those who received prior RT(either for a benign condition or for cancer) compared with those who have no history of therapeutic RT exposure.344-347 In patients who developed NMSC after prior RT, most NMSC lesions occurred within the radiation field, with elevated risk of NMSC confined to the site of RT exposure.The risk of NMSC was particularly high in patients who received therapeutic RT early in life.

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RT can result in poor cosmetic outcomes, including telangiectasia,changes in skin pigmentation, and fibrosis. More serious long-term complications include non-healing ulcers(especially for SCC in situ254,329,330); soft tissue, cartilage, bone, or brain necrosis; decreased sensation; and cataracts(for lesions in the periorbital region).326,328,329,331,348-350

Specifics about the application of RT, including total doses, treatment duration, and contraindications, are described under Principles of Radiation Therapy in the algorithm; however, appropriateness of RT treatment should be determined together with a radiation oncologist.Additional information can be found in the ASTRO Guideline on Definitive and Postoperative Radiation Therapy for Basal and Squamous Cell Cancers of the Skin.351 RT is contraindicated in patients with genetic conditions predisposing to irradiation-related skin cancer(eg, basal cell nevus syndrome[Corlin syndrome]352-356 and DNA-repair disorders such as Fanconi's anemia, xeroderma pigmentosum), and relatively contraindicated in patients with connective tissue diseases(eg, lupus,scleroderma).357-359 Given higher rates of poor cosmesis and complications with increasing cumulative radiation dose, 328,348,360 reirradiation should not be routinely utilized for recurrent disease within a prior radiation field.Protracted fractionation is associated with improved cosmetic results, 348,350,361 and should be utilized for poorly vascularized or cartilaginous areas. Retrospective studies have found that for patients with CSCC and PNI, progressive disease tends to occur along involved nerves.116,362,363 The NCCN Panel recommends including the course of the local nerves proximally for extensive PNI, clinically evident PNI, or involvement of named nerves(particularly in the head and neck region).

A variety of external beam options have been shown to be effective for treating CSCP and have similar cosmetic/safety results.328,348,361,364-366 Isotope-based brachytherapy can be an effective treatment for certain

sites of disease, particularly on the head and neck. ${ }^{367-373}$ A retrospective multicentric analysis of 1676 carcinomas of the skin of the nose and nasal vestibule yielded a local control rate of 93% with a minimum follow-up of 2 years. It was determined in this study that local control depended on tumor size (diameter $< 2$ cm: 96%, 2-3.9 cm: 88%, $\geq$ 4 cm: 81%) and tumor site (external surface of the nose: 94%, vestibule: 75%).372

On the other hand, there are insufficient long-term efficacy and safety data to support the routine use of electronic surface brachytherapy.374,375 Electronic brachytherapy (EB) uses electrically generated x-rays, which are not regulated by the Nuclear Regulatory Commission. One of the apparent advantages of EB devices is the decreased shielding requirements and the portability of the units, however, this may lead to EB use in settings unfamiliar with the hazards of therapeutic radiation delivery.376 The American Association of Physicists in Medicine (AAPM)task group 152 has provided guidelines for proper and safe EB use including having an authorized medical physicist (AMP) physically present from the initiation through the duration of all treatments involving an EB unit. The AMP is responsible for output calibration, quality assurance,training and treatment planning.376 Furthermore, training and educational requirements for those administering EB vary considerably from state to state, and users should consult their local radiation safety committee to confirm appropriate compliance. The American Brachytherapy Society(ABS) has published a consensus statement for electronic brachytherapy,noting a paucity of long-term clinical outcome data and lack of comparison to surgery or standard radiotherapy techniques.377 Particularly concerning is the absence of standardized dosimetry (in comparison to high dose rate[HDR] brachytherapy and external beam radiotherapy) to ensure adequate target coverage, skin surface dose, and plan quality assurance. The ABS,therefore, recommends that "EB treatment should be performed on clinical registry or trial at this time". The American Academy of Dermatology (AAD) has published a Position Statement: "The AAD believes additional

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research is needed on electronic surface brachytherapy particularly on long term outcomes". The AAD acknowledges concerns regarding aggressive marketing to dermatologists with a focus on revenue streams,potentially undermining quality of care and patient safety. The AAD also cautions dermatologists to be mindful of the Stark physician self-referral law. Recently, image guidance current procedural terminology(CPT)codes have been used for the delivery of EB, despite a lack of evidence demonstrating a benefit in clinical outcomes with image guidance. We do not support the use of image guidance with EB currently. In conclusion,EB should only be performed by Radiation Oncologists with Medical Physics support, on registry or clinical trial, with appropriate safeguards,and in adherence with all State and Federal regulations. Further research is needed regarding dose deposition and long-term clinical outcomes.

Sentinel Lymph Node Biopsy

The NCCN Panel recommends consideration of sentinel lymph node biopsy(SLNB) during treatment planning prior to primary treatment when the disease is recurrent or has multiple high-risk features for high-risk/very-high-risk CSCC where surgery or RT has a high likelihood of cure as well as for very-high-risk CSCC with significant risk of extensive local recurrence, nodal or in-transit metastasis. Studies have reported sub-clinical nodal metastases in 7% to 21% of patients with high-risk non-anogenital CSCC who underwent SLNB.76,86,114,115,378-384 Although small sample sizes and low rates of SLN positivity limit assessment of prognostic factors, a few studies suggest that risk factors for SLNB positivity include tumor diameter and thickness, LVI, PNI, and the presence of multiple high-risk factors.76,114,115,382,385

Several studies reported that among patients with localized SCC and a negative SLNB, nodal metastases were later detected in 2% to 15% of patients.76,86,114,115,379-381,383,386 In addition to false negatives, some studies documented patients with a negative SLNB who developed local

recurrences or metastases outside of the previously biopsied LN basin.86,115,379 For positive SLNB, multidisciplinary discussion is recommended after obtaining radiologic staging of the neck, chest,abdomen, and pelvis if not yet completed. In the absence of metastatic disease consider completion lymphadenectomy of the affected nodal basin. If surgery is not an option due to patient preference or poor performance status, then consider radiation therapy. Following neck dissection, see Very-high-risk CSC in the algorithm for additional recommendations. It has been shown that despite receiving completion lymph node dissection, patients with a positive SLN had higher rates of postoperative recurrence/metastases, ranging from 33% to 45%,114,115,379,382 and were also more likely to die from SCC, with significantly lower 3-year DSS rates compared to patients who have a negative SLN.86,115,382 Therefore, although SLNB may have prognostic value, it is unclear whether SLNB followed by completion lymph node dissection or adjuvant RT improve patient outcomes.

Regional Lymph Node Involvement in SCC

Regional nodal involvement significantly increases the risk of recurrence and mortality.36,85,97 Nodal metastasis also commonly coincides with other adverse histopathologic findings such as LVI, poor differentiation, and PNI.11,74,75,82,85,90,92,97,390 About 60% to 82% of patients with nodal disease show involvement in the parotid gland, while cervical neck node disease without parotid invasion is observed in 18% to 41% of patients.391

Workup for Suspicion of Regional Lymph Node Involvement

The presence of palpable regional LNs or suspicious LNs identified by imaging studies should prompt a fine-needle aspiration(FNA) or core biopsy of suspicious node(s). If initial pathology results are negative, the NCCN Panel recommends considering re-evaluation by clinical exam, CT with contrast imaging of the nodal basin, and/or pathology on additional LN specimens taken by repeat FNA, core biopsy, or excisional biopsy of

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the suspicious node(s).For patients with pathologic evidence of LN disease,preoperative imaging of the nodal basin by CT with contrast is recommended to determine the size, number, and location of involved nodes.CT with contrast of the nodal basin can be useful for RT planning.In addition, chest/abdomen/pelvis CT with contrast or FDG-PET/CT are recommended as clinically indicated to rule out distant metastatic disease.

Treatment of SCC with Regional Lymph Node Involvement

The NCCN Panel recommends resection of regional disease over RT or chemotherapy.RT with or without concurrent systemic therapy is reserved for patients who are not surgical candidates. Most studies of patients with regional involvement CSCC focus on treatment of parotid and/or cervical nodes either with surgery alone (parotidectomy and/or neck dissection) or surgery plus adjuvant RT. Some studies included patients receiving concomitant chemotherapy 56,392-398 or patients who received RT alone. 96,397,399-401 For studies where the majority of patients receive surgery plus adjuvant RT, recurrence rates are 20% to 35% and estimates of 5-year DFS and DSS are 59% to 83% and 63% to 83%,respectively.56,57,392,393,395-397,399,401-406 Many studies support that adjuvant RT improved local regional control, DFS, and OS compared with surgery or RT alone. 392,393,396,397,399,401-403,406 In contrast, other studies found no significant association between adjuvant RT and improved disease outcomes. 56,392,404,405 There may be subsets of patients who derive more clinical benefit from adjuvant RT than other patients; however, it is difficult to identify such patients. Results vary for all of the prognostic factors frequently considered such as immunosuppression, primary tumor size,LVI, PNI, differentiation, and features of the regional disease such extranodal extension (ENE) and number of involved nodes. 56,57,392,393,395,396,399,401,403,406,407

Several staging systems have been proposed for regional CSCC, as shown in Table 1.O'Brien proposed a staging system that separates

parotid involvement from neck LN involvement based on multivariate analysis showing improved local control for P1 compared with P2/P3.408 Multivariate analyses of survival and locoregional control have yielded favorable394,399,401,406 as well as discordant results57,394,403 regarding the prognostic value of O'Brien P-stage.O'Brien also showed that survival was significantly better for patients with N0/N1 compared with N2.408 Two studies supported this result,57,406 but several others did not.399,401,403 According to the AJCC 7th edition, N1 disease with no ENE had a 5-year cure rate of 92%.116 N2 disease with immunosuppression, in particular patients with transplants or those with hematologic malignancies, on the other hand, had a 5-year survival of 52%, in contrast to 72% for patients who are immunocompetent.409 The AJCC 7th edition staging does not separate parotid from cervical lymph node involvement and includes both 3-cm and 6-cm cutoffs for largest lymph node dimension.410 Forest et al found that lymph node size was related to ENE, and that 6-cm cutoff and 3-cm cutoff groups performed similarly.392 Risk stratification per the NCCN Guidelines takes into account both ENE403,411,412 and margin status after resection394,401,403,408,411 as prognostic factors for recurrence and survival.The updated AJCC staging system also includes ENE as a criterion for determining N-stage.133 It should be noted that there are studies that showed no significant association between outcomes and ENE or margin status.394,396

The NCCN-recommended and preferred treatment for CSCC with lymph node involvement is excision of the primary tumor and regional lymph node dissection for all surgical candidates. Patients treated with dissection of nodes in the trunk and extremities should consider adjuvant RT of the nodal bed, especially if multiple nodes are involved or if ENE is present.For patients with nodal metastasis to the head and neck, the extent of surgery should depend on the number, location, and size of affected nodes. Postoperative adjuvant treatment should depend on the pathologic findings after surgery-namely the extent of resection, number of positive

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nodes, and presence or absence of ENE. Patients with ENE or incompletely excised nodes should receive adjuvant RT and also consider concurrent systemic therapy depending on individual toxicity tolerance.Patients with inoperable nodal disease should be treated with RT of the nodal bed and consider concurrent systemic therapy. Multidisciplinary consultation is recommended for these patients and should consider the systemic therapies used to treat head and neck squamous cell carcinomas as indicated in the NCCN Guidelines for Head and Neck Cancers.For symptomatic sites, palliative RT or surgery should be considered.Stereotactic body radiation(SBRT) may be appropriate in select patients.

Satellitosis/In-transit Metastasis

Satellitosis or in-transit metastasis(S-ITM) is a clinically significant risk factor for the recurrence and defined by the presence of dermal lesions between the primary tumor and lymphatic nodal basins.413 Due to S-ITMs rarity and therefore scarcity of data, neither the AJCC 8th edition 414 nor the Brigham Women's Hospital( BWH) staging system74,75 include it as a CSCC risk factor. The NCCN Panel has strived to delineate treatment planning imaging options as well as primary treatment after a multidisciplinary discussion based on whether the tissue sampling confirmed S-ITM is operable, unresectable, or incompletely resected.Despite these steps S-ITM remains a challenge when encountered in the clinical setting. 415

Recurrence and Metastasis

Metastatic CSCC is rare, estimated at 1.9% to 2.7% of all CSCC, with nodal metastases and distant metastatic disease estimated at 3.7% and 0.4%, respectively.11,82 For the management of local tumor recurrence or new regional disease, the Algorithm directs clinicians to follow the appropriate pathways for primary treatment. Complicated high-risk tumors,regional recurrence, or the development of distant metastases should be managed by a multidisciplinary tumor board. The NCCN Panel

encourages participation in a clinical trial for patients with metastatic CSCC. Unfortunately, such trials are scarce. For symptomatic sites,palliative RT or surgery should be considered. SBRT may be appropriate in select patients. Under highly selective circumstances and in the context of multidisciplinary consultation, resection of limited metastases can be considered.

Systemic Therapy for Distant Metastatic Disease

Unfortunately, evidence regarding systemic therapy for distant metastatic CSCC is limited, except for in the case of the immunotherapy paradigm.Whereas a number of small studies have reported responses to cytotoxic therapy in patients with local or regional CSCC (See Principles of Systemic Therapy in the algorithm and Discussion section Systemic Therapy Options), few of these studies included patients with distant metastatic CSCC.

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Systemic Therapy Options

Very-high-risk CSCC with significant risk of extensive local recurrence,nodal, or in-transit metastasis treatment planning option includes cemiplab-rwc as a neoadjuvant therapy after multidisciplinary discussion if the tumor has rapid tumor growth, in-transit metastasis,lymphovascular invasion, is borderline resectable, or if surgery alone may not be curative or result in significant functional limitation. Systemic therapy is also an option that can be considered by a multidisciplinary team for patients with laCSCC. Locally advanced CSCC is defined as primary or recurrent extensive disease where surgery and/or RT may not result in a cure or would possibly produce significant functional impairment.416

Primary treatment for resectable laCSCC includes consideration of neoadjuvant cemiplimab-rwc after multidisciplinary discussion.For patients with laCSCC who cannot undergo surgery due to comorbidities,extent of disease, risk of functional or cosmetic defect, or inability to clear disease with surgery, primary treatment consists of RT with or without systemic therapy or systemic therapy alone if curative RT is not feasible.These primary treatment options also apply to unresectable, inoperable, or incompletely resected palpable regional lymph nodes identified by imaging after a multidisciplinary consultation. Additional treatment for patients with positive margins after resection also includes RT with or without systemic therapy or systemic therapy alone if curative RT is not feasible.Treatment of regional lymph nodes of the head and neck also include RT and consideration of concurrent systemic therapy in certain circumstances. For patients with confirmed S-ITM, systemic therapy with or without RT is a therapeutic option unresectable or incompletely resected disease after a multidisciplinary discussion while neoadjuvant systemic therapy can be considered for operable disease.

For locoregional disease for which surgery or RT are unlikely to be curative, both cytotoxic and epidermal growth factor receptor (EFRG)inhibitor systemic therapy (monotherapy or combination) have been successfully used to reduce tumor load, which in some cases enabled complete resection or complete response with or without concurrent/subsequent RT.417-421 In the absence of prospective comparative trial data, it is unclear whether systemic therapy provides additional clinical benefit when used postoperatively with RT. Small retrospective studies were unable to establish definitely that the addition of chemotherapy to postoperative RT significantly improved any disease-related outcome in patients with regional disease,395,412,422-424 except for one study.425 The emergence of anti-programmed cell death protein 1 (PD-1) inhibitors and robust clinical trial data have opened up novel treatment venues for patients with both locally advanced and metastatic CSCC not amenable to surgery and RT. It must be noted that the preferred recommendation for all of these settings is enrolment in a clinical trial.

The preferred systemic therapy for use with RT or surgery for regional recurrence following systemic treatment option recommended by the NCCN Panel is cisplatin.426-429 EGFR inhibitors (eg, cetuximab,420,428-436 erlotinib,437 getifinib,421 panitumab438) and carboplatin± 4 paclitaxel389,426,428,439,440 are considered other recommended regimens while cisplatin + 5-FU417,427,435,436,441 is a regimen useful in certain circumstances. Evidence supporting the efficacy of any of these regimens is mostly limited to case reports and small retrospective studies. In a small(N = 21) prospective phase II study in patients with locally advanced primary or nodal disease who received definitive RT with concurrent cisplatin or carboplatin, the overall complete response (CR) was reported to be 63%.426 Efficacy and safety data for cisplatin, cetuximab, or carboplatin + paclaxixel in combination with RT can also be extrapolated from large randomized trials in patients with non-cutaneous head and neck cancers. 387-389 On the other hand, data from a rare, large (N = 321)

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randomized trial in patients with CSCC of the head and neck testing RT $\pm$ carboplatin did not find an added benefit with carboplatin. ${ }^{422}$

The preferred systemic therapy options if curative RT or surgery is not feasible for locally advanced, recurrent, or metastatic disease for use alone without RT recommended by the NCCN Panel are cemiplimab-rwlc442-445 and pembrolizumab.446,447 Other recommended regimens for systemic therapy alone include nivolumab448 or if the patients are ineligible for or progressed on checkpoint inhibitors and clinical trials carboplatin +caplacitaxel± cetuximab449-453 and EGFR inhibitors(eg,cetuximab,419,420,429,430,432,434,436,454,455 panitumumab,438,456 definitis,457 dacomitinib,458 erlotinib459). Regimens that are useful in certain circumstances include neoadjuvant cemiplimab445 or if the patients are ineligible for or progressed on checkpoint inhibitors and clinical trials, cisplatin± 5-FU417,419,427,429,436 and capecitabine.

A phase II, multicenter, nonrandomized study for neoadjuvant cemiplimab-rwc enrolled 79 patients with CSCC and showed a 51% pathologic complete response and 13% pathologic major response in the neoadjuvant setting.445 Grade 3 or higher adverse events were only observed in 18% of patients. Therefore, the NCCN Panel recommends neoadjuvant cemiplimab-rwc be discussed as a treatment option for patients whose disease is considered borderline resectable, unresectable,or in which surgery may carry a high morbidity.

Published data reported an objective response rate(ORR) of 44% to 54%,CR of 0% to 13%, and partial response(PR) of 31% to 50% to cemiplimab-rwlc in patients with locally advanced, recurrent, or metastatic CSCC.442-444 Data from the phase II KEYNOTE-629 trial, which included patients with locally advanced, recurrent, or metastatic CSCC, reported an ORR of 34% to 50%, a CR of 4% to 17%, and a PR of 25% to 33% for patients treated with pembrolizumab.446,447 An open label, single-arm, phase II study evaluated the safety and efficacy of nivolumab as a first-line

systemic therapy in individuals with advanced CSCC(N= 24).448 A best ORR of 58.3% was achieved, yet no complete responses were reported.The study also reported a median follow-up of 17.6 months, estimated median PFS and OS of 12.7 and 20.7 months, respectively. A median DOR was not reached. Preliminary data and the clinical experience of NCCN Panel members suggest that other anti-PD-1 inhibitors may also be effective in this setting. It was demonstrated in a retrospective study that patients receiving immunotherapy showed a statistically significant better survival compared to those treated with other systemic therapies(P=.034) 429; the validity of this finding remains to be tested in prospective randomized studies. The use of immune checkpoint inhibitors might perhaps be extended to other indications, with early reports advocating its safety and efficacy concurrently with RT.462

In the case of EGFR inhibitors, all recommended regimens have been tested in small, single-arm phase ll clinical trials among patients with CSCC nonamenable to surgery and RT. However, low rates of response were documented. Among 25 patients who received cetuximab, 8 PR's and 2 CR's were documented, with a disease control rate of 69%.420 As for gefitinib, among 40 patients treated, the ORR was reported to be 16%,with an additional 35% achieving stable disease at 8 weeks.457 In a smaller study of 16 patients with CSCC testing panitumumab, the best ORR (PR and CR) was 31%, with a further 6 patients achieving stable disease.456 The response rates reported for 42 patients treated with dacomitinib were 2% CR, 26% PR, with a disease control rate of 86%.458 The ORR for 39 patients treated with erlotinib was 10%, with a disease control rate of 71%.459 Efficacy data for chemotherapeutic agents are not much better. In a systemic review of 60 patients with metastatic CSCC treated with cisplatin, the CR was reported to be 2%, with an ORR of 45% and median DFS of 14.6 months. ${}^{436}$ Data supporting carboplatin utility are even more limited, with most studies examining carboplatin combinations and not carboplatin monotherapy. ${}^{429,455}$

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Follow-up

It has been well-established that 13% to 50% of these patients will develop another SCC within 5 years. 463-465 This represents at least a 10-fold increase in risk compared to the general population.464,465 Patients with a prior SCC are also at increased risk of developing cutaneous melanoma and BCC, and patients with multiple prior SCCs are at even higher risk.73,464 Therefore, continued long-term surveillance of these patients is essential, as is patient education about sun protection and regular self-examination of the skin. Additionally, 70% to 80% of cutaneous SCC recurrences develop within 2 years of the initial therapy. 11,34,60,75,78 Therefore, close follow-up of these patients during this time period is critical.

Patient education is a key component of follow-up for patients who have had cutaneous SCC. All patients should be made aware of the various resources that discuss skin cancer prevention. Patients should be educated in strict sun protection and taught how to perform a comprehensive self-examination of the skin. For those who had regional SCC, training in self-examination of lymph nodes is also recommended.

Patients should also be monitored with regular physical exams including complete skin and regional lymph node examination. The frequency of follow-up should be adjusted based on risk (See Follow-up in the algorithm). For following disease, the imaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease (ie, local, regional, metastatic). Histologic confirmation is often sufficient to diagnose local recurrence, but MRI with or without contrast can be considered to assess extent of local disease. For nodal or distant metastases, histologic analysis and/or other imaging modalities can be used for confirmation and to gauge extent of disease. In certain patients at high risk for multiple primary tumors, increased surveillance and consideration of prophylactic measures may be indicated. Follow-up

with a dermatologist is strongly recommended if any of the following criteria are met: past or imminent solid organ, marrow, or stem cell transplant, one or more cutaneous melanomas in the past 5 years, or four or more nonmelanoma skin cancers in the past 5 years.

Care for Patients at High Risk of Developing Multiple SCCs

Treatment of SCC in Patients at High Risk

For individuals who rapidly develop multiple CSCC lesions, destructive techniques such as C&E and cryotherapy may be used. Some NCCN Panel members use a combination of shave removal to excise the bulk of the tumor and ensure sufficient material for pathology, and then destructive techniques for margin control. The details of the techniques used to remove CSCC lesions in patients at high risk with multiple lesions vary widely between NCCN Member Institutions and between practitioners at these institutions, and there is no standard language for describing these methods. Compared to the low-risk population, RT is used more frequently as an adjuvant therapy in patients at high risk and for PNI.466 Satellite lesions and in-transit cutaneous metastases may occur more frequently and are more likely to progress in this population.467,468 Analyses of large populations of patients with organ transplants have found that the incidence of new skin cancers is linked to the duration and dose of immunosuppression.469-471 Prospective randomized trials have shown that switching from other immunosuppressants to mTOR inhibitors reduces the risk of developing new CSCC lesions, particularly in patients with a history of one or more CSCCs.472-480 When surgery is impractical due to high CSCC burden, oral capecitabine has been suggested in the transplantation setting, although toxicity is a concern. 249

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Prevention in Patients at High Risk

Treatment of precancers at first development can help prevent the development of subsequent invasive tumors. Prophylactic treatment may be needed for patients with a history of multiple lesions and/or extensive diffuse AK or field cancerization. Oral retinol and synthetic retinoids(eg,acitretin, 247 isotretinoin, etretinate) have been tested in prospective studies in patients at high risk for multiple AKs or SCCs, including patients with transplants.481-486 patients with xeroderma pigmentosa,487 or with psoriasis and PUVA(psoralen plus UV-A) exposure.488 By comparison with placebo or with SCC incidence during treatment-free periods, data from these studies support that oral retinol and oral retinoids significantly reduce the incidence of new CSCCs in patients at very high risk for multiple lesions.482-485,487,488 Outside of these very-high-risk groups, the effectiveness of retinol/retinoid therapy for prophylaxis is less clear.489-491 Side effects may be significant and include mucocutaneous, such as cheilitis, excessive peeling of the skin, and hair disorders,486 but musculoskeletal, vascular, hepatic triglyceride, and neurologic adverse events have also been reported.485,487,490,492 In addition, these agents are teratogenic and must be used with extreme caution in individuals of child-bearing potential.493

The NCCN guidelines do not recommend topical retinoids as prophylactic treatment for patients at high risk for multiple AKs or CSCCs. Results of a large randomized trial in patients with a history of≥2 BCCs/SCCs showed that prophylactic topical rettinoin(0.1%) did not reduce the development of new cutaneous BCCs or SCCs compared with vehicle control.494 A double-blind randomized study showed that topical tazarotene had a chemo-preventative effect in only 6% of patients with basal cell nevus syndrome,a condition associated with frequent development of primary BCCs.495

Results from a randomized controlled study suggest that prophylactic nicotinamide may be effective at preventing the development of CSCC

recurrence or metastases in patients at high risk.152 Nicotinamide was associated with a 30% reduction in the 12-month rate of new SCCs(P=.05), and a 20% reduction in development of new BCCs(P=.12)compared to placebo. During the subsequent 6 months off treatment,there was a trend toward increased rates of new SCCs for the nicotinamide arm compared with placebo(59% relative difference; P=.07). Although there are currently no clinical trial data directly comparing nicotinamide with oral retinoids for CSCC prophylaxis, nicotinamide has a much better safety profile. Further clinical research is needed to determine whether nicotinamide provides long-term clinical benefit for patients at risk of developing multiple NMSCs and AK lesions.

Patient Education for Patients at High Risk

Patient education is especially important for those at high risk for CSCC progression or recurrence. Treatment delay is associated with larger tumor size, larger defect size from surgical removal, and more Mohs layers taken to obtain clear margins.107,496-499 Significant prognostic factors for patient delay in seeking care include serious comorbidity, low education level, non-recognition of the seriousness of symptoms, and SCC arising on pre-existing chronic lesions.500,501 Low education level is also associated with large NMSC tumor area at presentation.502 Educational interventions and physician advice have been shown to increase the likelihood of patients undergoing a complete skin exam, and patients with more knowledge of skin cancer are more likely to get regular complete skin exams.385,503,504

Patient education should begin, in the case of patients with transplants at transplantation and at birth or diagnosis for patients with xeroderma pigmentosum. Education should include discussion of individual risk assessment and the need for stringent sun avoidance and protection methods. Regular unscreen use can significantly reduce the rate of development of new AKs and CSCCs, and increases remission rates of AKs.147-150 Knowledge of more than one method for UV protection is

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associated with higher rates of using some form of protection,505 as is awareness of susceptibility/risk and overall education level.506,507

Having a prior NMSC has proved to be insufficient motivation for altering patient behavior regarding UV protection and avoidance. Although those with prior NMSC are more likely to use sunscreen and to avoid sun exposure, adoption of preventative measures was low: only 54% used sunscreen, and 20% to 45% used other avoidance/protective methods. 508 Another cross-sectional study showed that tanning bed use was similar among those with and without prior NMSC.509

Randomized trials have shown that educational interventions can effect significant changes in use of solar protection in outdoor workers and patients with transplants.504,510-515 While both extensive and repetitive education improve patient knowledge, repetitive education is needed to effect long-term change in patient behavior.516 This is especially important

for patients with transplants, as preoccupation with other medical concerns may make them unreceptive to skin cancer education.517 For patients with transplants, an intervention including text messaging reminders was shown to be more effective at improving patient knowledge and changing sun protective behaviors compared with more traditional approaches. 518

Monthly self-examination is recommended and should include all skin surfaces and LNs. Patients should be taught the proper method for systematic self-examination of the skin and lymph nodes. A randomized controlled trial has shown that educational intervention increased the frequency and sensitivity of self-examination of the skin among patients with transplants.519 In addition to more frequent and thorough self-examination, follow-up schedules for patients at high risk should be titrated to the frequency of tumor development, and in rare cases may occur weekly.

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Table 1. Staging Systems for Regional Cutaneous SCC of the Head and Neck

|O'Brien 2002 Staging System ${}^{408}$|| |---|---| |Parotid Stage|Parotid Stage| |Stage|Criteria| |P1|1 LN+≤3 cm| |P2|1 LN+>3 and ≤6 cm or ≥2 LN+| |P3|1 LN+>6 cm or Involves VII nerve or skull base| |Neck Stage|Neck Stage| |Stage|Criteria| |NO|No clinical neck disease| |N1|1 LN+≤3 cm ipsilateral| |N2|1 LN+>3 cm or ≥2 LN+ or ≥1 LN+ contralateral|

|AJCC 7th Edition (2009) Regional LN Staging410|| |---|---| |Stage|Criteria| |Stage|Criteria| |N1|1 LN+≤3 cm ipsilateral| |N2a|1 LN+ >3 and ≤6 cm ipsilateral| |N2b|≥2 LN+ all≤6 cm ipsilateral| |N2c|≥1 LN+ ≤6 cm bilateral/contralateral| |N3|≥1 LN+ >6 cm|

|AJCC 8th Edition (2017) Regional LN Pathological Staging133|| |---|---| |Stage|Criteria| |N1|1 LN+≤3 cm ENE(-)| |N2a|1 LN+,>3 and≤6 cm ipsilateral ENE(-) or 1 LN+≤3 cm ipsilateral ENE(+)| |N2b|≥2 LN+ all ≤6 cm ipsilateral ENE(-)| |N2c|≥1 LN+ all≤6 cm bilateral/ contralateral ENE(-) ENE(-)| |N3a|≥1 LN+>6 cm ENE(-)| |N3b|1 LN+≤3 cm ENE(+) contralateral, or 1 LN+ >3 cm ipsilateral ENE(+) or 2 LN+, any ENE(+)|

|Forest 2010 N1S3 Staging System $^{392}$|| |---|---| |Stage|Criteria| |I|1 LN+≤3cm| |II|1 LN+>3cm or ≥2 LN+≤3cm| |III|≥2 LN+>3cm|

|NCCN Guidelines|NCCN Guidelines| |---|---| |Risk Level|Criteria| |Low|1 LN+≤3 cm ENE(-)| |Medium|1 LN+>3 cm ENE(-) or ≥2 LN+ ENE(-)| |High|≥1 LN+ ENE(+) or Incompletely excised disease|

ENE(+),with extranodal extension;ENE(-),without extranodal extension;LN+，positive lymph node(s);SCC,squamous cell carcinoma.The pathologic criteria.

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References

1. Rubio-Casadevall J, Hernandez-Pujol AM, Ferreira-Santos MC, et al.Trends in incidence and survival analysis in non-melanoma skin cancer from 1994 to 2012 in Girona, Spain: A population-based study. Cancer Epidemiol 2016;45:6-10. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/27639035.

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491.Kadakia KC, Barton DL, Loprinzi CL, et al. Randomized controlled trial of acitretin versus placebo in patients at high-risk for basal cell or squamous cell carcinoma of the skin(North Central Cancer Treatment Group Study 969251). Cancer 2012;118:2128-2137. Available at:http://www.ncbi.nlm.nih.gov/pubmed/21882176.

492.Meyskens FL,Jr.,Gilmartin E,Alberts DS,et al.Activity of isotretinoin against squamous cell cancers and preneoplastic lesions.Cancer Treat Rep 1982;66:1315-1319. Available at:https://www.ncbi.nlm.nih.gov/pubmed/6211233.

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495.Tang JY,Chiou AS,Mackay-Wiggan JM,et al.Tazarotene:randomized, double-blind, vehicle-controlled, and open-label concurrent trials for basal cell carcinoma prevention and therapy in patients with basal cell nevus syndrome. Cancer Prev Res(Phila) 2014;7:292-299.

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496.Eide MJ,Weinstock MA,Dufresne RG,Jr.,et al.Relationship of treatment delay with surgical defect size from keratinocyte carcinoma(basal cell carcinoma and squamous cell carcinoma of the skin). J Invest Dermatol 2005;124:308-314. Available at:https://www.ncbi.nlm.nih.gov/pubmed/15675948.

497.Renzi C,Mastroeni S,Passarelli F,et al.Factors associated with large cutaneous squamous cell carcinomas. J Am Acad Dermatol 2010;63:404-411. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/20598396.

498. Diehl J, Choi YM, Liang LJ, Chiu M. Association between mohs surgery wait times and surgical defect size in patients with squamous cell

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

or basal cell carcinoma of the skin. Dermatol Surg 2015;41:768-774.

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499. Wollina U, Bayyoud Y, Kronert C, Nowak A. Giant epithelial malignancies(Basal cell carcinoma, squamous cell carcinoma): a series of 20 tumors from a single center. J Cutan Aesthet Surg 2012;5:12-19.

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502. Amber KT, Bloom R, Abyaneh MY, et al. Patient factors and their association with nonmelanoma skin cancer morbidity and the performance of self-skin exams: A cross-sectional study. J Clin Aesthet

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503.Janda M, Youl P, Neale R,et al. Clinical skin examination outcomes after a video-based behavioral intervention: analysis from a randomized clinical trial. JAMA Dermatol 2014;150:372-379. Available at:

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504.Firooz A,Amin-Nejad R, Bouzari N,et al. Sun protection in Iranian kidney transplant recipients: knowledge, attitude and practice. J Eur Acad Dermatol Venereol 2007;21:754-757. Available at:

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505. Goldenberg A, Nguyen BT, Jiang SI. Knowledge, understanding,and use of preventive strategies against nonmelanoma skin cancer in healthy and immunosuppressed individuals undergoing Mohs surgery.

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506. Borghi A, Corazza M, Battaglia Y, et al. What is the key to improving renal transplant recipients' awareness of skin cancer risk?

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507.Wohlk IM, Philipsen PA, Wulf HC. Factors associated with cessation of sunbed use among Danish women. Photodermatol

Photoimmunol Photommed 2016;32:191-198. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/27084577.

508. Fischer AH, Wang TS, Yenokyan G, et al. Sunburn and sun-protective behaviors among adults with and without previous nonmelanoma skin cancer(NMSC): A population-based study.J Am Acad Dermatol 2016;75:371-379.e5. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/27198078.

509.Wiznia L,Dai F,Chagpar AB. Do non-melanoma skin cancer survivors use tanning beds less often than the general public? Dermatol Online J 2016;22. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/27617935.

510. Girgis A, Sanson-Fisher RW, Watson A. A workplace intervention for increasing outdoor workers' use of solar protection. Am J Public Health 1994;84:77-81. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/8279616.

511.Robinson JK, Friedwald JJ, Desai A, Gordon EJ. Response across the health-literacy spectrum of kidney transplant recipients to a sun-protection education program delivered on tablet computers:

Randomized controlled trial. JMIR Cancer 2015;1:e8. Available at:https://www.ncbi.nlm.nih.gov/pubmed/28410176.

512. Loescher LJ, Hansen C, Hepworth JT, et al. A preliminary study of a video intervention to inform solid organ transplant recipients about skin cancer. Transplant Proc 2013;45:3187-3189. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/23747188.

513.Tavadia S,Dawn G,Payne C,et al.Skin-cancer awareness in Scottish cardiac transplant recipients. Clin Exp Dermatol 2006;31:354-357.Available at:https://www.ncbi.nlm.nih.gov/pubmed/16681574.

514. Ismail F, Mitchell L, Casabonne D, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol 2006;155:916-925. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/17034519.

515. Seite S, Del Marmol V, Moyal D, Friedman AJ. Public primary and secondary skin cancer prevention, perceptions and knowledge: an international cross-sectional survey. J Eur Acad Dermatol Venereol

![NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure5ad52a6c5a14481ab4243d5e9963697d_0_1.png) National Comprehensive Cancer Network®

NCCN Guidelines Version 1.2026 Squamous Cell Skin Cancer

2017;31:815-820. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/28045207.

516. Clowers-Webb HE, Christenson LJ, Phillips PJ, et al. Educational outcomes regarding skin cancer in organ transplant recipients:Randomized intervention of intensive vs standard education. Arch

Randomized intervention of intensive vs standard education. Arch

Dermatol 2006;142:712-718. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/16785373.

517.Kim NN,Boone SL,Ortiz S,et al.Squamous cell carcinoma in solid organ transplant recipients: influences on perception of risk and optimal time to provide education. Arch Dermatol 2009;145:1196-1197. Available at:https://www.ncbi.nlm.nih.gov/pubmed/19841415.

518.Robinson JK, Friedewald JJ, Desai A, Gordon EJ. A randomized controlled trial of a mobile medical app for kidney transplant recipients:Effect on use of sun protection. Transplant Direct 2016;2. Available at:https://www.ncbi.nlm.nih.gov/pubmed/26900599.

519.Robinson JK,Rturris R,Mallett KA,et al.Efficacy of an educational intervention with kidney transplant recipients to promote skin self-examination for squamous cell carcinoma detection. Arch Dermatol 2011;147:689-695. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/21339418.

表 1
Risk Group	Low Risk	High Risk	Very High Risk
Treatment options	SCC-4	SCC-5	SCC-5 and SCC-6
H&P	H&P	H&P	H&P
Location/diameter(cm)	Trunk, extremities <2cm	Trunk, extremities 2 cm -≤4cm	>4 cm (any location)
Location/diameter(cm)		Head,neck, hands,feet, pretibia, and anogenital area (any size)n
Clinical borders	Well-defined	Poorly-defined
Primary vs. recurrent	Primary	Recurrent
Immunosuppression	(-)	(+)
Site of prior RT or chronic inflammation	(-)	(+)
Rapid growth tumor	(-)	(+)
Neurologic symptoms	(-)	(+)
Pathology (SCC-A)	Pathology (SCC-A)	Pathology (SCC-A)	Pathology (SCC-A)
Degree of differentiation	Well or moderately differentiated		Poorly differentiated
Histologic subtype	(-)	(+)	(+)
Depth l,m: Thickness or level of invasion	<2 mm thick and no invasion beyond subcutaneous fat	2-6 mm depth and no invasion beyond subcutaneous fat	>6 mm or invasion beyond subcutaneous fat
Perineural involvement	(-)	(+)	Tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm
Lymphatic or vascular involvement	(-)	(-)	(+)

表 2
Primary Tumor	RT Dosing	Common examples
Adjuvant RT2	Adjuvant RT2
●Conventional fractionation (1.8-2 Gy/fraction)	BED10 of 60-79 Gy	●60-66 Gy in 2 Gy/fraction4 ●60-66 Gy in 1.8 Gy/fraction (reserved for areas with poor wound healing [eg, lower extremity])
●Hypofractionation	BED10 of 48-70 Gy	●2.5 Gy x 20 fractions5 ●3 Gy x 15-17 fractions to 45-51 Gy ●6 Gy x 5 fractions (non-consecutive days)
Definitive EBRT	Definitive EBRT	Definitive EBRT
●Conventional fractionation (1.8-2 Gy/fraction)	BED10 of 70-84 Gy	●60 Gy (for small tumors in cosmetically sensitive areas) ●66-70 Gy (for locally advanced tumors involving bone or cartilage)
●Hypofractionation	BED10 of 48-72 Gyc	●Tumors <2 cm: 2.5 Gy x 20 fractions ●Tumors≥2 cm: 2.5-3 Gy x 20-22 fractions ●3 Gy x 17-18 fractions to 51-54 Gy ●4.4 Gy x 10 fractions, 4 fractions per week7 ●6 -7 Gy x 5 fractions, 2 treatments per weekd, 7, 8
Regional Disease	Regional Disease	Regional Disease
●Conventional fractionation (1.8-2 Gy/fraction) Macroscopic/gross residual lymph nodes Lymph node + dissected nodal basins PNTsb.3	66-70 Gy 60 Gy 50-66 Gy
●Undissected at-risk nodal basins	1.8-2 Gy x 25-30 fractions
Satellitosis/ln-Transit Metastasis (S-ITM)
●Resected ●Unresected	50-60 Gy over 5 to 6 weeks 60-70 Gy over 6 to 7 weeks

表 3
Primary Tumor	RT Dosing	Common Examples
Definitive or Adjuvant Skin Brachytherapy
●Custom surface mold applicators: Prescription depth≤5 mm	GOAL BED10 at least 60 Gy	●3 Gy x 16 fractions (daily) ●5 Gy x 8 fractions (2 times per week [for non- cosmetically sensitive areas])
●Interstitial Brachytherapy: Prescription depth＞5 mm	GOAL BED10 at least 60 Gy	●4.4 Gy x 10 fractions (BID [6 hours minimum between fractions])
●Shielded single channel surface applicators(Leipzig or Valencia): Prescription depth≤3 mm	GOAL BED10 at least 60 Gy	●3 Gy x 12-16 fractions (daily)

表 4
Table 1: Therapy Options for Field Cancerization/Confluent Epermal Dysplasia
Preferred	Other Recommended	Useful in Certain Circumstances
●Topical Calcipotriene/Fluorouracil,b,3,4 ●Topical Fluorouracil	● Topical Aminolevulinic acid (in conjunction with PDT)	● Acitretin$^5$ ● Capecitabine$^1,6$ (for severe refractory disease that has progressed on oral retinoids) ● Isotretinoin ● Porimer sodium(in conjunction with PDT)

表 5
Table 2: Systemic Therapy Options for Use with RT (or Surgery for Regional Recurrence Following Systemic Treatment)
Preferred	Other Recommended	Useful in Certain Circumstances
●Cisplatin,9 ● Clinical trial	●Carboplatin ●Carboplatin/Paclitaxelh,13,14 ● EGFR inhibitors (eg, Cetuximab)h,15	●Cisplatin/Fluorouracilh,22
Table 3: Options for Systemic Therapy Alone
Preferred	Other Recommended	Useful in Certain Circumstances
●Cemiplimab-rwcli,j (if curative RTf or surgery is not feasible for locally advanced, recurrent, or metastatic disease)10,11 ●Pemblizumab1j (if curative RTf or surgery is not feasible for locally advanced, recurrent, or metastatic disease)12 ● Clinical trial	●Cosibelimab-iplif (if curative RTf or surgery is not feasible for locally advanced [category 2B] or metastatic disease)16 ● Nivolumabk ● If ineligible for or progressed on immune checkpoint inhibitors and clinical trials, consider: ● Carboplatin/Paclitaxelh17 ● Carboplatin/Paclitaxel+ Cetuximab18-21 ● EGFR inhibitors (eg, Cetuximab)h,15	●Neoadjuvant Cemiplimab-rwcl,10 ● If ineligible for or progressed on immune checkpoint inhibitors and clinical trials, consider: ● Capecitabine 23,24 ●Cisplatinh,i1 ● Cisplatin/Fluorouracilh,24

表 6
PDEMA Checklist	Yes	No
Is the entire peripheral margin of the surgical specimen microscopically visualized?
Is the entire deep margin of the surgical specimen microscopically visualized?
Is the surgical specimen oriented to the wound bed and marked such that any positive margin identified in histopathologic analysis can be accurately located and re-excised?
Is the process of excision and complete histologic examination repeated until no further cancer is identified or until further excision is no longer in the best interest of the patient?
Is the process rapid enough to prevent distortion of the wound bed that would decrease accuracy of tissue orientation?

表 7
T	N	M
Stage 0	Tis	N0
Stage I	T1	N0
Stage III	T2	N0
Stage III	T3	N0
T1	N1	N0
T2	N1	M0
T3	N1	M0
Stage IV	T1	N2

表 8
		ABBREVIATIONS
ALA	aminolevulinic acid	laCSCC locally advanced cutaneous squamous cell carcinoma
BED	biologically effective dose	NSGC NSGC National Society of Genetic Counselor
C&E	curettage and electrodesiccation
CLL	chronic lymphocytic leukemia	PDEMA peripheral and deep en face margin assessment
CSCC	cutaneous squamous cell carcinoma	assessment
EBRT	external beam RT	PNTS perineural invasion
ENE	extranodal extension	PNTS perineural tumor spread
ENI	elective nodal irradiation	RDEB recessive dystrophic epidermolysis bullosa
FDG	fluorodeoxyglucose
FNA	fine-needle aspiration
H&P	history and physical	SBRT stereotactic body radiation therapy
HIV	human immunodeficiency virus	S-ITM satellitis/in-transit metastasis SLNB
IGRT	image-guided radiation therapy
ILI	isolated limb infusion	UV ultraviolet
ILP	isolated limb perfusion
IMRT	intensity-modulated radiation therapy	XP xeroderma pigmentosum
KID	keratitis, ichthyosis, deafness

表 9
NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is isNCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 10
NCCN Categories of Preference
Preferred	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

表 11
O'Brien 2002 Staging System ${}^{408}$
Parotid Stage	Parotid Stage
Stage	Criteria
P1	1 LN+≤3 cm
P2	1 LN+>3 and ≤6 cm or ≥2 LN+
P3	1 LN+>6 cm or Involves VII nerve or skull base
Neck Stage	Neck Stage
Stage	Criteria
NO	No clinical neck disease
N1	1 LN+≤3 cm ipsilateral
N2	1 LN+>3 cm or ≥2 LN+ or ≥1 LN+ contralateral

表 12
AJCC 7th Edition (2009) Regional LN Staging410
Stage	Criteria
Stage	Criteria
N1	1 LN+≤3 cm ipsilateral
N2a	1 LN+ >3 and ≤6 cm ipsilateral
N2b	≥2 LN+ all≤6 cm ipsilateral
N2c	≥1 LN+ ≤6 cm bilateral/contralateral
N3	≥1 LN+ >6 cm

表 13
AJCC 8th Edition (2017) Regional LN Pathological Staging133
Stage	Criteria
N1	1 LN+≤3 cm ENE(-)
N2a	1 LN+,>3 and≤6 cm ipsilateral ENE(-) or 1 LN+≤3 cm ipsilateral ENE(+)
N2b	≥2 LN+ all ≤6 cm ipsilateral ENE(-)
N2c	≥1 LN+ all≤6 cm bilateral/ contralateral ENE(-) ENE(-)
N3a	≥1 LN+>6 cm ENE(-)
N3b	1 LN+≤3 cm ENE(+) contralateral, or 1 LN+ >3 cm ipsilateral ENE(+) or 2 LN+, any ENE(+)

表 14
Forest 2010 N1S3 Staging System $^{392}$
Stage	Criteria
I	1 LN+≤3cm
II	1 LN+>3cm or ≥2 LN+≤3cm
III	≥2 LN+>3cm

表 15
NCCN Guidelines	NCCN Guidelines
Risk Level	Criteria
Low	1 LN+≤3 cm ENE(-)
Medium	1 LN+>3 cm ENE(-) or ≥2 LN+ ENE(-)
High	≥1 LN+ ENE(+) or Incompletely excised disease

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图示：LOW-RISK CSCC PRIMARY TREATMENTX ·C&Ey or ·Shave removalzaa or ·Standard excision with 4- to 6-mm clinical margins and postoperative margin assessment. Tissue rearrangement(eg, flap reconstruction,extensive undermining) should not be undertaken until clear margins are identified (second intention healing, linear repair, or skin graft are acceptable) ·Mohsbb,cc,dd or other forms of PDEMAee or ·Re-excision if clinically feasible or ·RTff,gg for nonsurgical candidates ·SCC-11 ·R ·Follow-up(SCC-11)

图示：NCCN

图示：High-risk/very-high-risk CSCC TREATMENT PRIMARY TREATMENT^ · Mohsbb,cc.dd or other forms of PDEMA(pferred for very high risk)ee,jj,kk,ll consultation at center with specialized discuss options ● Multidisciplinary consultation at center with specialized specialized discuss options ● Consider sentinel lymph of node biopsy (SLNB)hh,ii in cases that are recurrent or with multiple high-risk features ● For nonsurgical candidates, consider definitive RTff,gg ● For nonsurgical variants ● If surgery and/or RTgg ● are not curative ● ADITIONAL TREATMENT^ +Re-resect, if feasible +RTff,gg ● Follow-up(RSCC disease) ● If expensive perineural, large or named nerve involvement, ● or other poor prognostic ● features,a,nn consider ● Adjuvant RTff,gg,oo Follow-up(SCC-11)

图示：Very-high-risk CSCC with significant risk of extensive local recurrence, nodal, or in-transit metastasis,a,b or · Consider SNLBh,ii in cases that are recurrent or with multiple high-risk features · Consider neoadjuvant therapy with Cemiplimab-rwc° if: keratoacanthomatous rapid growth tumors · For nonsurgical candidates, consider definitive functional limitation · Mohs b,cc,dd or other forms of PDEMD (preferred for very high risk) ee,jk, ll" ●Resident SNLBh,ii in cases that are recurrent or with multiple high-risk features · Consider neoadjuvant therapy with Cemiplimab-rwc° if: Nonreactive non-keratoacanthomatous rapid growth tumors · For nonsurgical candidates, consider definitive functional limitation · Standard excision with wider surgical margins mmms and posterior images and intention and second intention healing, linear repair, or skin graft ·For nonsurgical candidates, consider definitive or Tff,gg ·Re-resect, if feasible or RTff, gg-gll · Follow-up(SCC-11) · Follow-up (SCC-7) · In patients with extremely high risk nodal and non-nodal features, consider Cemiplimab-rwc' following adjuvant RT(category 1 preferred)PP ·For nonsurgical variants, consider definitive or Tff,gg, h

图示：laCSC (Primary or recurrent extensive disease and/or where surgery and/or RT may not result in a cure or would possibly produce a significant functional impairment.9q Multidisciplinary discussion for nonsurgical candidates, due to comorbidities, extent of disease, risk of functional or cosmetic defects,isability to clear disease with surgery: RTf,99± systemic therapy of Systemic therapyif curative RT99 is not feasible Re-resect, if feasible or RTff,ggt± systemic therapyor or Systemic therapyif curative RT99 is not feasible Standard excision with wider surgical margins and postoperative margin and assessment"If extensive perineural, large or named nerve involvement,or other poor prognostic features,a,nn consider: ● Adjuvant RTff,gg,oo for nonsurgical candidates, due to comorbidities, extent of disease, risk of functional or cosmetic defects,isability to clear disease with surgery: RTff,99± systemic therapy of Systemic therapyof curative RT99 is not feasible For nonsurgical candidates, due to comorbidities, extent of disease, risk of functional or cosmetic defects,isability to clear disease with surgery: RTff,99± systemic therapy of systemic solver for scientificly.

图示：CLINICAL STAGING AND PREOPERATIVE ASSESSMENT Consider re-evaluation:\cdot Clinical exam · CT with contrast of the nodal basin · Fast neither of the clinical trial, or excisional biopsy V Positive FNA or lymph nodes identified by imaging studies Turbital biopsy Positive Control evaluation:· Clinical exam · CT with contrast of the nodal basin · CT with contrast of the end of the nodal basin to determine size, number, and location of nodes Surgical and clinical trial evaluation ww Positive Trunk deadis ex Trunst and extremities relax tumor derect of a clinical diduse $xx\%$ Head and neck Excision of primary tumor and regional deventious relaxual inoretable Multidisciplinary consultation to discuss options:\cdot RTff,gg.yt\pm systemictherapy^{\circ}. Resubsequent resected disease^{\text{xx}} RT99 not feasible

图示：Tissue sampling confirmed S-ITM · Imaging of the anatomic region (ie, CT with contrast) capturing S-ITM to determine geographic footprint CT with contrast or FDG-PET/CT as clinically indicated to rule out distant disease Multidisciplinary discussion Unresectable or incompletely resected disease with consideration of adjuvant therapy zz,aaa · Imaging of the anatomic region (ie, CT with contrast) capturing S-ITM to determine geographic footprint CT with contrast or FDG-PET/CT as clinically indicated to rule out distant disease ● Unresectable or incompletely disease with Melphalan-based regimens\· Attenuative Index Unresectable or R is not not not not discovered in the RMB 342036 ● Isolated limb infusion/perfusion (ILI/ILP)with Melphalan-based regimens'bb (Useful in certain circumstances)

图示：REGIONAL LYMPH NODES TREATMENT OF HEAD AND NECK ${}^{X}$(FINDINGS One positive node RTff,gg or Observation Incompletely excised on nodal disease RTff,gg Observation Follow-up SCC-11) Prartid nodes Parotid nodes involvedccc Excision of primary tumor and generally superficial parotidectomy and ellipsoidal neck dissection if clinically indicated NCCN Guidelines Version 1.2026 NCCN Guidelines Version 1.2026 A few nodes RTff,gg Observation Follow-up(SCC-11)

图示：Local recurrencef SCC-5 and SCC-6 Locally advanced (laCSCC) recurrencef SSC-7 New or recurrent S-ITM SCC-9 New regional disease SCC-8 and SCC-10 Regional recurrence or distant metastases multidisciplinary consultationo,yy,iii

图示：Central tumor debulk

图示：原图识别中

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引用 / 出处

NCCN临床实践指南：皮肤鳞状细胞癌（2026.V1）. 2026.