FLEX November 2023

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Phillips et al. Journal of Otolaryngology - Head and Neck Surgery

https://doi.org/10.1186/s40463-019-0374-3

ORIGINAL RESEARCH ARTICLE

Open Access

Pathological margins and advanced cutaneous squamous cell carcinoma of the head and neck T. J. Phillips 1,2* , B. N. Harris 1 , M. G. Moore 1 , D. G. Farwell 1 and A. F. Bewley 1 Abstract Objective: The recommended treatment for cutaneous squamous cell cancer (CuSCC) of the head and neck is Mohs surgical excision or wide local excision. Excision is recommended to a gross surgical margin of 4 – 6 mm however this is based on limited evidence and specify a goal histologic margin. The objective of this study was therefore to examine the reported histological margin distance following WLE of advanced CuSCC and its association with recurrence and survival. Study design: Retrospective database review. Setting: All patients included received treatment at UC Davis Department of Otolaryngology-Head and Neck Surgery and/or Radiation Oncology in Sacramento, California. Subjects and methods: The patients included were treated for advanced CuSCC with primary surgery with or without adjuvant therapy. Kaplan Meier survival curves with log rank analysis were then performed to compare 5-year recurrence free survival, and disease-specific survival for patients with different margin distances. Results: Total number of subjects was 92. The overall 5-year DSS and RFS was 68.8 and 51.0% respectively. When the pathological margin distance was ≥ 5 mm, 5-year disease specific survival was improved when compared to margin distance less than 5 mm (94.7 vs 60.7 p =0.034). Conclusion: The findings of this study suggest that a histologic margin of at least 5 mm may increase survival in advanced head and neck CuSCC patients.

Introduction Cutaneous squamous cell cancer (CuSCC) is the second most common cancer, behind basal cell carcinoma with an incidence of roughly 2 million cases per year in the United States [1]. The majority of these cancers are small and have an excellent cure and survival rate of 90 – 99% [1]. However, CuSCC if neglected or aggressive does have the propensity to grow and destroy local structures along with the ability to send local and distant metastasis. CuSCC also has the tendency for more aggres sive behavior in patients who are immunocompromised [2]. Management of CuSCC depends on several factors * Correspondence: tjphilli@dal.ca 1 Department of Otolaryngology-Head and Neck Surgery, UC Davis, Sacramento, California, USA 2 Division of Head and Neck Surgery, Kingston Health Science Center, Queen ’ s University, 2nd Floor Murray Building, Hotel Dieu Hospital, Bagot Street, Kingston, Ontario, Canada

including the size, location, metastatic disease, and patient factors. In general, excision of the CuSCC with a normal tissue margin is the standard treatment [3]. The gold standard of care for CuSCC and other skin cancers is Moh ’ s surgical excision, which has a reported cure rate of 96 – 99% [3, 4]. However, Moh ’ s surgical resec tion is not always possible. A second, highly effective method of resection is wide local excision (WLE). This too has a high cure rate of 90 – 97% and can often be used when Mohs surgery is not indicated or available [3]. The treatment of CuSCC is outlined in the NCCN guidelines. For “ low-risk ” CuSCCs of the head and neck the recommended gross margins on surgical resections are 4 – 6 mm [5]. Obtaining this margin in the head and neck can be challenging given the proximity of vital anatomy. For patients with high-risk features the guide lines recommend taking a larger margin, however the

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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in the database, therefore only the histologic margin recorded by the pathologist was used in this study. Intra operative frozen sections were taken to confirm clear mar gins, as per NCCN guidelines. The frozen sections were taken “ off the patient ” rather than off the specimen. The exact method for analyzing the margins by the pathologist is unknown, due to the retrospective nature of this study. Statistical analyses were performed with SPSS 23.0 (SPSS Inc., Chicago, Illinois). A chi square analysis was conducted to assess for a correlation between outcome and margin status. The following factors were examined: recurrent cancer, LVI, PNI, immunosuppression, poorly differentiated SCC. Kaplan Meier survival curves with log rank analysis were performed to assess 5-year recur rence free survival (RFS) and disease free survival (DSS) at different margin distances.

exact increase is not defined. The margin of 4 – 6mm is based on a single prospective non-randomized study that used Moh ’ s technique. It recommended 4 mm for tu mors less than 2 cm in greatest dimension and 6 mm for those greater than 2 cm. It did not examine whether a 4 – 6 mm margin via WLE was equivalent to a 4-6 mm margin in Mohs nor did it study specific body site loca tion [4]. This study also describes only gross margins and not histologic margins. Histologic margin goals for CuSCC are not discussed within the NCCN for CuSCC and there are no previous papers that have addressed this topic. For oral mucosal SCC the importance of histological margin distance is well established. Loree et al orginally determined that a histological margin of 5 mm or more results in greater survival and less local recurrence than close or positive margins [6, 7]. It is also recommended that taking a gross 1 cm margin of mucosa will typically yield the recommended 5 mm histologic margin [8]. The precise relationship between gross margin and histologic margin is not known for CuSCC. The objective of this study was to examine the re ported histologic margin distance following WLE of advanced CuSCC and its association with recurrence and survival. Methods This study was designed as a retrospective chart review. Ethics approval was obtained from the University of Cali fornia ethics board. An established CuSCC database devel oped at UC Davis Otolaryngology-Head & Neck Surgery was used to identify patients [9]. The database contained patients treated from 1998 to 2014 for CuSCC of the head and neck. All patients undergoing surgical treatment with or without adjuvant therapy for curative intent were in cluded in the study. The database contained patient infor mation (age, sex, and immunologic status) and data regarding tumor characteristics (primary site, DOI, diam eter, lymphovascular invasion, PNI, presence of regional nodal disease, histologic differentiation, adjuvant therapy, margin status, and whether tumors were recurrent on presentation). Patients were considered immunocom promised if they were HIV+, on immunosuppression drugs for transplantation, or undergoing chemotherapy. The numbers of each type of immunosuppressed patient were not recorded. All patients were treated in a head and neck oncology practice and consequently all had advanced stage (III & IV) disease as defined by primary tumor size ≥ 4 cm, deep invasion (beyond subQ fat or > 6 mm), bone erosion, PNI, or presence of nodal disease. For the surgical technique, a wide margin was marked around the tumor site. The extent of the tumor was based on palpation and visual inspection by the surgeon. The gross margin taken by the surgeon was not recorded

Table 1 Patient Demographics and Tumor Characteristics

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Fig. 1 The 5-year disease specific survival (68.8%) and recurrence free survival (51.0%) for all patients ( N =92)

Results A total of 232 patients were entered in the database. 92 (40%) of these had a recorded histologic margin distance. The remaining patients either had clear margins without distance recorded (45%) or no primary cancer remaining (15%). Demographic and tumor characteristics are sum marized in Table 1. Of the patients included in the study the average age was 69 and the majority of participants were male (85%) (Table 1). The overall 5-year disease spe cific survival and recurrence free survival was 68.8 and 51.0% respectively (Fig. 1). For patients with recorded margins the average margin distance was 3.6 mm. There was 55 patients with 0 – 2 mm margins (59%), 16 with 2-4 mm (17%), 6 with 4-6 mm (7%), 4 with 6-8 mm (4%), 6 with 8 – 10 mm margin (7%), and 4 with > 10 mm margins (4%). Patients were then divided into groups based on the distance of their closest margin (< 1 vs ≥ 1mm, <2 vs ≥ 2mm, … .. <5 vs ≥ 5 mm). Kaplan Meier survival analysis was then used to compare 5 year RFS and 5 year DSS between these groups for each margin threshold (Fig. 2). At a margin

distance of ≥ 5 mm we observed significantly improved DSS (94.7 vs 60.7 p = 0.034) and a non-significant trend towards improved RFS (62.4 vs 47.9% p =0.20). A Chi-square analysis did not show any significant correlation between margin distance and recurrent cancer, LVI, PNI, immunosuppression, and poorly differentiated CuSCC. Discussion There is a paucity of evidence regarding margin goals for resection of CuSCC. The findings of this study demonstrate that histologic margins of 5 mm or more may increase survival in patients undergoing WLE for advanced CuSCC of the head and neck. Examining histologic margins in CuSCC in relation to survival has not been examined before, however the results reflect the recommendations for oral mucosa SCC [6, 7]. As previously mentioned the NCCN guidelines recom mend a gross margin of 4 – 6 mm for CuSCC [5]. This was based on a single study by Brodland and Zitelli from 1992

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Fig. 2 Change in DSS and RFS as margin distance increases

studied either. One study did specifically examine margin shrinkage after Moh ’ s surgical excision and found a de crease in distance by 10% for head and neck specimens [10]. Also, it is known that there is roughly a 10 – 17% shrinkage of skin specimens after resection. Whether this rate of shrinkage can be applied to margin distance after WLE has not been assessed. This study used closest histologic margins, meaning that the distance reported by the pathologist after the

that used Mohs technique [4]. With Mohs technique the surgeon performs both gross and histologic assessment of the tumor at the time of resection. With WLE, surgeons rely on visual and tactile feedback in taking appropriate margins with selected use of frozen section. There have been no studies examining whether a 4 – 6 mm margin via WLE is equivalent to a 4 – 6 mm margin using Mohs. The relationship of the gross margin compared to the final histologic margin after WLE for CuSCC has not been

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guidelines suggest taking a “ larger margin ” for these patients, but do not specify how much larger [5]. The European guidelines suggests 10 mm, but this is based mainly on expert opinion [11]. It would be beneficial to try to determine an appropriate margin distance in this at-risk group of patients in order to guide management. In conclusion, this study suggests that a 5 mm or greater histologic margin may increase survival in head and neck CuSCC patients, which correlates with the recommendations for Oral SCC. Further prospective studies are required to provide appropriate guidelines for managing advanced or high risk CuSCC. Authors ’ contributions TJP- Author prepared the manuscript, aided in study design, updated the data base, and helped complete the data analysis. BNH-Designed the original database, input a large portion of data, and edited the final manuscript MGM-Editor of final manuscript, provided patient data for study, aided in study design. DGF- Editor of final manuscript, provided patient data for study, aided in study design. AFB- Editor of final manuscript, provided patient data for study, aided in study design, provided data analysis. All authors read and approved the final manuscript.

specimen underwent pathological processing. Histologic margin goals are not addressed by the NCCN for CuSCC and this is not a topic that has been previous studied. For mucosal disease an established histologic margin of 5 mm is the recommendation to ensure in creased disease survival and decreased locoregional recur rence [7]. The shrinkage rate of oral mucosal specimens have also been established, and having a 1 cm margin intraorally should allow for a 5 mm histologic margin [8]. Further prospective studies need to be performed to establish this relationship for CuSCC. A strength of this study is that it assessed CuSCC only of the head and neck. Establishing treatment recommen dations specific to the head and neck is important as a high proportion of skin cancers develop on the head and neck, and the anatomy and lymphatic drainage of the head and neck is unique. Also, given the functional and aesthetic importance of the head and neck, appropriate margin distance is paramount to minimizing the mor bidity of resection. This study also distinguishes itself as it examined ad vanced head and neck CuSCC. All the patients in the present study were considered advanced either due to size, location, recurrence, or locoregional metastatic spread. This study suggests that even with advanced disease, a > 5 mm histologic margin results in greater survival than a < 5 mm margin. Another limitation within the study is that only 40% of patients within the database had reported margins. This is possibly due to reporting standards changing for path ology. Therefore, it is possible that the 40% included in the study could not be a representative sample. One final point that was difficult to explain was why DSS was associated with margin distance but RFS was not. One would assume that patients who recur are more likely to die of their disease and as such they should be tightly associated. The correlation between the margin status and DSS may be stronger than with RFS because there was other prognostic factors that had a significant influence on RFS, which “ dilutes ” this correlation. There are multiple directions that future studies could take. A comparison of gross surgical margins, final histo logic margins and oncologic outcomes would certainly be informative. This would help to determine what gross margins are required to obtain a pathologic margin goal of 5 mm or more. There is hope that data from outside centers will eventually be added to the study to provide more robust data. Further work could also include examining high risk patients. These include immunocompromised patients such as transplant patients. This group of patients have a much higher risk of developing CuSCC, have more aggressive cancers, and worse outcomes. The NCCN

Funding No external funding was used to complete this study.

Availability of data and materials The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request. Ethics approval and consent to participate Ethics approval for this study was obtained from the UC Davis Ethics Board prior to the start of the study.

Consent for publication Consent for publication was not required for this study.

Competing interests The authors declare that they have no competing interests.

Received: 1 March 2019 Accepted: 21 September 2019

References 1. Garcia-Zuazaga J, Olbricht SM. Cutaneous Squamous Cell Carcinoma. Adv Dermatol. 2008;24:33 – 57. 2. Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol. 2016;17(5):491 – 508. 3. Breuninger H, et al. Brief S2k guidelines – Cutaneous squamous cell carcinoma. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2013;11(s3):37 – 45. 4. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. Journal of American Academic Dermatology. 1992;27(2 Pt 1):241 – 8. 5. NCCN clinical practice guidelines in oncology (NCCN Guidelines®) squamous cell skin cancer. 2018 11/08/2018. 6. Williams M. Determining adequate margins in head and neck cancers: practice and continued challenges. Curr Oncol Rep. 2016;18(9):1 – 7. 7. Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg. 1990;160(4):410 – 4. 8. Umstattd LA, et al. Shrinkage in oral squamous cell carcinoma: an analysis of tumor and margin measurements in vivo, post-resection, and post formalin fixation. Am J Otolaryngol. 2017;38(6):660 – 2. 9. Harris BN, et al. Factors associated with recurrence and regional Adenopathy for head and neck cutaneous squamous cell carcinoma. Otolaryngol Head Neck Surg. 2017;156(5):863 – 9.

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10. Gardner ES, Sumner WT, Cook JL. Predictable tissue shrinkage during frozen section Histopathologic processing for Mohs micrographic surgery. Dermatol Surg. 2001;27(9):813 – 8. 11. Stratigos A, et al. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51(14):1989 – 2007. Publisher ’ s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

HHS Public Access Author manuscript Cancer . Author manuscript; available in PMC 2023 May 16. Published in final edited form as: Cancer . 2021 December 01; 127(23): 4413–4420. doi:10.1002/cncr.33773.

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Elective Neck Dissection Versus Observation in Patients With Head and Neck Cutaneous Squamous Cell Carcinoma Moran Amit, MD, PhD 1 , Chuan Liu, MD 1 , Jobran Mansour, MD 1 , Frederico O. Gleber-Netto, DDS, PhD 1 , Samantha Tam, MD, MPH 2 , Erez N. Baruch, MD, PhD 3 , Mohamed Aashiq, MD 1 , Adel K. El-Naggar, MD 4 , Amy C. Moreno, MD 5 , David I. Rosenthal, MD 5 , Bonnie S. Glisson, MD 6 , Renata Ferrarotto, MD 6 , Michael K. Wong, MD 7 , Kenneth Tsai, MD 8 , Elsa R. Flores, PhD 9 , Michael R. Migden, MD 10 , Deborah A. Silverman, MS 1,7 , Goujun Li, MD, PhD 1 , Anshu Khanna, MPH 1 , Ryan P. Goepfert, MD 1 , Priyadharsini Nagarajan, MD, PhD 4 , Randal S. Weber, MD 1 , Jeffrey N. Myers, MD, PhD 1 , Neil D. Gross, MD 1 1 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 2 Department of Otolaryngology–Head and Neck Surgery, Henry Ford Health System and Henry Ford Cancer Institute, Detroit, Michigan Moran Amit: Concept; acquisition and performance of the analysis; drafting of the manuscript, tables, and figures; responsibility for the overall content; and review of the final document and approval for publication. Chuan Liu: Data acquisition and review of the final document and approval for publication. Jobran Mansour: Data acquisition and review of the final document and approval for publication. Frederico O. Gleber-Netto: Substantial contributions to the acquisition and performance of the analysis and review of the final document and approval for publication. Samantha Tam: Substantial contributions to the acquisition and performance of the analysis and review of the final document and approval for publication. Erez N. Baruch: Substantial contributions to the acquisition and performance of the analysis and review of the final document and approval for publication. Mohamed Aashiq: Concept and review of the final document and approval for publication. Adel K. El-N aggar: Concept and review of the final document and approval for publication. Amy C. Moreno: Concept and review of the final document and approval for publication. David I. Rosenthal: Concept and review of the final document and approval for publication. Bonnie S. Glisson: Concept and review of the final document and approval for publication. Renata Ferrarotto: Concept and review of the final document and approval for publication. Michael K. Wong: Concept and review of the final document and approval for publication. Michael R. Migden: Concept and review of the final document and approval for publication. Goujun Li: Concept and review of the final document and approval for publication. Anshu Khanna: Data acquisition and review of the final document and approval for publication. Ryan P. Goepfert: Concept and review of the final document and approval for publication. Priyadharsini Nagarajan: Data acquisition and review of the final document and approval for publication. Randal S. Weber: Concept and review of the final document and approval for publication. Jeffrey N. Myers: Concept and review of the final document and approval for publication. Neil D. Gross: Concept; drafting of the manuscript, tables, and figures; responsibility for the overall content; and review of the final document and approval for publication. Additional supporting information may be found in the online version of this article. CONFLICT OF INTEREST DISCLOSURES David I. Rosenthal reports participation on an advisory board for Merck. Renata Ferrarotto reports consulting fees from Bicara Therapeutics and payments or honoraria from Medscape and Intellisphere as well as participation on a data safety monitoring board or advisory board for Regeneron-Sanofi and Prelude Therapeutics. Kenneth Tsai reports consulting fees from Sanofi/Regeneron, Merck, Pfizer, Sun Pharma, and NFlection Therapeutics and stock or stock options in NFlection Therapeutics. Michael K. Wong reports participation on a data safety monitoring board or advisory board for Pfizer, EMD-Serono, Bristol-Myers Squibb, Regeneron, Adagene, Castle Biosciences, and Exicure and on an editorial board for CURE Magazine. Priyadharsini Nagarajan reports a leadership role in the American Society of Dermatopathology. Neil D. Gross reports clinical trial support from Regeneron; consulting fees from Sanofi-Genzyme; participation on advisory boards for Regeneron, PDS Biotechnology, and Shattuck Labs; and stock options in PDS Biotechnology. The other authors made no disclosures. Corresponding Authors: Moran Amit, MD, PhD, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 123, Houston, TX 77030 (mamit@mdanderson.org); Neil D. Gross, MD, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1445, Houston, TX 77030 (ngross@mdanderson.org). AUTHOR CONTRIBUTIONS

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3 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 5 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 6 Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 7 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 8 Department of Pathology, Moffitt Cancer Center, Tampa, Florida 9 Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida 10 Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas Abstract BACKGROUND: The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. METHODS: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. RESULTS: A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group ( P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3–4), those who underwent END did not have improved survival rates. CONCLUSIONS: Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.

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Keywords head and neck; lymph node; metastasis; neck dissection; skin; squamous cell carcinoma; survival

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INTRODUCTION

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Cutaneous squamous cell carcinoma (cSCC) most commonly occurs in the head and neck region. 1 The majority of newly diagnosed cSCCs are early-stage tumors that can be successfully cured with surgical excision. 2 However, a subset of cSCCs is associated with high-risk features such as poor histologic differentiation; greater depth of invasion (≥2 mm); perineural, vascular, or lymphatic invasion; and patient immunosuppression. These high-risk cSCCs carry an increased risk for local recurrence and regional metastasis. 2–6 Although the management of regional cSCC metastases to the parotid gland and neck with therapeutic nodal dissection and optional adjuvant radiotherapy—and, in selective cases, chemoradiotherapy—is widely accepted, the optimal management of high-risk, node negative head and neck cSCC remains controversial. 7,8 Depending on their age, morbidity, and clinical and pathologic risk factors, these patients may be managed by either a wait-and see approach (observation) or elective neck dissection (END). 7 Furthermore, the impact of occult nodal metastasis on survival in cSCC remains to be established. 9 In this study, we wanted to determine the effect of END on patient survival in clinically node-negative head and neck cSCC. Secondary aims were to determine the incidence of occult regional disease and regional disease control. On June 16, 2020, we searched the REDCap cSCC registry in the Department of Head and Neck Surgery of The University of Texas MD Anderson Cancer Center for patients with head and neck cSCC who had undergone primary surgery at our institution from 1995 to 2017. Inclusion criteria included no evidence of regional metastasis (cN0) on physical examination reports or imaging studies (ie, ultrasonography, computed tomography, positron emission tomography–computed tomography, or magnetic resonance imaging). 10 Patients with less than 6 months of follow-up were excluded unless an event (ie, disease-specific death or recurrence) was recorded within 6 months of surgery. Patients with prior neck regional dissection or radiotherapy were excluded. Staging was determined by physical examination, computed tomography, ultrasonography, magnetic resonance imaging, and/or positron emission tomography–computed tomography. All staging was completed according to the guidelines of the American Joint Committee on Cancer (8th edition). 11 All cases were presented at a multidisciplinary conference. Adjuvant radiotherapy with or without concurrent systemic therapy was administered to patients with T3–4 or N2–3 tumors, extranodal extension, involved margins, or perineural invasion. Indications for END were tumor extension to high-risk regions according to the National Comprehensive Cancer Network guidelines for cSCC (ie, central face, lips, preauricular and postauricular skin, temple, and ears), the presence of perineural or lymphovascular invasion on presurgical biopsy, and recurrence on presentation that required free flap reconstruction. 12 Univariate analysis followed by multivariate logistic regression analysis of patients undergoing END versus observation was used to confirm that in our cohort, a high-risk site ( P = .012) and recurrence on presentation ( P = .034) were significant determinants of neck management (Supporting Table 1). Observed cases were monitored with physical examination and neck

MATERIALS AND METHODS Patients

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computed tomography or ultrasonography every 1 to 3 months for year 1, every 2 to 4 months for year 2, and every 4 to 6 months for years 3 to 5.

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Histopathologic Analysis

Both primary and neck dissection specimens underwent a standard pathologic evaluation by a certified dermatopathologist or head and neck pathologist. Specimens were dissected and tissues were sampled as recommended by the guidelines for the histopathologic evaluation of head and neck carcinoma. 13

Statistical Analysis

We used the Kaplan-Meier method to calculate the rates of overall survival (OS; the time elapsed from the date of surgery to the date of death or censoring at last follow-up), disease-specific survival (DSS; the time elapsed from the date of diagnosis to death resulting from cSCC), disease-free survival (the time elapsed from the date of surgery to the first signs or symptoms of cSCC recurrence), and regional control (the time elapsed from the date of surgery to the first signs or symptoms of cSCC nodal recurrence). The log-rank test was used to assess the differences in survival and control rates. 14,15 The Cox proportional hazards regression model was used to compare the factors with prognostic potential. 16 We applied a process of several steps to develop a final model. The first step was to study the correlation between DSS or OS and each covariable via a univariable Cox proportional hazards regression model and then a preliminary multivariable Cox proportional hazards regression model. Thus, covariates with a univariable P value < .2 were included in the preliminary multivariable model. Variables that remained statistically significant ( P < .05) were included in the final multivariable model. A 2-step matching process was implemented. First, all eligible controls were matched according to their age, sex, and T classification. In the second step, we applied 1:1 propensity score matching with the Mahalanobis distance. The variables included in the propensity score matching were age, sex, ethnicity, recurrence status on presentation, immunosuppression status, and T classification. P < .05 was defined as significant, and 2-sided statistical tests were used in all calculations using JMP (version 14; SAS Institute, Inc, Cary, North Carolina). The study was approved by the institutional review board committees of MD Anderson Cancer Center. A total of 1582 patients were surgically treated consecutively for head and neck cSCC at our institution during the study period; 1111 of those patients presented with no evidence of nodal disease and were eligible for study inclusion (Fig. 1). One hundred seventy-three patients (16%) underwent END; 131 of these (12%) involved parotidectomy. The remaining 938 patients (84%) were managed with observation followed by therapeutic neck dissection at the time of regional recurrence. Patients’ demographic and clinical characteristics are summarized in Table 1. Of the 1111 patients included in this study, 952 (86%) were male, and 159 (14%) were female; the median age was 70 years (range, 19–97 years). The distribution of the patients according to ethnicity was as follows: White, 1055 (95%); Asian, 34 (3%); and Hispanic, African

RESULTS

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American, or other, 22 (2%). Chronic immunosuppression was present in 256 patients (23%), hematologic malignancies (eg, chronic lymphocytic leukemia) were present in 86 (8%), and organ transplantation was performed in 38 patients (3%). Advanced disease (T3–4) was more common in the patients who underwent END (58% vs 25%; P < .001). Fifty-four patients (31%) in the END group received adjuvant therapeutic dose irradiation to the lateral neck fields, whereas 47 (5%) did in the no-E ND group ( P < .001). Total radiation doses ranged from 50 to 70 Gy, with no difference in the mean doses (52 ± 1.24 and 52 ± 1.33 Gy in the END and no-END groups, respectively; P = .798). The 5-year OS rate was 52% for patients who underwent END and 63% for patients who did not ( P = .003 [log-rank]; Fig. 1). The 5-year DSS rate was 74% for patients who underwent END and 89% for patients who did not ( P < .001 [log-rank]; n = 1001 [the cause of death was not available for 110 patients]). At 5 years, the disease-free survival rates were similar in the END and observation groups (73% vs 75%; P = .429). Throughout the study period, there were 34 recurrences (14 of which were regional) and 97 deaths in the END group and 155 recurrences (49 of which were regional) and 282 deaths in the observation group. The 5-year regional recurrence rates did not differ between patients who underwent END (8%) and those who did not (5%; P = .138; Fig. 2). Notably, 41 of the 49 patients (84%) who developed regional recurrence after observation were treated with therapeutic neck dissection for their relapse; only 6 patients with regional recurrence treated with therapeutic neck dissection died of head and neck cSCC. The overall rate of occult nodal metastasis among patients who underwent END was 21% (36 of 173). A subgroup analysis of OS and DSS rates by nodal status in patients who underwent END revealed no differences between patients with and without occult metastases (Supporting Fig. 1). Because many more patients underwent observation (84%) rather than END, to control for a potential selection bias, we matched 298 patients (149 per group) for age, sex, ethnicity, recurrence status on presentation, immunosuppression status, and T classification. This internal validation method was chosen over others because matching techniques have been shown to produce stable and nearly unbiased estimates of predictive accuracy with increased power and decreased variability, regardless of the sample size. As shown in Supporting Figure 2, there were no differences in OS ( P = .754 [log-rank]) or DSS ( P = .192 [log-rank]) between the matched groups. The 5-year OS rate was 44% for patients with locally advanced disease (T3–4) who underwent END and 54% for those who did not undergo END ( P = .070 [log-rank]; Fig. 3); among patients with T1–2 tumors, the 5-year OS rate was 61% for those who had END and 66% for those who did not ( P = .431 [log-rank]). Interestingly, patients with early disease (T1–2) who did not have END had better 5-year DSS rates than those who had END (94% vs 78%; P < .001 [log-rank]). Among patients with locally advanced disease (T3–4), we found no difference in DSS ( P = .428). The variables that were introduced into the Cox regression model (n = 1111) were age, sex, immune-suppression status, recurrence status at presentation, margin status, T and N classification, presence/absence of neural invasion, treatment group (surgery, surgery and

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radiotherapy, or surgery and chemoradiation), and neck management (END vs observation). In the multivariate analysis, age, immunosuppression status, and presence/absence of neural invasion, but not neck management, were independently associated with both OS and DSS (Table 2).

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DISCUSSION

Most cSCCs present at an early stage, and data on the impact of nodal metastases on cSCC outcomes are scarce and insufficient to determine the optimal role of elective neck treatment. In mucosal head and neck squamous cell carcinoma (SCC), an END is generally indicated if the probability of occult cervical metastases is greater than 15% to 20%. 17 Our finding of a 20% rate of occult neck metastases in patients with cSCC would seem to support the performance of END in patients with cSCC as practiced in those with mucosal SCC. However, our data indicate a lack of a survival advantage in patients who had END compared with those who were observed. The low rate of regional recurrence in patients who were observed (49 of 938 [5%]) makes the overall occult incidence rate for this study much lower than the conventional threshold for END. This might explain the favorable neck control rates in our study and should be taken into consideration when one is contemplating management of the neck in cSCC. Furthermore, our subgroup analyses suggest that END did not improve survival rates, even for patients with advanced disease (T3–4). Interestingly, the regional recurrence rate in the observation group was lower than the rate of occult nodal metastasis in the END group. This patient population is generally older, and it is possible that patients with occult nodal metastasis are lost to follow-up because of a non– cancer-related death before the clinical presentation of regional recurrence. Although this might suggest a selection bias associated with the decision of whether to perform END, it also highlights the potentially modest impact that END has in this patient population. This should be further evaluated prospectively. Still, regardless of the patient characteristics or clinical reasons that led to the performance of END, regional recurrence was not different between the END and observation groups, and most patients in the observation group who had a regional recurrence were successfully treated with salvage therapeutic neck dissection. The less prominent survival advantage of END in cSCC versus mucosal SCC may be due to the older age of cSCC patients (median age, 70 vs 55 years) and the higher rates of immunosuppressive comorbidities (eg, insulin-dependent diabetes mellitus and hematologic malignancies). This is further demonstrated by the relatively low rate of cancer-related death after 5 years among patients who did not have END (11%) in comparison with the overall death rate (37%). Also, our multivariate regression analysis identified only age, immunosuppression status, and the presence/absence of neural invasion, rather than the systemic treatment regimen (ie, adjuvant chemotherapy), as independent determinants of both OS and DSS. This is consistent with our hypothesis that patient factors, rather that tumor pathologic features (especially nodal metastasis), are associated with survival, and it is supported by previous data also showing that immunosuppression is a predictor of both outcomes and rates of nodal metastasis in cSCC. 18,19

This study has several limitations. Treatment was not assigned in a randomized fashion; this might suggest underlying issues that resulted in worse prognoses for patients who had END.

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That said, our multivariate analysis revealed that adjuvant radiotherapy was associated with a significantly lower risk of death of any cause ( P = .004) and a marginally significantly lower risk of cancer-specific death ( P = .08). These findings, together with previous reports with a higher rate of occult regional metastasis and the potential survival benefit with neck radiation in patients with cSCC, suggest that adjuvant radiation might be beneficial and should be considered in these patients. 20,21 Although it is not possible to disentangle these patient factors from the “direct” effect of END, our propensity score–based matching validation showed no survival benefit for patients who had END, even among patients with advanced disease. Although our finding of significantly higher DSS rates in patients with early disease (T1–2) who did not have END in comparison with those who had END suggests that deaths in this patient population might be related to preexisting or procedure-associated morbidities, the study design precluded us from concluding that. We found higher rates of advanced and recurrent disease in the END group, yet our multivariate regression analysis did not identify these factors as potential causes of the difference in survival rates. The study spans over 25 years, and although treatment trends have changed during this period of time, we present a standardized approach practiced by our multidisciplinary team. Furthermore, no evidence of heterogeneity between time periods (1995–2009 and 2010–2 019) was noted. It is important to note that most patients were closely monitored for regional recurrence by physical examination and ultrasonography or computed tomography in the first 2 years after their surgery. Hence, the feasibility of neck surveillance and salvage surgery in case of recurrence should be considered when one is deciding whether or not to perform an END. Taken together, these findings support further evaluation of less extensive surgical approaches (eg, sentinel lymph node biopsy for high-risk T1 patients or any T2 patient) or observation of the regional lymphatics in patients who are clinically node negative, even those with advanced or recurrent disease at the primary site. Although this was a large study and there was internal validation by matching, a prospective clinical trial is needed to fully assess the role of END in cSCC. Until then, the regional treatment of patients with cSCC should be based on risk stratification and multidisciplinary input.

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Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

FUNDING SUPPORT

Moran Amit’s work is supported by the Disruptive Science Grant of the Moon Shot Program (MD Anderson Cancer Center) and NIH/NCI R37 CA242006-01A1. Deborah A. Silverman reports support from the Dr. John J. Kopchick Fellowship, the National Institutes of Health/National Cancer Institute (F30CA228258), and the American Legion Auxiliary Fellowship for Cancer Research.

We thank Dawn Chalaire, associate director of the Research Medical Library at The University of Texas MD Anderson Cancer Center, for editing this manuscript.

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REFERENCES

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Figure 1. Patient population and Kaplan-Meier analysis. (A) Consolidated Standards of Reporting Trials flowchart of the study population. (B) Five-year OS and (C) DSS calculated by the Kaplan-Meier method according to the neck management status. cSCC indicates cutaneous squamous cell carcinoma; DSS, disease-specific survival; END, elective neck dissection; OS, overall survival.

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Figure 2. Kaplan-Meier analysis. (A) Five-year RR and (B) DFS calculated by the Kaplan-Meier method according to the neck management status. DFS indicates disease-free survival; RR, regional recurrence.

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Figure 3. Kaplan-Meier analysis. Five-year OS of patients with (A) early (T1–2) and (C) advanced (T3–4) head and neck cutaneous squamous cell carcinoma and 5-year DSS of patients with (B) early (T1–2 ) and (D) advanced (T3–4) head and neck cutaneous squamous cell carcinoma calculated by the Kaplan-Meier method according to the neck management status. AJCC indicates American Joint Committee on Cancer; DSS, disease-specific survival; OS, overall survival.

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Author Manuscript Author Manuscript Author Manuscript Author Manuscript TABLE 1.

Patient Demographic and Clinical Characteristics Variable Elective Neck Dissection No Neck Dissection P No. of patients (%) 173 (16) 938 (84) Recurrence on presentation, No. (%) 90 (52) 257 (27) <.001 Age, mean ± SD, y 69 ± 11 70 ± 12 .732 Sex, No. (%) .365 Male 152 (88) 800 (85) Female 21 (12) 138 (15) Immunosuppression, No. (%) .826 None 134 (77) 714 (77) IDDM 21 (12) 74 (8) Hem/Onc 4 (2) 82 (9) Organ transplant 8 (5) 39 (3) Steroid use 4 (2) 20 (2) AID 1 (<1) 15 (2)

Lateral neck irradiation: yes, No. (%) 54 (31) 47 (5) <.001 Adjuvant chemotherapy: yes, No. (%) 36 (21) 34 (4) <.001 Follow-up, median (range), mo 26 (6–217) 24 (2–254) .7518 Abbreviations: AID, autoimmune disease; Hem/Onc, hematologic/oncologic; IDDM, insulin-dependent diabetes mellitus; N/A, not applicable.

Pathologic T classification, No. (%) <.001 T1 36 (21) 607 (65) T2 37 (21) 101 (11) T3 75 (43) 183 (19) T4 25 (15) 47 (5)

Pathologic N classification, No. (%) N/A N0 137 (79) N1 17 (10) N2 9 (5) N3 10 (6)

HIV/AIDS 0 (0) 3 (<1) Other 4 (2) 19 (2)

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