Original Article. KEYWORDS: head and neck cancer, lymph nodes, oral cancer, oropharyngeal cancer, squamous cell carcinoma, staging.

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1 Original Article Number of Positive Nodes Is Superior to the Lymph Node Ratio and American Joint Committee on Cancer N Staging for the Prognosis of Surgically Treated Head and Neck Squamous Cell Carcinomas Thomas J. Roberts, BA 1 ; A. Dimitrios Colevas, MD 2 ; Wendy Hara, MD 3 ; F. Christopher Holsinger, MD 1 ; Ingrid Oakley-Girvan, PhD, MPH 4,5,6,7 ; and Vasu Divi, MD 1,7 BACKGROUND: Recent changes in head and neck cancer epidemiology have created a need for improved lymph node prognostics. This article compares the prognostic value of the number of positive nodes (pn) with the value of the lymph node ratio (LNR) and American Joint Committee on Cancer (AJCC) N staging in surgical patients. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify cases of head and neck squamous cell carcinomas from 2004 to The sample was grouped by the AJCC N stage, LNR, and pn and was analyzed with Kaplan-Meier and multivariate Cox proportional hazards models. The sample was also analyzed by the site of the primary tumor. RESULTS: This study identified 12,437 patients. Kaplan-Meier survival curves showed superior prognostic ability for LNR and pn staging in comparison with AJCC staging. Patients with a pn value > 5 had the worst overall survival (5-year survival rate, 16%). Patients with oropharyngeal tumors had better outcomes for all groupings, and a pn value > 5 for oropharyngeal cancers was associated with decreased survival. Multivariate regressions demonstrated larger hazard ratios (HRs) and a lower Akaike information criterion for the pn model versus the AJCC stage and LNR models. The HRs were 1.78 (95% confidence interval, ) for a pn value of 1, 2.53 (95% confidence interval, ) for a pn value of 2 to 5, and 4.64 (95% confidence interval, ) for a pn value > 5. CONCLUSIONS: The pn models demonstrated superior prognostic value in comparison with the LNR and AJCC N staging. Future modifications of the nodal staging system should be based on the pn with a separate system for oropharyngeal cancers. Future trials should consider examining adjuvant treatment escalation in patients with >5 lymph nodes. Cancer 2016;122: VC 2016 American Cancer Society. KEYWORDS: head and neck cancer, lymph nodes, oral cancer, oropharyngeal cancer, squamous cell carcinoma, staging. INTRODUCTION Cancer staging is an important process that helps physicians, patients, and researchers communicate clearly about disease status, prognosis, and treatment options. The most commonly used staging system for head and neck cancer is the American Joint Committee on Cancer (AJCC) system, which stages patients on the basis of TNM staging. AJCC N staging is uniform for all mucosal head and neck cancers except for nasopharyngeal cancers and melanomas (Fig. 1). It combines information about the number, size, and laterality of positive nodes into an aggregate measure of nodal disease. 1 Lymph node involvement is well established as an important prognostic factor for head and neck cancer, with the presence of even 1 positive lymph node being associated with as much as a 50% reduction in overall survival. 2 Because of the evolving epidemiology of head and neck cancer, most notably the rise of human papillomavirus (HPV) associated cancers, there is considerable interest in developing improved lymph node based prognostics. Recent literature has suggested that the lymph node ratio (LNR) may be superior to the AJCC N stage for estimating a prognosis on the basis of nodal disease. 3-6 LNR is calculated as the number of pathologically positive lymph nodes divided by the total number of lymph nodes pathologically examined. This metric is felt by some to be a better measurement of prognosis because it combines information about the burden of regionally metastatic disease and the extent of the neck dissection and thus addresses the role of neck dissection as both therapeutic and diagnostic. 7,8 Corresponding author: Vasu Divi, MD, Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, 801 Welch Road, Stanford, CA 94305; Fax: (650) ; vdivi@stanford.edu 1 Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, California; 2 Department of Medicine Oncology, Stanford University School of Medicine, Stanford, California; 3 Department of Radiation Oncology Radiation Therapy, Stanford University School of Medicine, Stanford, California; 4 Cancer Prevention Institute of California, Fremont, California; 5 Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; 6 Canary Center at Stanford for Cancer Early Detection, Stanford, California; 7 Stanford Cancer Institute, Stanford, California DOI: /cncr.29932, Received: November 10, 2015; Revised: January 22, 2016; Accepted: January 26, 2016, Published online March 11, 2016 in Wiley Online Library (wileyonlinelibrary.com) 1388 Cancer May 1, 2016

2 Lymph Node Prognostics for HNSCC/Roberts et al Figure 1. American Joint Committee on Cancer N staging (seventh edition) for cancers of the oropharynx, larynx, oral cavity, and hypopharynx. LN indicates lymph node. However, the relationship between nodal yield and overall survival is not linear. At low lymph node yields, there is likely an increase in survival associated with greater numbers of lymph nodes examined, presumably because of degrees of suboptimal treatment of neck disease. At higher nodal yields, increasing nodal yield does not appear to continue to improve outcomes. 9,10 At nodal yields greater than 32 nodes, Ebrahimi et al 11 found an inverse relationship between nodal yield and survival, presumably because of increasingly aggressive dissections planned for more concerning primary tumors. This nonlinear relationship may attenuate the prognostic value of the LNR. In addition, the contribution of the nodal yield to the LNR has been shown to vary because of factors unrelated to the extent of the neck dissection, further questioning the contribution of the nodal yield to the prognostic ability of the LNR. 12 There is little published research looking at the prognostic value of the number of positive nodes (pn), a term used to describe the number of pathologically positive lymph nodes identified after neck dissection. This metric does not incorporate the nodal yield and, therefore, may be of greater prognostic significance. Here we compare the prognostic value of pn, LNR, and AJCC N staging for head and neck cancers to determine the optimal metric for cancer staging. MATERIALS AND METHODS The Surveillance, Epidemiology, and End Results (SEER) program was started by the National Cancer Institute in The program collects and publishes information on cancer incidence and survival from population-based registries across the United States. Collectively, these registries cover 28% of the US population. 13 The November 2014 release of SEER data was used for this analysis. This analysis was restricted to incident cases from 2004 to The inclusion criteria included histologically confirmed cases of squamous cell carcinoma from the following primary tumor sites: oral cavity, oropharynx, hypopharynx, and larynx. Only cases with upfront surgical resection of the primary tumor and regional lymph node surgery were included. Additional inclusion criteria included reporting sources with unified medical records and records meeting AJCC criteria for the pathological staging of nodes. We excluded patients who had fewer than 10 lymph nodes examined, had distant metastases at the time of diagnosis, were diagnosed at autopsy only, and had incomplete information for the variables included in the analysis. LNR groups were defined as 0%, 0% to 6%, 6% to 12.5%, and 12.5% on the basis of prior literature. 3 Maximally selected rank statistics, as described by Lausen and Schumacher, 14 were used to select the optimal cut points to create the pn groups. For AJCC N staging, AJCC sixth edition definitions were used as derived in the SEER database on the basis of the Collaborative Stage site-specific schema. AJCC sixth edition definitions for nodal staging do not differ from AJCC seventh edition definitions. 1 Covariates were selected on the basis of the strength of prior evidence linking covariates with the dependent variable, and Pearson s correlation and chi-square tests were used to assess for multicollinearity. Covariates included sex, age at diagnosis, year of diagnosis, AJCC T stage, site of the primary tumor, race, whether the patient received radiation, and marital status at diagnosis. Extracapsular extension was not included as a potential covariate in this study because documentation from the Collaborative Stage Data Collection System indicated that this variable was obsolete in the November 2014 release. 15 The HPV status was not included as a covariate because HPV information was not released in the November 2014 release. The SEER database does not include information about chemotherapy administration, smoking status, or alcohol consumption, so these potential covariates could not be included in this analysis. The data were analyzed with Kaplan-Meier survival analysis, with the interval of analysis defined as the time from diagnosis to 60 months after diagnosis. The effects of covariates were assessed with Cox proportional hazards models; the outcome of interest was overall survival, and the interval of analysis was defined as the time from diagnosis to 60 months after diagnosis. The reference groups were defined as a pn value of 0, an LNR of 0%, and AJCC stage N0. The Cox proportional hazards models Cancer May 1,

3 Original Article TABLE 1. Demographic Characteristics of the Study Population for Categorical Variables Age, mean, y 60 Year of diagnosis, mean 2008 AJCC T stage, No. (%) T (31) T (32) T (14) T (23) AJCC TNM stage, No. (%) I 1972 (16) II 1630 (13) III 2598 (21) IVa 5830 (47) IVb 407 (3) Sex, No. (%) Male 8841 (71) Female 3596 (29) Race, No. (%) White, non-hispanic 9633 (77) White, Hispanic 906 (7) Black 1109 (9) Native American 78 (1) Asian 711 (6) Marital status, No. (%) Single (never married) 2263 (18) Married 6789 (55) Divorced/widowed 2828 (23) Unknown 557 (4) Tumor site, No. (%) Oral cavity 7165 (58) Oropharynx 3037 (24) Larynx 1880 (15) Hypopharynx 355 (3) Radiation, No. (%) Yes 7567 (61) No 4870 (39) Abbreviation: AJCC, American Joint Committee on Cancer. Figure 2. Flow chart illustrating how the inclusion and exclusion criteria were applied to achieve the final sample included in the analysis. AJCC indicates American Joint Committee on Cancer. 16 were then compared with the Akaike information criterion to assess their relative predictive quality. Statistical analyses were performed with Stata statistical software (version 13.1) and R (version 3.2.1). The code is available upon request. RESULTS Data We identified a total of 101,854 records in the SEER database for patients with head and neck cancer diagnosed between 2004 and Figure 2 shows how the exclusion criteria were applied to achieve a final cohort of 12,437. Of the records initially identified, 24% underwent upfront surgical treatment with subsequent pathological analysis of lymph nodes. The demographic characteristics of the study sample are shown in Table 1. Seventy-one percent of the patients were male, and 77% were white; 7040 patients (57%) had at least 1 pathologically confirmed positive lymph node. The 5-year survival rate for the study population was 56%. With maximally selected rank statistics, 2 cut points were identified to divide patients into risk-stratified groups according to their pn. 14 Patients with 1 positive node were found to be at the lowest risk, and patients with more than 5 positive nodes were found to be at the highest risk. Thus, the pn groups were defined as follows: 1 positive node, 2 to 5 positive nodes, and >5 positive nodes. Table 2 shows the patients divided by nodal staging with the AJCC N stage, pn, and LNR methods Cancer May 1, 2016

4 Lymph Node Prognostics for HNSCC/Roberts et al TABLE 2. Nodal Groupings Within the Study Sample AJCC N stage, No. (%) N (42) N (20) N2a 693 (6) N2b 2917 (23) N2c 844 (7) N3 218 (2) Number of positive nodes, No. (%) (57) (20) (27) (9) Lymph node ratio, No. (%) 0% 5397 (43) 0%-6% 3052 (25) 6%-12.5% 2037 (16) 12.5% 1951 (16) Abbreviation: AJCC, American Joint Committee on Cancer. Kaplan-Meier Analysis The Kaplan-Meier survival curves for overall survival based on the AJCC N stage, pn, and LNR are shown in Figure 3. The superior prognostic values of the pn and LNR are indicated by the clear pattern of worsening outcomes with higher groupings. The AJCC N stage plot does not show a clear pattern. N2a carcinomas have a curve similar to the curve for N0 cancers with 5-year survival rates of 68% and 66%, respectively, and N2c, rather than N3, is associated with the worst outcomes (5-year survival rate, 29%). Across all 3 plots, the survival curve for pn group 3 (>5 positive nodes) was most strongly associated with poor outcomes with a 5-year survival rate of 28%. When we analyzed the curves for the current AJCC system by separating out oropharyngeal cancers, it was apparent that the favorable outcomes for the N2a group were driven by different patterns for tumors of the oropharynx. N2a tumors were associated with better outcomes than other N stages in oropharyngeal tumors (Fig. 4A). In the oropharynx, bilateral disease (N2c) appeared to be a significant negative prognostic factor, with all other node-positive categories (N1, N2b, and N3) following similar patterns with 5-year survival rates of approximately 70%. For tumors outside the oropharynx, AJCC N staging showed a decrease in survival between N0, N1, and N2 patients (Fig. 4B). N2a, N2b, and N3 demonstrated similar survival with 5-year survival rates of 35%, 32%, and 43%, respectively, and N2c was associated with the worst outcomes with a 5-year survival rate of 23%. pn and LNR demonstrated worsening outcomes with each increasing group for nonoropharyngeal tumors (Fig. 4D,F). More than 5 positive nodes were strongly associated with the worst outcomes with a 5-year survival rate of 15%. Figure 3. Kaplan-Meier survival plots of overall survival based on (A) the AJCC N stage, (B) the number of positive nodes, and (C) the lymph node ratio. AJCC indicates American Joint Committee on Cancer. LNRs greater than 12.5% were also associated with poor outcomes for nonoropharyngeal tumors (5-year survival rate, 22%) but not to the same extent as more than 5 nodes. Oropharyngeal tumors were associated with much more favorable outcomes than nonoropharyngeal tumors for all groupings in all 3 staging systems (Fig. 4). LNRs greater than 12.5% were associated with decreased Cancer May 1,

5 Original Article Figure 4. Kaplan-Meier survival plots for overall survival broken down by the site of the primary tumor for (A,B) AJCC N staging, (C,D) the number of positive nodes, and (E,F) the lymph node ratio. Cases are broken down by tumors of the oropharynx and tumors of other sites (larynx, oral cavity, and hypopharynx). AJCC indicates American Joint Committee on Cancer. mortality in comparison with other LNR groupings (5- year survival rate, 60%), but more than 5 positive nodes in the pn system were again most strongly associated with decreased survival with a 5-year survival rate of 53%. When the Kaplan-Meier survival analyses were repeated for tumors grouped by 3 sites (oral cavity, oropharynx, and larynx/hypopharynx), it was found that there was no significant variation between the survival curves and 5-year survival rates for tumors of the oral cavity and the larynx/hypopharynx (Table 3). To assess the effect of the pn groupings on overall TNM staging, a modified TNM staging system was developed in which N0 was defined as a pn value of 0, N1 was defined as a pn value of 1, N2 was defined as a pn value 1392 Cancer May 1, 2016

6 Lymph Node Prognostics for HNSCC/Roberts et al TABLE 3. Five-Year Survival Rates by the Tumor Site Oropharynx Oral Cavity Larynx/Hypopharynx AJCC N Stage N ( ) 0.66 ( ) 0.64 ( ) N ( ) 0.46 ( ) 0.45 ( ) N2a 0.83 ( ) 0.35 ( ) 0.38 ( ) N2b 0.71 ( ) 0.32 ( ) 0.35 ( ) N2c 0.49 ( ) 0.23 ( ) 0.26 ( ) N ( ) 0.43 ( ) 0.34 ( ) pn ( ) 0.66 ( ) 0.63 ( ) ( ) 0.48 ( ) 0.45 ( ) ( ) 0.36 ( ) 0.39 ( ) > ( ) 0.15 ( ) 0.19 ( ) LNR 0% 0.70 ( ) 0.66 ( ) 0.63 ( ) 0%-6% 0.78 ( ) 0.47 ( ) 0.46 ( ) 6%-12.5% 0.75 ( ) 0.38 ( ) 0.35 ( ) 12.5% 0.60 ( ) 0.22 ( ) 0.24 ( ) Abbreviations: AJCC, American Joint Committee on Cancer; LNR, lymph node ratio; pn, number of positive nodes. Ninety-five percent confidence intervals are listed in parentheses. of 2 to 4, and N3 was defined as a pn value 5. Records were assigned a modified TNM stage by direct substitution of the new N stages into the AJCC TNM staging schema. 1 A Kaplan-Meier survival analysis comparing the current AJCC system with a modified system showed the differences across oropharyngeal and nonoropharyngeal disease (Fig. 5). The modified system showed differences in oropharyngeal patients with stage 4 disease. Multivariate Analysis In multivariate analyses using Cox proportional hazards models, the AJCC N stage, pn, and LNR were all found to be prognostic for overall survival. Table 4 summarizes the results. Stages N2b and N2c were associated with the worst outcomes of the AJCC N stages with hazard ratios (HRs) of 2.79 (95% confidence interval [CI], ) and 3.38 (95% CI, ), respectively. For pn and LNR, values greater than 5 and 12.5% had the largest HRs of 4.41 (95% CI, ) and 3.60 (95% CI, ), respectively. The 95% confidence intervals did not overlap, indicating pn value > 5 was associated with significantly worse outcomes than an LNR > 12.5%. When we compared the models (Table 4), we found that the Akaike information criterion was lowest for the pn model; this indicates that among the 3 models analyzed, this model was the best fit for the data. When a Cox proportional hazards model was run with both LNR and pn groups included as independent variables, the HRs for pn remained statistically significant for the 3 groups (group 1, 2.50 [95% CI, ]; group 2, 3.00 [95% CI, ]; group 3, 4.77 [95% CI, ]), and the prognostic value for all 3 LNR groups was lost, with the confidence intervals crossing 1.0 for all HRs. DISCUSSION This study has analyzed the prognostic value of pn, LNR, and AJCC N staging with the SEER database. We have demonstrated that the pn is a better prognostic system for grouping patients than the current AJCC system for pathologically staged patients. This appears true for both oropharyngeal and nonoropharyngeal tumors. The pn staging system also appears superior to LNR staging for all tumor sites analyzed. This study highlights the lack of prognostic stratification in the current AJCC N staging and proposes methods to improve it, particularly for oropharyngeal carcinoma. Our study is the first effort to compare pn, LNR, and AJCC N staging side by side with a large study population, and the results suggest that the pn has the strongest prognostic value for head and neck cancers. The evidence presented here indicates that the pn may serve as a better basis for an alternative staging system than the LNR. The previously documented uncertainties about the reliability of the nodal yield appear to reduce the prognostic value of the LNR, as hypothesized in this study. 11,12 The purpose of a staging system is to group patients into similar categories of survival and potentially identify patients who would be better candidates for treatment intensification. A staging system should propose the simplest model that accurately captures the necessary prognostic information. The pn appears to provide superior prognostic information and better guidance for clinical Cancer May 1,

7 Original Article Figure 5. Kaplan-Meier survival plots for overall survival by AJCC staging for (A) oropharyngeal and (B) nonoropharyngeal subsites and Kaplan-Meier survival plots for the modified staging system for (C) oropharyngeal and (D) nonoropharyngeal subsites. The modified staging system assumes that N0 is equal to 0 positive nodes, N1 is equal to 1 positive node, N2 is equal to 2 to 5 positive nodes, and N3 is equal to greater than 5 positive nodes. AJCC indicates American Joint Committee on Cancer. decisions within a simpler metric. In addition, the improved outcomes for oropharyngeal tumors versus nonoropharyngeal tumors is consistent with recent literature indicating a rising prevalence of HPV-associated oropharyngeal tumors and improved outcomes for patients with these tumors. 17,18 This finding illustrates the need for an updated head and neck cancer staging system that includes site-specific staging. The use of pathological data for nodal staging limits our analysis to patients who underwent upfront surgery. Without pathological staging, we would not be able to ascertain the LNRs in the SEER database. Therefore, all patients who were included in this study needed to have surgical treatment of the neck and formal pathological staging. To adequately assess this alternative nodal staging system for clinically staged patients, we would need to evaluate a data set that contained information on the pn based on imaging. This is an appropriate goal for future research but would require collecting data at the institutional level. This selection bias is relevant because many patients are currently treated with nonsurgical therapy, and their staging is based on imaging and clinical staging alone. Clinical staging tends to understage patients because positive nodes that are not detected on imaging are not counted Although the prognostic differences between our different categories may not be as large in clinically staged patients because of underestimation of disease burden, the overall trend appears more consistent than the current system. Our results also highlight important trends and differences that distinguish the oropharynx from other subsites. The finding that patients with >5 nodes in all subsites showed markedly decreased survival is particularly clinically significant. Prior clinical trials that have examined the use of postoperative chemotherapy used 2 or more lymph nodes to group patients into higher and lower risk groups. 22,23 Our data suggest that although patients with 2 or more involved lymph nodes do have worse survival, the difference, consistent with other recent 1394 Cancer May 1, 2016

8 Lymph Node Prognostics for HNSCC/Roberts et al TABLE 4. Multivariate Regression Outputs Showing Hazard Ratios for the AJCC N Stage, pn, and LNR Groups and Included Covariates AJCC N Stage pn LNR Nodal group N ( ) ( ) 0%-6% 1.77 ( ) N2a 2.00 ( ) ( ) 6%-12.5% 2.44 ( ) N2b 2.79 ( ) > ( ) 12.5% 3.60 ( ) N2c 3.38 ( ) N ( ) Age at diagnosis, y 1.03 ( ) 1.02 ( ) 1.02 ( ) Year of diagnosis 0.98 ( ) 0.98 ( ) 0.99 ( ) T stage (reference 5 T1) T ( ) 1.57 ( ) 1.59 ( ) T ( ) 2.52 ( ) 2.59 ( ) T ( ) 2.56 ( ) 2.66 ( ) Sex: female (reference 5 male) 0.95 ( ) 0.96 ( ) 0.95 ( ) Radiation: not received (reference 5 received) 1.35 ( ) 1.34 ( ) 1.35 ( ) Marital status (reference 5 single) Married 0.75 ( ) 0.76 ( ) 0.76 ( ) Divorced/widowed 0.95 ( ) 0.94 ( ) 0.93 ( ) Unknown 0.79 ( ) 0.77 ( ) 0.78 ( ) Race (reference 5 white) Hispanic 1.11 ( ) 1.08 ( ) 1.05 ( ) Black 1.19 ( ) 1.18 ( ) 1.21 ( ) Native American 1.35 ( ) 1.34 ( ) 1.36 ( ) Asian 1.05 ( ) 1.06 ( ) 1.05 ( ) Site of primary tumor (reference 5 oral cavity) Oropharynx 0.46 ( ) 0.45 ( ) 0.45 ( ) Larynx 0.68 ( ) 0.68 ( ) 0.70 ( ) Hypopharynx 0.78 ( ) 0.75 ( ) 0.76 ( ) Akaike information criterion 71,240 70,924 70,950 Abbreviations: AJCC, American Joint Committee on Cancer; LNR, lymph node ratio; pn, number of positive nodes. Ninety-five percent confidence intervals are listed in parentheses. The reference groups for the lymph node groups were N0 for the AJCC N stage, 0 for pn, and 0% for LNR. findings, is most pronounced with >5 lymph nodes involved. 24 Future trials should consider examining treatment escalation in patients with >5 lymph nodes. In addition, for patients with oropharyngeal cancer, the lack of change in survival with up to 5 positive lymph nodes suggests that these patients should be separately evaluated for possible de-intensification protocols, which are currently ongoing. The current AJCC system highlights the prognostic importance of bilateral neck disease, particularly in the oropharynx. At all subsites, N2c patients had the worst prognosis, with 50% 5-year survival for oropharyngeal disease. Unfortunately, the data in the SEER database are not adequate for combining laterality with the pn or LNR to create a combined measure. On the basis of our findings, it is possible that combining the pn and the laterality of neck disease could create a new optimal prognostic system for the oropharynx. Adding a modification of the nodal staging system provides a small improvement to the prognostic ability of the overall TNM stage for oropharyngeal carcinoma. In particular, it separates stage 4 patients from stage 1 to 3 patients. The current AJCC system demonstrates minimal separation of the survival curves, and this suggests that the nodal status is particularly important in prognostics for oropharyngeal carcinoma. This study has several limitations that provide opportunities for future research. The primary study limitations are the quality of the SEER data and the availability of selected variables in the SEER database. The broader limitations of the SEER database have been discussed in detail elsewhere. 25 Particular to head and neck cancers, the inability to use variables describing extracapsular extension, chemotherapy, HPV status, smoking, and alcohol consumption (variables of known prognostic significance) limits the interpretability of these results. 26,27 In addition, the structure of the SEER data prevented the incorporation of data on the laterality of nodal metastases, another important prognostic indicator. However, we felt that the large study sample and numerous covariates available in the SEER data outweighed these limitations and created a strong opportunity to explore the research question. Cancer May 1,

9 Original Article The HPV status and extracapsular extension are both important tumor factors that have a significant impact on a patient s overall survival. Because of the historical survival rates for non HPV-related oropharyngeal cancer, the superior survival outcomes in this data set and the differences in survival based on the nodal status suggest that a substantial fraction of patients from 2004 to 2012 were HPV-positive. We presume that the findings related to the nodal prognosis predominantly pertain to HPV-positive patients, although we would need to perform further studies to isolate the effect of HPV on the staging system. This will be particularly relevant if the HPV status is used to create a separate staging system. The presence of extracapsular extension may be a confounder in our data set if the presence of extracapsular extension correlates with increasing pn. The prognosis of higher numbers of positive nodes (>5) may be due to higher rates of extracapsular extension, which could explain a part of the survival difference. We strongly advocate for accurate collection of these 2 important variables by cancer registries to help in making appropriate adjustments for these important variables in future studies. The pn models demonstrated superior prognostic value in comparison with the LNR and AJCC N staging in the overall study sample and the site-specific analyses. Patients with more than 5 positive nodes had significantly worse survival at all subsites. Future research opportunities seeking to validate these results in clinically staged patients and other study samples (particularly samples including data on extracapsular extension, the HPV status, and the laterality of nodal metastases) will provide further evidence to guide efforts to develop a new nodal staging system. FUNDING SUPPORT Ingrid Oakley-Girvan reports pilot funds to conduct Surveillance, Epidemiology, and End Results Medicare analyses and prepare manuscripts from Stanford University during the conduct of the study. Vasu Divi reports pilot funds as a recipient of a 2013 Stanford Cancer Institute-Developmental Cancer Research Award (DCRA) grant. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. AUTHOR CONTRIBUTIONS Thomas J. Roberts: Conceptualization, methodology, software, validation, formal analysis, investigation, writing original draft, writing review and editing, visualization, and project administration. A. Dimitrios Colevas: Conceptualization, methodology, investigation, writing review and editing, and visualization. Wendy Hara: Writing review and editing. F. Christopher Holsinger: Conceptualization, validation, writing original draft, and writing review and editing. Ingrid Oakley-Girvan: Methodology and writing original draft. 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