Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases

Ardalan Ebrahimi; Ruta Gupta; Lachlan McDowell; Matthew J R Magarey; Paul N Smith; Klaus-Martin Schulte; Diana M Perriman; Michael Veness; Sandro Porceddu; Tsu-Hui Hubert Low; Allan Fowler; Jonathan R Clark

doi:10.1001/jamaoto.2024.3103

. 2024 Sep 26;150(11):986–994. doi: 10.1001/jamaoto.2024.3103

Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases

Ardalan Ebrahimi ^1,^2,^3,^✉, Ruta Gupta ^4,⁵, Lachlan McDowell ^6,⁷, Matthew J R Magarey ^8,⁹, Paul N Smith ¹, Klaus-Martin Schulte ¹, Diana M Perriman ¹, Michael Veness ^5,¹⁰, Sandro Porceddu ^11,¹², Tsu-Hui Hubert Low ^2,⁵, Allan Fowler ¹³, Jonathan R Clark ^2,⁵

¹Medical School, College of Health and Medicine, Australian National University, Canberra, Australian Capital Territory, Australia

²Department of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Sydney, New South Wales, Australia

³Department of Head and Neck Surgery, The Canberra Hospital, Canberra, Australian Capital Territory, Australia

⁴Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

⁵University of Sydney, Sydney, New South Wales, Australia

⁶Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

⁷Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

⁸Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

⁹Department of Medical Education, University of Melbourne, Melbourne, Victoria, Australia

¹⁰Department of Radiation Oncology, Westmead Hospital, Sydney, New South Wales, Australia

¹¹Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia

¹²School of Medicine, University of Queensland, Brisbane, Queensland, Australia

¹³Department of Radiation Oncology, Liverpool Hospital, Sydney, New South Wales, Australia

Accepted for Publication: July 29, 2024.

Published Online: September 26, 2024. doi:10.1001/jamaoto.2024.3103

^✉

Corresponding Author: Ardalan Ebrahimi, MPH, Medical School, College of Health and Medicine, Australian National University, Canberra, Australia (ardalan@canberraheadandneck.com.au).

Author Contributions: Dr Ebrahimi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ebrahimi, Veness, Clark.

Acquisition, analysis, or interpretation of data: Ebrahimi, Magarey, Smith, Schulte, Low, Clark.

Drafting of the manuscript: Ebrahimi, Clark.

Critical review of the manuscript for important intellectual content: Ebrahimi, Magarey, Smith, Schulte, Veness, Low, Clark.

Statistical analysis: Ebrahimi.

Administrative, technical, or material support: Ebrahimi, Smith, Veness, Low, Clark.

Supervision: Smith, Schulte.

Conflict of Interest Disclosures: None reported.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC11428024 PMID: 39325436

Key Points

Question

Is the poor performance of 8th edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) for patients with nodal metastases possibly due to the inclusion of extranodal extension (ENE)?

Findings

In this cohort study of 1151 patients with nodal metastatic HNcSCC, 5-year disease-specific survival ranged from 8% to 88% in the ENE-positive subset (860 [81.6%]) based on risk stratification using other clinicopathological variables, despite all these patients being classified as TNM stage IV.

Meaning

The study results suggest that including ENE in HNcSCC staging needs reassessment as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV.

Abstract

Importance

The eighth edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) is a poor predictor of survival in patients with lymph node metastases, possibly due to the inclusion of extranodal extension (ENE).

Objective

To identify the key determinants of prognosis in patients with nodal metastatic HNcSCC and analyze the association of ENE with TNM stage and investigate for prognostic heterogeneity in ENE-positive disease.

Design, Setting, and Participants

This retrospective, multicenter cohort study was conducted at 4 Australian tertiary referral centers using prospectively collected data in patients treated between 1980 and 2017 with a median (IQR) follow-up of 3.2 (3.9) years. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes. After excluding cases with perioperative mortality, missing data, or follow-up, the final study population included 1151 patients.

Exposure

Curative intent surgery ± adjuvant radiotherapy.

Main Outcomes and Measures

Differences in locoregional control (LRC), disease-specific survival (DSS), and overall survival were determined using Cox regression analysis.

Results

Among 1151 patients, 976 (84.8%) were male and 175 (15.2%) female, with a median age of 73.3 years (range, 18-100 years). On multivariable analysis, immunosuppression (hazard ratio [HR], 2.48; 95% CI, 1.64-3.74), perineural invasion (HR, 1.69; 95% CI, 1.25-2.30), ENE (HR, 1.53; 95% CI, 0.95-2.44), size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), and number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]) were associated with DSS. Similar results were found for LRC and overall survival. More than 90% of the population was categorized as TNM stage IV, with 32% attributable to ENE. In the ENE-positive subset (n = 860), DSS ranged from 8% to 88% based on stratification using other clinicopathological factors.

Conclusions and Relevance

The study results suggest that immunosuppression, perineural invasion, ENE, and size and number of nodal metastases are associated with reduced survival and LRC in HNcSCC with nodal metastases. The inclusion of ENE in HNcSCC staging needs to be reassessed, as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV, despite many having a high chance of cure.

This cohort study examines key determinants of prognosis in patients with nodal metastatic head and neck cutaneous squamous cell carcinoma.

Introduction

In the seventh edition of the American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging system for head and neck cutaneous squamous cell carcinoma (HNcSCC), the pathological lymph node (pN) classification used for mucosal head and neck cancer was adopted.¹ Subsequently, the eighth edition of the staging manual introduced extranodal extension (ENE) to the pN classification for the first time. ENE-positive (ENE⁺) disease is upstaged to N2a in the presence of a single ipsilateral or contralateral lymph node that is 3 cm or smaller, while ENE⁺ disease larger than 3 cm or associated with multiple, bilateral, or contralateral nodes is classified as N3b. Irrespective of the distinction in the N category, N2 and N3 disease are classified as TNM stage IV.²

Given that ENE is a well-accepted prognostic factor in mucosal head and neck squamous cell carcinoma (SCC), its incorporation into the HNcSCC staging system was welcomed as an intuitive evolution and expected to improve prognostic performance. However, most HNcSCC cases with lymph node metastases exhibit ENE, effectively upstaging most patients to TNM stage IV, even in the presence of very curable disease.^3,4 Accordingly, several smaller studies have shown that the eighth edition pN and TNM staging stratify risk poorly for HNcSCC with nodal metastases.^3,4

The poor prognostic performance of the AJCC staging system in HNcSCC with lymph node metastases emphasizes the need to develop a staging system specific to the disease that reflects its distinct tumor biology, demographic profile, and management. Based on the large proportion of ENE⁺ patients and clinical experience, we hypothesized there may be more significant prognostic heterogeneity in ENE⁺ disease based on other clinicopathological features than the current TNM staging assumes. In light of these issues, the primary aim of this study was to identify the key determinants of recurrence and survival in a large multicenter cohort of Australian patients with nodal metastatic HNcSCC. Our secondary aims were to critically analyze the effect of ENE in HNcSCC and its association with the current staging system and investigate for prognostic heterogeneity in ENE⁺ disease.

Methods

Study Population

This multicenter study included prospectively collected data from 4 Australian comprehensive cancer centers: Chris O’Brien Lifehouse/Royal Prince Alfred Hospital, Westmead Hospital, Peter MacCallum Cancer Centre, and Liverpool Hospital. Ethical approval was obtained from the institutional research ethics committees of each participating institution. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes treated with curative intent by surgery ± adjuvant therapy. Cases with perioperative mortality, missing data, or follow-up were excluded. Patients were treated between 1980 and 2017. Demographic, clinicopathological, treatment, and follow-up data were retained for all patients. We used deidentified patient data after institutional ethics approval (a multicentre ethics approval and then site specific approvals at each centre). Individual patient consent was not required in the context of this study design by the ethics departments.

Statistical Analysis

Statistical analysis was performed using Stata, version 18.0 MP (StataCorp). All statistics were 2-sided, and statistical significance was defined as P < .05. The end points of interest included overall survival (OS), disease-specific survival (DSS), and locoregional control (LRC). OS was calculated from the date of surgery to the date of death of any cause or last follow-up. For DSS and LRC, patients who died of causes other than HNcSCC were censored at the time of death. Differences in the association of covariates with survival and recurrence were determined using univariate Cox regression analysis, and survival curves generated using the Kaplan-Meier method. Shared frailty models were used to account for the presumed heterogeneity between institutions. The proportional hazards assumption was tested using Schoenfeld residuals. For LRC and DSS, the analyses were repeated using a competing risk model according to the method of Fine and Gray, with death of non-HNcSCC causes considered a competing risk to ensure the results were robust.

Prognostic factors of interest included age at diagnosis (≤60, 60-80, >80 years), sex, immunosuppression (absent, present), AJCC T category, laterality of nodal disease (unilateral, bilateral), number of nodal metastases (1-2, 3-4, ≥5), size of the largest nodal metastasis (≤3 cm, >3 to 6 cm, >6 cm), differentiation (well to moderate, poor, or undifferentiated), perineural invasion (PNI; absent, present), surgical margin status (clear to close, involved) and ENE (absent, present). Patients with soft tissue deposits were classified as ENE⁺. Treatment choice (surgery, surgery + adjuvant radiotherapy [RT], surgery + adjuvant chemoradiotherapy [CRT]) and time of treatment provision (1980-1999, 2000-2017) were also tested for prognostic significance. We split the period before and after 2000 based on an earlier study showing that DSS improved between 1980 to 2000 but has been stable since.⁵ We believe patients treated since 2000 represent a contemporary cohort in terms of approaches to management and outcomes. Statistically significant and clinically important covariates were used to develop multivariable Cox proportional hazards models to identify independent predictors of survival and LRC using purposeful selection of covariates according to the method of Hosmer, Lemeshow, and May.⁶ Interaction terms were used selectively to explore for potential interactions between prognostic factors that may be relevant to future staging systems.

Results

Study Cohort

The study cohort included 1151 patients, with 976 men (84.8%) and 175 women (15.2%) and a median age at diagnosis of 73.3 years (range, 18-100 years). The median follow-up was 3.2 years (range, 0.08-16.4 years). Among the 647 patients (56%) without documented death from any cause, 182 (28.1%) had a minimum of 5 years of follow-up, and 420 (64.9%) had a minimum of 2 years of follow-up. Relevant demographic, treatment, and clinicopathological details are summarized in Table 1.

Table 1. Patient Demographic, Treatment, and Clinicopathological Details.

Variable	No. (%)
Age, y
≤60	185 (16.1)
>60-80	656 (57.0)
>80	310 (26.9)
Sex
Female	175 (15.2)
Male	976 (84.8)
Institution
Chris O’Brien Lifehouse	480 (41.7)
Westmead Hospital	382 (33.2)
Peter MacCallum	195 (16.9)
Liverpool Hospital	94 (8.2)
Period of treatment
1980-1999	206 (17.9)
2000-2017	945 (82.1)
Treatment
Surgery alone	219 (19.0)
Surgery + adjuvant RT	857 (74.5)
Surgery + adjuvant CRT	75 (6.5)
Extent of surgery
Parotidectomy alone	167 (14.5)
Parotidectomy + SND	501 (43.5)
Parotidectomy + CND	225 (19.6)
SND alone	160 (13.9)
CND alone	88 (7.6)
Other	10 (0.9)
Immunosuppression
Absent	1050 (91.2)
Present	101 (8.8)
Nodal metastasis size, cm
≤3	811 (70.5)
>3 to ≤6	306 (26.6)
>6	34 (2.9)
No. of nodes
1-2	870 (75.6)
3-4	146 (12.7)
≥5	135 (11.7)
Extranodal extension^a
Absent	194 (18.4)
Present	860 (81.6)
Perineural invasion
Absent	829 (72.0)
Present	322 (28.0)
Differentiation^a
Well to moderate	453 (51.1)
Poor to undifferentiated	434 (48.9)
Margin status^a
Clear to close	519 (55.6)
Involved	415 (44.4)
Bilateral nodal metastases
No	1117 (97.1)
Yes	34 (2.9)

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Abbreviations: CND, comprehensive neck dissection; CRT, adjuvant chemoradiotherapy; RT, adjuvant radiotherapy; SND, selective neck dissection.

^{^a}

There were missing data for extranodal extension (n = 97), differentiation (n = 264), and margin status (n = 217).

LRC Analysis

Locoregional recurrence occurred for 236 patients (20.5%) at a median (IQR) of 8.6 (13.3) months from the date of surgery. The 5-year LRC rate was 75.5%. The results of univariate and multivariable LRC analyses are shown in Table 2. On multivariable analysis, independent predictors of locoregional recurrence included immunosuppression (hazard ratio [HR], 2.25; 95% CI, 1.54-3.29), nodal size (>6 cm vs ≤3 cm; HR, 3.11; 95% CI, 1.81-5.32), number of nodal metastases (3-4 vs 1-2 [HR, 1.41; 95% CI, 0.97-2.04]; ≥5 vs 1-2 [HR, 1.52; 95% CI, 1.04-2.22]), ENE (HR, 2.46; 95% CI, 1.50-4.04), PNI (HR, 1.47; 95% CI, 1.10-1.95), involved surgical margins (HR, 1.39; 95% CI, 1.03-1.88), and bilateral nodal metastases (HR, 2.79; 95% CI, 1.53-5.09). There was no difference in LRC between nodes that were 3 to 6 cm vs 3 cm or smaller (HR, 1.04; 95% CI, 0.77-1.40) and a minimal incremental increase when comparing 5 or more metastatic nodes with 3 to 4 nodes (HR, 1.08; 95% CI, 0.68-1.73). There was also no difference between 1 vs 2 metastatic nodes (HR, 1.22; 95% CI, 0.85-1.75). The effect of nodal metastasis size was not modified by location in the parotid vs neck. Based on the HRs, LRC was most associated with nodal metastasis larger than 6 cm, bilateral nodal disease, ENE, and immunosuppression. The risk of locoregional recurrence was reduced by 32% in patients undergoing surgery and adjuvant RT (±chemotherapy) vs surgery alone (HR, 0.68; 95% CI, 0.48-0.98).

Table 2. Univariate and Multivariable Analyses of Locoregional Control.

Variable	HR (95% CI)
Variable	Univariate	Multivariable
Age, y
≤60	1 [Reference]	NA
>60-80	0.96 (0.68-1.35)
>80	0.89 (0.59-1.35)
Sex
Female	1 [Reference]	NA
Male	1.17 (0.80-1.72)	NA
Immunosuppression
Absent	1 [Reference]	1 [Reference]
Present	2.36 (1.62-3.43)	2.25 (1.54-3.29)
Period of treatment
1980-1999	1 [Reference]	1 [Reference]
2000-2017	0.92 (0.67-1.28)	0.76 (0.54-1.06)
Treatment
Surgery alone	1 [Reference]	1 [Reference]
Surgery + RT/CRT	0.85 (0.61-1.20)	0.68 (0.48-0.98)
Nodal metastasis size, cm
≤3	1 [Reference]	1 [Reference]
>3 to ≤6	1.19 (0.88-1.60)	1.04 (0.77-1.40)
>6	3.41 (2.00-5.81)	3.11 (1.81-5.32)
Nodal metastasis No.
1-2	1 [Reference]	1 [Reference]
3-4	1.47 (1.02-2.12)	1.41 (0.97-2.04)
≥5	1.79 (1.25-2.56)	1.52 (1.04-2.22)
Extranodal extension
Absent	1 [Reference]	1 [Reference]
Present	2.98 (1.84-4.83)	2.46 (1.50-4.04)
Perineural invasion
Absent	1 [Reference]	1 [Reference]
Present	1.71 (1.30-2.24)	1.47 (1.10-1.95)
Differentiation
Well to moderate	1 [Reference]	NA
Poor to undifferentiated	0.91 (0.68-1.21)	NA
Margin status
Clear to close	1 [Reference]	1 [Reference]
Involved	1.58 (1.17-2.13)	1.39 (1.03-1.88)
Bilateral nodal metastases
No	1 [Reference]	1 [Reference]
Yes	2.31 (1.29-4.15)	2.79 (1.53-5.09)

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Abbreviations: CRT, adjuvant chemoradiotherapy; HR, hazard ratio; NA, not applicable; RT, adjuvant radiotherapy.

DSS Analysis

There were 196 deaths (17.0%) due to HNcSCC, with a 5-year DSS of 77.6%. The results of the univariate and multivariable DSS analyses are shown in Table 3. On multivariable analysis, significant predictors of DSS included immunosuppression (HR, 2.48; 95% CI, 1.64-3.74), treatment between 2000 and 2017 (HR, 0.52; 95% CI, 0.37-0.74), nodal size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]), and PNI (HR, 1.69; 95% CI, 1.25-2.30). ENE failed to reach statistical significance (HR, 1.53; 95% CI, 0.95-2.44), as did administration of adjuvant RT (HR, 0.73; 95% CI, 0.49-1.09) and bilateral nodal metastases (HR, 1.69; 95% CI, 0.85-3.34).

Table 3. Univariate and Multivariable Analyses of Disease-Specific Survival.

Variable	HR (95% CI)
Variable	Univariate	Multivariable
Age, y
≤60	1 [Reference]	NA
>60-80	0.98 (0.67-1.43)
>80	1.13 (0.73-1.76)
Sex
Female	1 [Reference]	NA
Male	1.17 (0.77-1.78)	NA
Immunosuppression
Absent	1 [Reference]	1 [Reference]
Present	2.44 (1.62-3.66)	2.48 (1.64-3.74)
Period of treatment
1980-1999	1 [Reference]	1 [Reference]
2000-2017	0.69 (0.49-0.97)	0.52 (0.37-0.74)
Treatment
Surgery alone	1 [Reference]	1 [Reference]
Surgery + RT/CRT	0.92 (0.63-1.35)	0.73 (0.49-1.09)
Nodal metastasis size, cm
≤3	1 [Reference]	1 [Reference]
>3 to ≤6	1.68 (1.23-2.29)	1.41 (1.03-1.93)
>6	5.32 (3.19-8.88)	5.01 (2.98-8.42)
Nodal metastasis No.
1-2	1 [Reference]	1 [Reference]
3-4	1.52 (1.01-2.30)	1.54 (1.01-2.34)
≥5	3.22 (2.30-4.52)	2.86 (1.99-4.11)
Extranodal extension
Absent	1 [Reference]	1 [Reference]
Present	2.04 (1.29-3.21)	1.53 (0.95-2.44)
Perineural invasion
Absent	1 [Reference]	1 [Reference]
Present	1.83 (1.36-2.45)	1.69 (1.25-2.30)
Differentiation
Well to moderate	1 [Reference]	NA
Poor to undifferentiated	1.02 (0.75-1.40)	NA
Margin status
Clear to close	1 [Reference]	NA
Involved	1.14 (0.82-1.58)	NA
Bilateral nodal metastases
No	1 [Reference]	1 [Reference]
Yes	1.91 (0.98-3.75)	1.69 (0.85-3.34)

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Abbreviations: CRT, adjuvant chemoradiotherapy; HR, hazard ratio; NA, not applicable; RT, adjuvant radiotherapy.

OS Analysis

The 5-year OS was 53.1%, with 504 deaths. Univariate and multivariable OS analyses are shown in Table 4. On multivariable analysis, significant predictors of OS included immunosuppression (HR, 2.38; 95% CI, 1.77-3.19), nodal size (>3-6 cm vs ≤3 cm [HR, 1.22; 95% CI, 1.00-1.49]; >6 cm vs ≤3 cm [HR, 3.37; 95% CI, 2.23-5.11]; ≥5 nodal metastases vs 1-2 [HR, 1.96; 95% CI, 1.51-2.55]), ENE (HR, 1.67; 95% CI, 1.25-2.21), PNI (HR, 1.48; 95% CI, 1.21-1.80), and administration of adjuvant RT (HR, 0.69; 95% CI, 0.55-0.86). These were similar to the factors associated with DSS; however, in general, the association with OS was less pronounced with lower HRs. This presumably reflects the fact that the patient population was elderly, and death of non-HNcSCC age-related comorbidities would be relatively common. In addition, as expected, age was significantly associated with OS (>60-80 vs ≤60 years [HR, 1.57; 95% CI, 1.17-2.11]; >80 vs ≤60 years [HR, 3.31; 95% CI, 2.40-4.58]).

Table 4. Univariate and Multivariable Analyses of Overall Survival.

Variable	HR (95% CI)
Variable	Univariate	Multivariable
Age, y
≤60	1 [Reference]	1 [Reference]
>60-80	1.55 (1.15-2.08)	1.57 (1.17-2.11)
>80	3.20 (2.34-4.38)	3.31 (2.40-4.58)
Sex
Female	1 [Reference]	NA
Male	1.36 (1.03-1.79)	NA
Immunosuppression
Absent	1 [Reference]	1 [Reference]
Present	2.33 (1.74-3.11)	2.38 (1.77-3.19)
Period of treatment
1980-1999	1 [Reference]	1 [Reference]
2000-2017	1.15 (0.92-1.45)	0.82 (0.65-1.04)
Treatment
Surgery alone	1 [Reference]	1 [Reference]
Surgery + RT/CRT	0.68 (0.55-0.85)	0.69 (0.55-0.86)
Nodal metastasis size, cm
≤3	1 [Reference]	1 [Reference]
>3 to ≤6	1.43 (1.18-1.74)	1.22 (1.00-1.49)
>6	3.42 (2.27-5.16)	3.37 (2.23-5.11)
Nodal metastasis No.
1-2	1 [Reference]	1 [Reference]
3-4	1.14 (0.87-1.50)	1.17 (0.89-1.55)
≥5	1.80 (1.40-2.31)	1.96 (1.51-2.55)
Extranodal extension
Absent	1 [Reference]	1 [Reference]
Present	2.00 (1.52-2.63)	1.67 (1.25-2.21)
Perineural invasion
Absent	1 [Reference]	1 [Reference]
Present	1.69 (1.39-2.05)	1.48 (1.21-1.80)
Differentiation
Well to moderate	1 [Reference]	NA
Poor to undifferentiated	0.96 (0.79-1.17)	NA
Margin status
Clear to close	1 [Reference]	NA
Involved	1.31 (1.05-1.62)	NA
Bilateral nodal metastases
No	1 [Reference]	NA
Yes	1.28 (0.75-2.18)	NA

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Abbreviations: CRT, adjuvant chemoradiotherapy; HR, hazard ratio; NA, not applicable; RT, adjuvant radiotherapy.

Sensitivity Analyses

We performed several sensitivity analyses to ensure the findings were robust. This included repeating the analysis after excluding patients treated with surgery alone as well as separate analyses excluding patients treated before 2000. These demonstrated consistent results for OS, DSS, and LRC. We also performed univariate and multivariable analyses for LRC and DSS using competing risk models adjusted for institution (eTable 1 and eTable 2 in Supplement 1, respectively). The results were consistent with Cox regression analyses, albeit the prognostic effect of most variables based on HRs was reduced using the competing risks approach as expected.

Extranodal Extension

ENE was present in 81.6% of the study population, resulting in most patients being classified as N2a (33.7%: 94% of whom were upstaged from N1 to N2a based on ENE) or N3b (49.5%: 95% of which were upstaged from N2a, N2b and N2c disease to N3b). As a result, more than 90% of the cohort were categorized as TNM stage IV. For comparison, using the seventh edition of the TNM staging, 58% of the cohort would be classified as stage IV; thus, including ENE upstaged 32% of the cohort.

We then investigated for prognostic heterogeneity using a multivariable analysis of DSS in the 860 ENE⁺ patients. As shown in eTable 3 in Supplement 1, after adjusting for adjuvant therapy and period of treatment, factors with a significant association with DSS included immunosuppression (HR, 2.34; 95% CI, 1.50-3.65), nodal size (>3-6 cm vs ≤3 cm [HR, 1.38; 95% CI, 0.97-1.95]; >6 cm vs ≤3 cm [HR, 4.80; 95% CI, 2.73-8.43]), number of nodal metastases (3-4 vs 1-2 [HR, 1.64; 95% CI, 1.05-2.56]; ≥5 vs 1-2 [HR, 2.76; 95% CI, 1.87-4.06]), and PNI (HR, 1.82; 95% CI, 1.31-2.51), with comparable HRs with the analysis performed in the entire study population.

Figure, A, shows 5 example clinical scenarios with predicted DSS curves based on the multivariable model presented in eTable 3 in Supplement 1 for ENE⁺ patients: (1) 1 to 2 lymph nodes 3 cm or smaller with no PNI or immunosuppression (5-year DSS, 88%); (2) 3 to 4 metastatic nodes 3 cm or smaller (5-year DSS, 77%); (3) 5 or more metastatic nodes 3 cm or smaller (5-year DSS, 62%); (4) 1 to 2 nodal metastases with the largest being larger than 6 cm (5-year DSS, 43%); and (5) 5 or more nodal metastases with the largest being larger than 6 cm (5-year DSS, 8%). This demonstrates good risk stratification in ENE⁺ patients based on other adverse clinicopathological features. The estimated 5-year DSS was 88% in the lowest risk scenario vs 8% in the highest risk scenario. Furthermore, as shown in Figure, B, the same model and clinical scenarios applied to ENE⁻ disease showed similar risk stratification (group 1: 5-year DSS, 88%; group 2: 5-year DSS, 81%; group 3: 5-year DSS, 58%; group 4: 5-year DSS, 41%; group 5: 5-year DSS, 4%). This implies these are critical predictors of survival in ENE⁻ and ENE⁺ disease and the current TNM staging system ascribes excessive importance to ENE compared with other factors.

Discussion

The eighth edition AJCC staging system for HNcSCC has been reported to stratify risk poorly in patients with lymph node metastases.^3,4 In addition, previous studies in this patient cohort have been limited by small sample size and report conflicting results regarding prognostic factors, highlighting the need for further study to identify the key determinants of survival and recurrence. In this large multicenter Australian study of 1151 patients with nodal metastatic HNcSCC treated with curative intent, we found nodal metastasis size, number, ENE, PNI, immunosuppression, and treatment with surgery alone to be consistently associated with reduced LRC and survival.

Nodal Metastasis Size

The AJCC N category for HNcSCC classifies lymph node metastases based on size cut-offs of 3 cm or smaller, smaller than 3 to 6 cm, and larger than 6 cm based on an established convention used in mucosal head and neck cancer staging.² Despite the intuitive inclusion of size in nodal staging, literature investigating the prognostic significance of maximum metastatic lymph node size in HNcSCC has demonstrated conflicting results.^{7,8,9,10,11,12,13,14,15,16} We found nodal metastases larger than 6 cm to be the most important factor associated with locoregional failure and reduced survival but limited effect when comparing nodes smaller than 3 cm to 6 cm vs those 3 cm or smaller. This suggests that good-quality surgery and adjuvant RT may mitigate the adverse effect of nodal size to an extent.

Number of Nodal Metastases

The number of lymph node metastases has increasingly been recognized as an important prognostic factor in many cancers, resulting in the AJCC adopting a more detailed risk stratification system based on the number of involved nodes in several cancer types, including breast, colon, gastric, esophageal, and melanoma.² Despite this, the number of nodal metastases has received limited attention in HNcSCC, with the literature to date reporting inconsistent findings.^7,8,17,18,19 The eighth edition AJCC N category for HNcSCC only distinguishes between single vs multiple lymph node metastases.² We categorized the number of nodal metastases as 1 to 2, 3 to 4, and 5 or more based on previous modeling²⁰ and confirmed a strong association with recurrence and survival, particularly in the presence of 5 or more metastases. We recommend incorporating this information into future staging systems.

Extranodal Extension

While ENE has long been recognized as a predictor of recurrence and survival in head and neck SCC, most of the data come from mucosal cancers. In that context, ENE not only informs patient prognosis, it is an indication for intensified adjuvant treatment with concurrent chemoradiotherapy.²¹ While several studies have identified ENE as an independent adverse prognostic factor in HNcSCC,^{16,22,23,24,25} many others have failed to show an association with outcome.^{12,19,26,27,28,29,30} Furthermore, reported rates of ENE in these studies vary between 26% to 86%. This variation may represent factors such as the extent of pathological sampling and reporting of minor microscopic ENE as well as the approach to soft tissue metastases, which may have been classified as ENE⁻. In our cohort, ENE was present in 81.6% of patients, resulting in most patients being classified as N2a or N3b and hence TNM stage IV. Although we found ENE to be an independently associated with locoregional control and survival on multivariable analyses, we believe the current staging system ascribes too much weight to ENE compared with other factors. This was supported by multivariable modeling showing a very wide range of predicted survival outcomes in ENE⁺ patients based on the number and size of nodal metastases, immunosuppression, and PNI (8%-88% 5-year DSS).

Two additional issues require further study in the context of ENE in HNcSCC. First, the binary classification of ENE as absent or present may be suboptimal for risk stratification. While there is some evidence to suggest that the extent of ENE further substratifies prognosis in mucosal head and neck SCC,^31,32,33,34 to our knowledge no data are available in the context of HNcSCC. A secondary issue is the distinction between ENE and soft tissue metastases (STM), defined as tumor deposits within soft tissues lacking continuity with the primary tumor and without discernible associated lymphoid tissue.³⁵ In a recent analysis of 535 patients with metastatic HNcSCC, Hasmat and colleagues²² found that ENE and STM were independently associated with reduced OS, with a similar clinical effect based on the HRs. Based on current evidence, we recommend considering STM to be equivalent to ENE from a staging, prognostic, and treatment perspective; however, this requires further study.

Perineural Invasion

Another important finding was the consistent association between PNI and all end points of interest in view of the conflicting results in previous studies.^{11,14,15,19,24,26,28,30,36,37,38,39} Unfortunately we did not have data available to subclassify PNI into incidental (or microscopic) vs clinical PNI (involvement of facial and/or trigeminal nerves with clinical symptoms and/or magnetic resonance imaging changes); however, based on the literature and clinical experience, we expect the latter to be more concerning,^{15,19,36,37,40,41,42} with the likelihood of cure inversely associated with the proximal extension of perineural spread and ability to offer complete surgical resection and adjuvant RT.⁴³ Furthermore, there is evidence in oral SCC to suggest that quantitative subcategorization of microscopic PNI based on the size of involved nerves and number of foci seen on histopathology is associated with better risk stratification.^44,45 Although nodal PNI appears to be an important prognostic factor, further study is needed to delineate the relative importance based on the extent of microscopic and clinical PNI, which represent a spectrum of disease progression.

Immunosuppression

Although several previous studies and a meta-analysis have reported reduced survival in immunosuppressed patients with metastatic HNcSCC,^{11,14,16,17,36,46,47,48,49} the previous studies were relatively small and heterogeneous. Our work confirms the findings of earlier studies in a large study population. The demonstration of inferior outcomes in immunosuppressed patients despite most (90%) receiving aggressive multimodality therapy with surgery and postoperative RT in experienced cancer centers, combined with the current lack of data supporting treatment intensification, underlines the importance of prevention and early detection of cutaneous SCC in this cohort of patients.

Limitations

Although this study had several strengths, such as the large sample size, it had limitations characteristic of its retrospective design, albeit the data were collected prospectively in several participating institutions. Any treatment related bias would likely lead to underestimation of the prognostic effect of relevant clinicopathological variables and reflects clinical outcomes relevant to TNM staging. Another issue is the lack of data on medical comorbidities, which are associated with OS for a relatively elderly study population. An additional potential limitation is the 4-decade period of the study. However, in an earlier study, we had shown that DSS outcomes have been stable since 2000,⁵ and we accounted for differences over time by performing sensitivity analyses to ensure the results were robust to exclusion of patients treated before 2000. To account for potential institutional differences, we stratified all regression analyses by institution and performed a sensitivity analysis including only patients treated with surgery and adjuvant RT, the currently accepted criterion standard. Notwithstanding, there may have been residual confounding that we could not adjust for based on the available data, and this could affect the generalizability of the results. Finally, additional information on the extent of PNI and ENE may have provided further insights in these analyses and merits further study.

Conclusions

In this large multicenter cohort study of patients with HNcSCC with lymph node metastases treated with curative intent, we demonstrated that the size and number of nodal metastases, ENE, PNI, immunosuppression, and single modality therapy were consistently associated with reduced LRC and survival. ENE is exceedingly common in this cancer. The inclusion of ENE in HNcSCC staging needs to be reassessed as it currently upstages most patients to TNM stage IV disease despite many ENE⁺ patients having a high chance of cure. Furthermore, we demonstrated a very wide range in survival outcomes for ENE²² patients based on other key clinicopathological features, suggesting the current TNM staging system ascribes too much weight to ENE, which has only a modest prognostic effect. Based on our findings, we also recommend that future revisions of the AJCC staging system consider incorporating more detailed information on the number of nodal metastases (1-2, 3-4, ≥5) as well as PNI and immunosuppression.

Supplement 1.

eTable 1. Competing risk analysis of locoregional control

eTable 2. Competing risk analysis of disease-specific survival

eTable 3. Analysis of disease-specific survival in patients with extranodal extension

jamaotolaryngolheadnecksurg-e243103-s001.pdf^{(177.5KB, pdf)}

Supplement 2.

Data sharing statement

jamaotolaryngolheadnecksurg-e243103-s002.pdf^{(14.3KB, pdf)}

References

1.Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. Springer; 2010. [Google Scholar]
2.Amin M, Edge SB, Green FL, et al. , eds. AJCC Cancer Staging Manual. 8th ed. Springer; 2017. [Google Scholar]
3.Liu J, Ebrahimi A, Low TH, et al. Predictive value of the 8th edition American Joint Commission Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck. J Surg Oncol. 2018;117(4):765-772. doi: 10.1002/jso.24883 [DOI] [PubMed] [Google Scholar]
4.Sood A, Wykes J, Roshan D, et al. A critical analysis of the prognostic performance of the 8th edition American Joint Committee on Cancer staging for metastatic cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2019;41(6):1591-1596. doi: 10.1002/hed.25599 [DOI] [PubMed] [Google Scholar]
5.Hasmat S, Ebrahimi A, Luk PP, et al. Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four-decades: multicenter study. Head Neck. 2019;41(11):3826-3832. doi: 10.1002/hed.25912 [DOI] [PubMed] [Google Scholar]
6.Hosmer D, Lemeshow S, May S. Applied Survival Analysis: Regression Modeling of Time-to-Event Data. 2nd ed. John Wiley & Sons; 2008. doi: 10.1002/9780470258019 [DOI] [Google Scholar]
7.Veness MJ, Palme CE, Smith M, Cakir B, Morgan GJ, Kalnins I. Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy. Laryngoscope. 2003;113(10):1827-1833. doi: 10.1097/00005537-200310000-00031 [DOI] [PubMed] [Google Scholar]
8.Forest VI, Clark JJ, Veness MJ, Milross C. N1S3: a revised staging system for head and neck cutaneous squamous cell carcinoma with lymph node metastases: results of 2 Australian cancer centers. Cancer. 2010;116(5):1298-1304. doi: 10.1002/cncr.24855 [DOI] [PubMed] [Google Scholar]
9.O’Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck. 2002;24(5):417-422. doi: 10.1002/hed.10063 [DOI] [PubMed] [Google Scholar]
10.Palme CE, O’Brien CJ, Veness MJ, McNeil EB, Bron LP, Morgan GJ. Extent of parotid disease influences outcome in patients with metastatic cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2003;129(7):750-753. doi: 10.1001/archotol.129.7.750 [DOI] [PubMed] [Google Scholar]
11.McDowell LJ, Tan TJ, Bressel M, et al. Outcomes of cutaneous squamous cell carcinoma of the head and neck with parotid metastases. J Med Imaging Radiat Oncol. 2016;60(5):668-676. doi: 10.1111/1754-9485.12484 [DOI] [PubMed] [Google Scholar]
12.Hirshoren N, Danne J, Dixon BJ, et al. Prognostic markers in metastatic cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2017;39(4):772-778. doi: 10.1002/hed.24683 [DOI] [PubMed] [Google Scholar]
13.Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical staging of metastatic cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment outcomes. Cancer. 2006;106(5):1078-1083. doi: 10.1002/cncr.21698 [DOI] [PubMed] [Google Scholar]
14.Shao A, Wong DK, McIvor NP, et al. Parotid metastatic disease from cutaneous squamous cell carcinoma: prognostic role of facial nerve sacrifice, lateral temporal bone resection, immune status and P-stage. Head Neck. 2014;36(4):545-550. doi: 10.1002/hed.23323 [DOI] [PubMed] [Google Scholar]
15.Audet N, Palme CE, Gullane PJ, et al. Cutaneous metastatic squamous cell carcinoma to the parotid gland: analysis and outcome. Head Neck. 2004;26(8):727-732. doi: 10.1002/hed.20048 [DOI] [PubMed] [Google Scholar]
16.Oddone N, Morgan GJ, Palme CE, et al. Metastatic cutaneous squamous cell carcinoma of the head and neck: the immunosuppression, treatment, extranodal spread, and margin status (ITEM) prognostic score to predict outcome and the need to improve survival. Cancer. 2009;115(9):1883-1891. doi: 10.1002/cncr.24208 [DOI] [PubMed] [Google Scholar]
17.Schmidt C, Martin JM, Khoo E, Plank A, Grigg R. Outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center. Head Neck. 2015;37(12):1808-1815. doi: 10.1002/hed.23843 [DOI] [PubMed] [Google Scholar]
18.Mizrachi A, Hadar T, Rabinovics N, et al. Prognostic significance of nodal ratio in cutaneous squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol. 2013;270(2):647-653. doi: 10.1007/s00405-012-2050-3 [DOI] [PubMed] [Google Scholar]
19.Makki FM, Mendez AI, Taylor SM, et al. Prognostic factors for metastatic cutaneous squamous cell carcinoma of the parotid. J Otolaryngol Head Neck Surg. 2013;42(1):14. doi: 10.1186/1916-0216-42-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Ebrahimi A, Gupta R, Luk P, et al. Number of nodal metastases and the American Joint Committee on cancer staging of head and neck cutaneous squamous cell carcinoma: a multicenter study. Oral Oncol. 2020;111:104855. doi: 10.1016/j.oraloncology.2020.104855 [DOI] [PubMed] [Google Scholar]
21.Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck. 2005;27(10):843-850. doi: 10.1002/hed.20279 [DOI] [PubMed] [Google Scholar]
22.Hasmat S, Mooney C, Gao K, et al. Regional metastasis in head and neck cutaneous squamous cell carcinoma: an update on the significance of extra-nodal extension and soft tissue metastasis. Ann Surg Oncol. 2020;27(8):2840-2845. doi: 10.1245/s10434-020-08252-9 [DOI] [PubMed] [Google Scholar]
23.Kelder W, Ebrahimi A, Forest VI, Gao K, Murali R, Clark JR. Cutaneous head and neck squamous cell carcinoma with regional metastases: the prognostic importance of soft tissue metastases and extranodal spread. Ann Surg Oncol. 2012;19(1):274-279. doi: 10.1245/s10434-011-1986-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Creighton F, Lin A, Leavitt E, Lin D, Deschler D, Emerick K. Factors affecting survival and locoregional control in head and neck cSCCA with nodal metastasis. Laryngoscope. 2018;128(8):1881-1886. doi: 10.1002/lary.27048 [DOI] [PubMed] [Google Scholar]
25.Sood A, Wykes J, Roshan D, et al. Number of nodal metastases and prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck. ANZ J Surg. 2019;89(7-8):863-867. doi: 10.1111/ans.15086 [DOI] [PubMed] [Google Scholar]
26.Ch’ng S, Maitra A, Allison RS, et al. Parotid and cervical nodal status predict prognosis for patients with head and neck metastatic cutaneous squamous cell carcinoma. J Surg Oncol. 2008;98(2):101-105. doi: 10.1002/jso.21092 [DOI] [PubMed] [Google Scholar]
27.Dona E, Veness MJ, Cakir B, Morgan GJ. Metastatic cutaneous squamous cell carcinoma to the parotid: the role of surgery and adjuvant radiotherapy to achieve best outcome. ANZ J Surg. 2003;73(9):692-696. doi: 10.1046/j.1445-2197.2003.02737.x [DOI] [PubMed] [Google Scholar]
28.Goh RY, Bova R, Fogarty GB. Cutaneous squamous cell carcinoma metastatic to parotid - analysis of prognostic factors and treatment outcome. World J Surg Oncol. 2012;10:117. doi: 10.1186/1477-7819-10-117 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Trosman SJ, Zhu A, Nicolli EA, Leibowitz JM, Sargi ZB. High-risk cutaneous squamous cell cancer of the head and neck: risk factors for recurrence and impact of adjuvant treatment. Laryngoscope. 2021;131(1):E136-E143. doi: 10.1002/lary.28564 [DOI] [PubMed] [Google Scholar]
30.Hinerman RW, Indelicato DJ, Amdur RJ, et al. Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes. Laryngoscope. 2008;118(11):1989-1996. doi: 10.1097/MLG.0b013e318180642b [DOI] [PubMed] [Google Scholar]
31.Wreesmann VB, Katabi N, Palmer FL, et al. Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head Neck. 2016;38(Suppl 1)(suppl 1):E1192-E1199. doi: 10.1002/hed.24190 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Yamada S, Yanamoto S, Otani S, et al. Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2016;45(2):141-146. doi: 10.1016/j.ijom.2015.09.005 [DOI] [PubMed] [Google Scholar]
33.Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck. 1998;20(1):16-21. doi: 10.1002/(SICI)1097-0347(199801)20:1<16::AID-HED3>3.0.CO;2-6 [DOI] [PubMed] [Google Scholar]
34.Prabhu RS, Hanasoge S, Magliocca KR, et al. Extent of pathologic extracapsular extension and outcomes in patients with nonoropharyngeal head and neck cancer treated with initial surgical resection. Cancer. 2014;120(10):1499-1506. doi: 10.1002/cncr.28596 [DOI] [PubMed] [Google Scholar]
35.Jose J, Ferlito A, Rodrigo JP, Devaney KO, Rinaldo A, MacLennan K. Soft tissue deposits from head and neck cancer: an under-recognised prognostic factor? J Laryngol Otol. 2007;121(12):1115-1117. doi: 10.1017/S002221510700028X [DOI] [PubMed] [Google Scholar]
36.Bobin C, Ingrand P, Dréno B, Rio E, Malard O, Espitalier F. Prognostic factors for parotid metastasis of cutaneous squamous cell carcinoma of the head and neck. Eur Ann Otorhinolaryngol Head Neck Dis. 2018;135(2):99-103. doi: 10.1016/j.anorl.2017.09.006 [DOI] [PubMed] [Google Scholar]
37.Southwell KE, Chaplin JM, Eisenberg RL, McIvor NP, Morton RP. Effect of immunocompromise on metastatic cutaneous squamous cell carcinoma in the parotid and neck. Head Neck. 2006;28(3):244-248. doi: 10.1002/hed.20321 [DOI] [PubMed] [Google Scholar]
38.Coombs AC, Butler A, Allison R. Metastatic cutaneous squamous cell carcinoma of the parotid gland: prognostic factors. J Laryngol Otol. 2018;132(3):264-269. doi: 10.1017/S0022215117001323 [DOI] [PubMed] [Google Scholar]
39.Sweeny L, Zimmerman T, Carroll WR, Schmalbach CE, Day KE, Rosenthal EL. Head and neck cutaneous squamous cell carcinoma requiring parotidectomy: prognostic indicators and treatment selection. Otolaryngol Head Neck Surg. 2014;150(4):610-617. doi: 10.1177/0194599814520686 [DOI] [PubMed] [Google Scholar]
40.Mendenhall WM, Amdur RJ, Williams LS, Mancuso AA, Stringer SP, Price Mendenhall N. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck. 2002;24(1):78-83. doi: 10.1002/hed.10025 [DOI] [PubMed] [Google Scholar]
41.Jackson JE, Dickie GJ, Wiltshire KL, et al. Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach. Head Neck. 2009;31(5):604-610. doi: 10.1002/hed.20991 [DOI] [PubMed] [Google Scholar]
42.Panizza B, Warren T. Perineural invasion of head and neck skin cancer: diagnostic and therapeutic implications. Curr Oncol Rep. 2013;15(2):128-133. doi: 10.1007/s11912-012-0288-y [DOI] [PubMed] [Google Scholar]
43.Warren TA, Panizza B, Porceddu SV, et al. Outcomes after surgery and postoperative radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma. Head Neck. 2016;38(6):824-831. doi: 10.1002/hed.23982 [DOI] [PubMed] [Google Scholar]
44.Aivazian K, Ebrahimi A, Low TH, et al. Perineural invasion in oral squamous cell carcinoma: quantitative subcategorisation of perineural invasion and prognostication. J Surg Oncol. 2015;111(3):352-358. doi: 10.1002/jso.23821 [DOI] [PubMed] [Google Scholar]
45.Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29(2):167-178. doi: 10.1097/01.pas.0000149687.90710.21 [DOI] [PubMed] [Google Scholar]
46.Arbab M, Margalit DN, Tishler RB, et al. Outcomes following radiation for cutaneous squamous cell carcinoma of the head and neck: associations between immune suppression and recurrence. Head Neck. 2019;41(7):2111-2115. doi: 10.1002/hed.25663 [DOI] [PubMed] [Google Scholar]
47.Manyam BV, Garsa AA, Chin RI, et al. A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck. Cancer. 2017;123(11):2054-2060. doi: 10.1002/cncr.30601 [DOI] [PubMed] [Google Scholar]
48.Elghouche AN, Pflum ZE, Schmalbach CE. Immunosuppression impact on head and neck cutaneous squamous cell carcinoma: a systematic review with meta-analysis. Otolaryngol Head Neck Surg. 2019;160(3):439-446. doi: 10.1177/0194599818808511 [DOI] [PubMed] [Google Scholar]
49.Ebrahimi A, Clark JR, Ahmadi N, Palme CE, Morgan GJ, Veness MJ. Prognostic significance of disease-free interval in head and neck cutaneous squamous cell carcinoma with nodal metastases. Head Neck. 2013;35(8):1138-1143. doi: 10.1002/hed.23096 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Competing risk analysis of locoregional control

eTable 2. Competing risk analysis of disease-specific survival

eTable 3. Analysis of disease-specific survival in patients with extranodal extension

jamaotolaryngolheadnecksurg-e243103-s001.pdf^{(177.5KB, pdf)}

Supplement 2.

Data sharing statement

jamaotolaryngolheadnecksurg-e243103-s002.pdf^{(14.3KB, pdf)}

[ooi240066r1] 1.Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. Springer; 2010. [Google Scholar]

[ooi240066r2] 2.Amin M, Edge SB, Green FL, et al. , eds. AJCC Cancer Staging Manual. 8th ed. Springer; 2017. [Google Scholar]

[ooi240066r3] 3.Liu J, Ebrahimi A, Low TH, et al. Predictive value of the 8th edition American Joint Commission Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck. J Surg Oncol. 2018;117(4):765-772. doi: 10.1002/jso.24883 [DOI] [PubMed] [Google Scholar]

[ooi240066r4] 4.Sood A, Wykes J, Roshan D, et al. A critical analysis of the prognostic performance of the 8th edition American Joint Committee on Cancer staging for metastatic cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2019;41(6):1591-1596. doi: 10.1002/hed.25599 [DOI] [PubMed] [Google Scholar]

[ooi240066r5] 5.Hasmat S, Ebrahimi A, Luk PP, et al. Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four-decades: multicenter study. Head Neck. 2019;41(11):3826-3832. doi: 10.1002/hed.25912 [DOI] [PubMed] [Google Scholar]

[ooi240066r6] 6.Hosmer D, Lemeshow S, May S. Applied Survival Analysis: Regression Modeling of Time-to-Event Data. 2nd ed. John Wiley & Sons; 2008. doi: 10.1002/9780470258019 [DOI] [Google Scholar]

[ooi240066r7] 7.Veness MJ, Palme CE, Smith M, Cakir B, Morgan GJ, Kalnins I. Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy. Laryngoscope. 2003;113(10):1827-1833. doi: 10.1097/00005537-200310000-00031 [DOI] [PubMed] [Google Scholar]

[ooi240066r8] 8.Forest VI, Clark JJ, Veness MJ, Milross C. N1S3: a revised staging system for head and neck cutaneous squamous cell carcinoma with lymph node metastases: results of 2 Australian cancer centers. Cancer. 2010;116(5):1298-1304. doi: 10.1002/cncr.24855 [DOI] [PubMed] [Google Scholar]

[ooi240066r9] 9.O’Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck. 2002;24(5):417-422. doi: 10.1002/hed.10063 [DOI] [PubMed] [Google Scholar]

[ooi240066r10] 10.Palme CE, O’Brien CJ, Veness MJ, McNeil EB, Bron LP, Morgan GJ. Extent of parotid disease influences outcome in patients with metastatic cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2003;129(7):750-753. doi: 10.1001/archotol.129.7.750 [DOI] [PubMed] [Google Scholar]

[ooi240066r11] 11.McDowell LJ, Tan TJ, Bressel M, et al. Outcomes of cutaneous squamous cell carcinoma of the head and neck with parotid metastases. J Med Imaging Radiat Oncol. 2016;60(5):668-676. doi: 10.1111/1754-9485.12484 [DOI] [PubMed] [Google Scholar]

[ooi240066r12] 12.Hirshoren N, Danne J, Dixon BJ, et al. Prognostic markers in metastatic cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2017;39(4):772-778. doi: 10.1002/hed.24683 [DOI] [PubMed] [Google Scholar]

[ooi240066r13] 13.Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for clinical staging of metastatic cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment outcomes. Cancer. 2006;106(5):1078-1083. doi: 10.1002/cncr.21698 [DOI] [PubMed] [Google Scholar]

[ooi240066r14] 14.Shao A, Wong DK, McIvor NP, et al. Parotid metastatic disease from cutaneous squamous cell carcinoma: prognostic role of facial nerve sacrifice, lateral temporal bone resection, immune status and P-stage. Head Neck. 2014;36(4):545-550. doi: 10.1002/hed.23323 [DOI] [PubMed] [Google Scholar]

[ooi240066r15] 15.Audet N, Palme CE, Gullane PJ, et al. Cutaneous metastatic squamous cell carcinoma to the parotid gland: analysis and outcome. Head Neck. 2004;26(8):727-732. doi: 10.1002/hed.20048 [DOI] [PubMed] [Google Scholar]

[ooi240066r16] 16.Oddone N, Morgan GJ, Palme CE, et al. Metastatic cutaneous squamous cell carcinoma of the head and neck: the immunosuppression, treatment, extranodal spread, and margin status (ITEM) prognostic score to predict outcome and the need to improve survival. Cancer. 2009;115(9):1883-1891. doi: 10.1002/cncr.24208 [DOI] [PubMed] [Google Scholar]

[ooi240066r17] 17.Schmidt C, Martin JM, Khoo E, Plank A, Grigg R. Outcomes of nodal metastatic cutaneous squamous cell carcinoma of the head and neck treated in a regional center. Head Neck. 2015;37(12):1808-1815. doi: 10.1002/hed.23843 [DOI] [PubMed] [Google Scholar]

[ooi240066r18] 18.Mizrachi A, Hadar T, Rabinovics N, et al. Prognostic significance of nodal ratio in cutaneous squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol. 2013;270(2):647-653. doi: 10.1007/s00405-012-2050-3 [DOI] [PubMed] [Google Scholar]

[ooi240066r19] 19.Makki FM, Mendez AI, Taylor SM, et al. Prognostic factors for metastatic cutaneous squamous cell carcinoma of the parotid. J Otolaryngol Head Neck Surg. 2013;42(1):14. doi: 10.1186/1916-0216-42-14 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ooi240066r20] 20.Ebrahimi A, Gupta R, Luk P, et al. Number of nodal metastases and the American Joint Committee on cancer staging of head and neck cutaneous squamous cell carcinoma: a multicenter study. Oral Oncol. 2020;111:104855. doi: 10.1016/j.oraloncology.2020.104855 [DOI] [PubMed] [Google Scholar]

[ooi240066r21] 21.Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck. 2005;27(10):843-850. doi: 10.1002/hed.20279 [DOI] [PubMed] [Google Scholar]

[ooi240066r22] 22.Hasmat S, Mooney C, Gao K, et al. Regional metastasis in head and neck cutaneous squamous cell carcinoma: an update on the significance of extra-nodal extension and soft tissue metastasis. Ann Surg Oncol. 2020;27(8):2840-2845. doi: 10.1245/s10434-020-08252-9 [DOI] [PubMed] [Google Scholar]

[ooi240066r23] 23.Kelder W, Ebrahimi A, Forest VI, Gao K, Murali R, Clark JR. Cutaneous head and neck squamous cell carcinoma with regional metastases: the prognostic importance of soft tissue metastases and extranodal spread. Ann Surg Oncol. 2012;19(1):274-279. doi: 10.1245/s10434-011-1986-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ooi240066r24] 24.Creighton F, Lin A, Leavitt E, Lin D, Deschler D, Emerick K. Factors affecting survival and locoregional control in head and neck cSCCA with nodal metastasis. Laryngoscope. 2018;128(8):1881-1886. doi: 10.1002/lary.27048 [DOI] [PubMed] [Google Scholar]

[ooi240066r25] 25.Sood A, Wykes J, Roshan D, et al. Number of nodal metastases and prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck. ANZ J Surg. 2019;89(7-8):863-867. doi: 10.1111/ans.15086 [DOI] [PubMed] [Google Scholar]

[ooi240066r26] 26.Ch’ng S, Maitra A, Allison RS, et al. Parotid and cervical nodal status predict prognosis for patients with head and neck metastatic cutaneous squamous cell carcinoma. J Surg Oncol. 2008;98(2):101-105. doi: 10.1002/jso.21092 [DOI] [PubMed] [Google Scholar]

[ooi240066r27] 27.Dona E, Veness MJ, Cakir B, Morgan GJ. Metastatic cutaneous squamous cell carcinoma to the parotid: the role of surgery and adjuvant radiotherapy to achieve best outcome. ANZ J Surg. 2003;73(9):692-696. doi: 10.1046/j.1445-2197.2003.02737.x [DOI] [PubMed] [Google Scholar]

[ooi240066r28] 28.Goh RY, Bova R, Fogarty GB. Cutaneous squamous cell carcinoma metastatic to parotid - analysis of prognostic factors and treatment outcome. World J Surg Oncol. 2012;10:117. doi: 10.1186/1477-7819-10-117 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ooi240066r29] 29.Trosman SJ, Zhu A, Nicolli EA, Leibowitz JM, Sargi ZB. High-risk cutaneous squamous cell cancer of the head and neck: risk factors for recurrence and impact of adjuvant treatment. Laryngoscope. 2021;131(1):E136-E143. doi: 10.1002/lary.28564 [DOI] [PubMed] [Google Scholar]

[ooi240066r30] 30.Hinerman RW, Indelicato DJ, Amdur RJ, et al. Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes. Laryngoscope. 2008;118(11):1989-1996. doi: 10.1097/MLG.0b013e318180642b [DOI] [PubMed] [Google Scholar]

[ooi240066r31] 31.Wreesmann VB, Katabi N, Palmer FL, et al. Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head Neck. 2016;38(Suppl 1)(suppl 1):E1192-E1199. doi: 10.1002/hed.24190 [DOI] [PMC free article] [PubMed] [Google Scholar]

[ooi240066r32] 32.Yamada S, Yanamoto S, Otani S, et al. Evaluation of the level of progression of extracapsular spread for cervical lymph node metastasis in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2016;45(2):141-146. doi: 10.1016/j.ijom.2015.09.005 [DOI] [PubMed] [Google Scholar]

[ooi240066r33] 33.Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck. 1998;20(1):16-21. doi: 10.1002/(SICI)1097-0347(199801)20:1<16::AID-HED3>3.0.CO;2-6 [DOI] [PubMed] [Google Scholar]

[ooi240066r34] 34.Prabhu RS, Hanasoge S, Magliocca KR, et al. Extent of pathologic extracapsular extension and outcomes in patients with nonoropharyngeal head and neck cancer treated with initial surgical resection. Cancer. 2014;120(10):1499-1506. doi: 10.1002/cncr.28596 [DOI] [PubMed] [Google Scholar]

[ooi240066r35] 35.Jose J, Ferlito A, Rodrigo JP, Devaney KO, Rinaldo A, MacLennan K. Soft tissue deposits from head and neck cancer: an under-recognised prognostic factor? J Laryngol Otol. 2007;121(12):1115-1117. doi: 10.1017/S002221510700028X [DOI] [PubMed] [Google Scholar]

[ooi240066r36] 36.Bobin C, Ingrand P, Dréno B, Rio E, Malard O, Espitalier F. Prognostic factors for parotid metastasis of cutaneous squamous cell carcinoma of the head and neck. Eur Ann Otorhinolaryngol Head Neck Dis. 2018;135(2):99-103. doi: 10.1016/j.anorl.2017.09.006 [DOI] [PubMed] [Google Scholar]

[ooi240066r37] 37.Southwell KE, Chaplin JM, Eisenberg RL, McIvor NP, Morton RP. Effect of immunocompromise on metastatic cutaneous squamous cell carcinoma in the parotid and neck. Head Neck. 2006;28(3):244-248. doi: 10.1002/hed.20321 [DOI] [PubMed] [Google Scholar]

[ooi240066r38] 38.Coombs AC, Butler A, Allison R. Metastatic cutaneous squamous cell carcinoma of the parotid gland: prognostic factors. J Laryngol Otol. 2018;132(3):264-269. doi: 10.1017/S0022215117001323 [DOI] [PubMed] [Google Scholar]

[ooi240066r39] 39.Sweeny L, Zimmerman T, Carroll WR, Schmalbach CE, Day KE, Rosenthal EL. Head and neck cutaneous squamous cell carcinoma requiring parotidectomy: prognostic indicators and treatment selection. Otolaryngol Head Neck Surg. 2014;150(4):610-617. doi: 10.1177/0194599814520686 [DOI] [PubMed] [Google Scholar]

[ooi240066r40] 40.Mendenhall WM, Amdur RJ, Williams LS, Mancuso AA, Stringer SP, Price Mendenhall N. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck. 2002;24(1):78-83. doi: 10.1002/hed.10025 [DOI] [PubMed] [Google Scholar]

[ooi240066r41] 41.Jackson JE, Dickie GJ, Wiltshire KL, et al. Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach. Head Neck. 2009;31(5):604-610. doi: 10.1002/hed.20991 [DOI] [PubMed] [Google Scholar]

[ooi240066r42] 42.Panizza B, Warren T. Perineural invasion of head and neck skin cancer: diagnostic and therapeutic implications. Curr Oncol Rep. 2013;15(2):128-133. doi: 10.1007/s11912-012-0288-y [DOI] [PubMed] [Google Scholar]

[ooi240066r43] 43.Warren TA, Panizza B, Porceddu SV, et al. Outcomes after surgery and postoperative radiotherapy for perineural spread of head and neck cutaneous squamous cell carcinoma. Head Neck. 2016;38(6):824-831. doi: 10.1002/hed.23982 [DOI] [PubMed] [Google Scholar]

[ooi240066r44] 44.Aivazian K, Ebrahimi A, Low TH, et al. Perineural invasion in oral squamous cell carcinoma: quantitative subcategorisation of perineural invasion and prognostication. J Surg Oncol. 2015;111(3):352-358. doi: 10.1002/jso.23821 [DOI] [PubMed] [Google Scholar]

[ooi240066r45] 45.Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29(2):167-178. doi: 10.1097/01.pas.0000149687.90710.21 [DOI] [PubMed] [Google Scholar]

[ooi240066r46] 46.Arbab M, Margalit DN, Tishler RB, et al. Outcomes following radiation for cutaneous squamous cell carcinoma of the head and neck: associations between immune suppression and recurrence. Head Neck. 2019;41(7):2111-2115. doi: 10.1002/hed.25663 [DOI] [PubMed] [Google Scholar]

[ooi240066r47] 47.Manyam BV, Garsa AA, Chin RI, et al. A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck. Cancer. 2017;123(11):2054-2060. doi: 10.1002/cncr.30601 [DOI] [PubMed] [Google Scholar]

[ooi240066r48] 48.Elghouche AN, Pflum ZE, Schmalbach CE. Immunosuppression impact on head and neck cutaneous squamous cell carcinoma: a systematic review with meta-analysis. Otolaryngol Head Neck Surg. 2019;160(3):439-446. doi: 10.1177/0194599818808511 [DOI] [PubMed] [Google Scholar]

[ooi240066r49] 49.Ebrahimi A, Clark JR, Ahmadi N, Palme CE, Morgan GJ, Veness MJ. Prognostic significance of disease-free interval in head and neck cutaneous squamous cell carcinoma with nodal metastases. Head Neck. 2013;35(8):1138-1143. doi: 10.1002/hed.23096 [DOI] [PubMed] [Google Scholar]

PERMALINK

Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases

Ardalan Ebrahimi, MPH

Ruta Gupta, MBBS, MD

Lachlan McDowell, MBBS

Matthew J R Magarey, BMed

Paul N Smith, MBBS

Klaus-Martin Schulte, MD

Diana M Perriman, PhD

Michael Veness, MMed, MD

Sandro Porceddu, MBBS, MD

Tsu-Hui Hubert Low, BSc Med

Allan Fowler, MMed, MD

Jonathan R Clark, MBBS, BSc (Med), MBiostat

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposure

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Population

Statistical Analysis

Results

Study Cohort

Table 1. Patient Demographic, Treatment, and Clinicopathological Details.

LRC Analysis

Table 2. Univariate and Multivariable Analyses of Locoregional Control.

DSS Analysis

Table 3. Univariate and Multivariable Analyses of Disease-Specific Survival.

OS Analysis

Table 4. Univariate and Multivariable Analyses of Overall Survival.

Sensitivity Analyses

Extranodal Extension

Figure. Disease-Specific Survival Curves Based on Multivariable Models in 5 Clinical Scenarios for Patients With and Without Extranodal Extension (ENE).

Discussion

Nodal Metastasis Size

Number of Nodal Metastases

Extranodal Extension

Perineural Invasion

Immunosuppression

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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