The association between level IV/V metastasis and the recurrence,distant metastasis,and survival outcomes in hypopharyngeal squamous cell carcinoma

Abstract

Background:

The presence of level IV/V metastasis is a significant prognostic factor for patients with oral and oropharyngeal cancer, while level IV lymphadenopathy defines the N3 stage in nasopharyngeal carcinoma. However, the current staging system for hypopharyngeal squamous cell carcinoma (HPSCC) does not consider the location of involved nodes.

Objectives:

To evaluate the risk factors and prognostic impact of level IV/V metastasis in patients with HPSCC.

Methods:

The analysis included 2740 HPSCC patients from the SEER (Surveillance, Epidemiology, and End Results) database, followed by a validated study on 232 patients with pathologically positive nodes (pN+) at our center.

Results:

Of the 2740 patients, 1961 presented with metastatic lymph nodes (LNs), 20.8% and 14.1% had nodal involvement in level IV and level V, respectively. Multivariate analysis revealed that N3 and M1 stages were independently associated with level IV/V metastasis. Level IV metastasis was the sole independent adverse factor for overall survival (OS) among all LN regions (p < 0.05). Regarding cancer-specific survival (CSS), only level IV and V involvement were independent predictors of prognosis (p < 0.05). The rate of pN+ at levels IV and V in our center was 35.8% and 16.4%, respectively. The advanced pN stage was independently associated with metastasis to level IV or V. Patients with level IV/V metastasis had significantly higher rates of regional recurrence and distant metastases (p < 0.001). Multivariate analysis confirmed a significant association regarding OS, CSS, locoregional relapse-free survival (LRFS), or distant metastasis-free survival between patients with and without level IV metastasis (p < 0.05). Patients with level IV/V disease exhibited decreased survival rates across stages pN1 to pN3. Postoperative chemoradiotherapy improved LRFS in patients with level IV lymphadenopathy and OS/CSS in patients with level V metastasis.

Conclusion:

Metastasis to level IV/V was associated with a worse prognosis in HPSCC patients. The level IV/V should be considered for future improvements to the staging system.

Design:

A retrospective study.

Keywords

distant metastasis hypopharyngeal squamous cell carcinoma level IV/V metastasis recurrence survival predictive values

Introduction

Due to the extensive lymphatic drainage network and atypical symptoms associated with hypopharyngeal squamous cell carcinoma (HPSCC), over 80% of patients are diagnosed with locoregionally advanced disease (stages III–IV) at presentation.¹ Cervical lymph node (LN) metastasis holds significant prognostic implications for patients with HPSCC. To achieve better treatment outcomes, it is necessary to acquire information on the distribution patterns of cervical nodal metastasis, and whether the lower neck involvement is associated with a worse prognosis.² Notably, the presence of extranodal extension (ENE), multiple LN metastases, and lymphatic invasion has been proven to correlate with worse prognosis in head and neck squamous cell carcinoma (HNSCC).^2–4 Our previous research has shown that the existence of three or more positive LNs (NPLN ⩾ 3) and an LN ratio above 0.138 (LN ratio ⩾ 0.138) are independent prognostic indicators for HPSCC.⁵ In addition, the presence of LN metastases in lower neck levels appears to be associated with a poorer prognosis and an increased risk of developing distant metastases in oral cancer.^6,7 Based on the treatment outcomes in the EORTC trial,³ the presence of levels IV and V lymphadenopathy in patients with oral and oropharyngeal cancer is regarded as a significant prognostic factor.^4,8 Therefore, the National Comprehensive Cancer Network (NCCN) guidelines classified level IV/V metastasis as an intermediate risk factor for recurrence in the oral cavity or oropharyngeal cancers.^3,4,9 However, the characteristics and outcomes of HPSCC patients who have level IV/V metastasis were not comprehensively reported up to date. Treatment recommendations for this specific population among HPSCC are also lacking in NCCN guidelines.

The involvement of neck nodes in tumors does not occur randomly.^7,10,11 A detailed analysis of LN involvement patterns is crucial to assess the prognostic value of level IV/V metastases. For nasopharyngeal carcinoma, level IV lymphadenopathy is defined as the N3 stage. However, for HPSCC, the current staging system does not take into account the location of involved nodes. The previous studies have relied, to some extent, solely on clinical or radiological data from a heterogeneous patient population. To reveal the impact of level IV/V lymphadenopathy on the prognosis of HPSCC, we analyzed the patterns of nodal spread using information from the SEER (Surveillance, Epidemiology, and End Results) database. In addition, the significant multivariate relationships among risk factors for level IV/V metastasis were investigated. To verify the findings from the SEER database, we further explored the prognosis of HPSCC patients with pathologically positive LNs (pN+) treated with pharyngolaryngectomy and neck dissection in our center. Moreover, the role of adjuvant therapy in improving the prognosis according to these risk factors was studied.

Materials and methods

SEER database

The patient data from 2004 to 2015 were collected using the SEER software available at “https://seer.cancer.gov.” The selection process is provided in Figure 1. The records were based on the following primary sites: C129, C130, C131, C132, C138, and C139 as per the site codes of ICD-O-3. Exclusion criteria were as follows: AJCC stage status unavailable; not squamous cell carcinomas; without positive histology; without complete survival information; not the first tumor; total number of tumors was not 1; TNM stage status unavailable; and the variable of CS (Collaborative Stage, which allows combined pathological and clinical “mixed” or “best” stages to be captured) site-specific factor 3/4/5/6 was 999 (lacking information on LN metastasis was excluded). After screening, 2740 patients were included.

Figure 1.

Data selection process from SEER database.

The analysis covered clinical and sociodemographic characteristics as well as treatment modalities (Table 1). The correlation between surgery and radiation was extracted from the variables of radiation sequence with surgery, the reason for no cancer-directed surgery, and radiation recode. The type of surgery of the primary site was extracted from the variable of RX Summ-Surg Prim Site (1998+). The neck dissection was extracted from the variable of regional nodes examined (1988+). The distribution of metastases in cervical LNs was determined by the variable of CS site-specific factors 3, 4, 5, and 6. The HPSCC cancer-specific survival (CSS) and non-CSS were extracted from the SEER variables of cause-specific death classification and other causes of death classifications.

Table 1.

Patient characteristics in SEER database.

Variable	No.	(%)
Median age, year (range)	62.5	(20–97)
Race
White	2072	(75.6)
Black	485	(17.7)
Others	183	(6.7)
Gender
Male	2236	(81.6)
Female	504	(18.4)
Year of diagnosis
2004–2009	1286	(46.9)
2010–2015	1454	(53.1)
Primary subsite
Pyriform sinus	1435	(52.4)
Postcricoid region	74	(2.7)
Aryepiglottic fold	183	(6.7)
Posterior pharyngeal wall	184	(6.7)
Overlapping lesion or NOS	864	(31.5)
Grade
Well differentiated	111	(4.1)
Moderately differentiated	1140	(41.6)
Poorly or undifferentiated	971	(35.4)
Unknown	518	(18.9)
Stage
I	100	(3.6)
II	296	(10.8)
III	501	(18.3)
IVA	1322	(48.2)
IVB	308	(11.2)
IVC	213	(7.8)
T status
T1	274	(10)
T2	962	(35.1)
T3	519	(18.9)
T4a	735	(26.8)
T4b	250	(9.1)
N status
N0	779	(28.4)
N1	598	(21.8)
N2	1217	(44.4)
N3	146	(5.3)
M status
M0	2527	(92.2)
M1	213	(7.8)
Neck dissection
Yes	462	(16.9)
No/unknown	2278	(83.1)
Surgery to the primary lesion
Yes	513	(18.7)
No/unknown	2227	(81.3)
Radiotherapy
Yes	2233	(81.5)
No/unknown	507	(18.5)
Chemotherapy
Yes	1905	(69.5)
No/unknown	835	(30.5)
Insurance status at diagnosis
Any	1981	(72.3)
None or unknown	759	(27.7)
Marital status at diagnosis
Married	1233	(45)
Others	1507	(55)
Level IV metastasis
No	2333	(85.1)
Yes	407	(14.9)
Level V metastasis
No	2463	(89.9)
Yes	277	(10.1)

SEER, Surveillance, Epidemiology, and End Results.

Patient data in our center

We selected the verification cohort with the following criteria for our study: (1) HPSCC patients who underwent pharyngolaryngectomy as the primary surgery combined with neck dissection, followed by postoperative radiotherapy or concurrent chemoradiotherapy (CCRT), (2) HPSCC patients with pN+ and no evidence of distant metastasis, and (3) treated at the Eye & ENT Hospital, Fudan University from November 2011 to December 2020. Exclusion criteria were as follows: any T4b stage; those who underwent induction chemotherapy or any antitumor treatment prior to surgery; patients presenting with a synchronous second primary tumor; recurrent HPSCC; patients who failed to complete the treatment; and incomplete clinical data or follow-up information.

After screening, 232 patients with pN+ were eligible for inclusion. All patients underwent electronic laryngoscopy, neck computed tomography (CT) and/or magnetic resonance imaging (MRI), esophageal gastroscopy, abdominal ultrasonography, as well as chest radiography. The histopathological specimens, including primary and neck dissection samples, were thoroughly examined by pathologists dedicated to head and neck tumors. Special attention was paid to record the margins, ENE, perineural invasion, vascular/lymphatic invasion, and pathological node status (numbers of total and positive LNs, specific regions of LN metastasis). The LN ratio was calculated as the ratio of positive LNs to the exact number of LNs removed, regardless of whether bilateral or unilateral neck dissection was performed.

The decision regarding postoperative adjuvant therapy was made by a multidisciplinary team. Restaging was performed according to the 8th edition of the AJCC for HPSCC. Three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or volumetric modulated arc therapy at a curative dose of 54–70 Gy was delivered based on radiologic or pathologic characteristics. Cisplatin alone was prescribed for concurrent chemotherapy depending on the adverse prognostic features and also the patient’s tolerance during radiotherapy.

Information on tumor control and survival status was obtained through outpatient visits or telephone follow-ups. Electronic laryngoscopy and MRI/CT scans were performed regularly. Follow-up time started from the first treatment to December 2023. The median follow-up time was 74.37 months (range, 5.77–145 months). The reporting of this study conforms to the ESMO Guidance for Reporting Oncology Real-World evidence (GROW) statement¹² (Supplemental Files).

Statistical analysis

The Chi-square test and Fisher’s exact test were performed to compare categorical variables among different groups. Multivariate analysis with logistic regression was conducted to determine the odds ratio (OR) and independent factors by including significant variables identified in the univariate analysis. Kaplan–Meier method was used to estimate the overall survival (OS), CSS, locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). Survival was calculated as the date of first administration of therapy to the date of the event or last follow-up. The log-rank test and Cox hazard model were used in univariate and multivariate analyses, respectively. Only variables with a p-value less than 0.05 in the univariate analyses were included in the multivariate Cox proportional hazard regression analyses. All statistical analyses were carried out using SPSS 29.0 (SPSS, Chicago, IL, USA), and a two-sided p-value less than 0.05 was deemed statistically significant.

Results

Patient characteristics in the SEER database

A total of 2740 patients were enrolled (Table 1), including 2236 males and 504 females, with a median age of 62.5 years. The majority of patients were white (75.6%), originating from the pyriform sinus (52.4%), with moderately differentiated tumors (41.6%) and stage IVA cancer (48.2%).

The distribution of regional LN spread is shown in Table 2. The overall metastasis rates in level I–VII and retropharyngeal LNs were 10.8%, 45.4%, 32%, 14.9%, 10.1%, 1.9%, 0.9%, and 2.6%. Among the 1961 patients with LN involvement, 407 (20.8%) and 277 (14.1%) developed metastasis in level IV and level V, respectively. Univariate analysis (Supplemental Table 1) revealed a significantly higher rate of N3 status and M1 status in patients with level IV or V metastasis than those without (p < 0.05). The multivariate analysis (Table 3) demonstrated that race of black (OR = 1.381), male (OR = 1.474), N3 status (OR = 1.482), involvement of levels III (OR = 3.509), V (OR = 2.42), and VI (OR = 2.15) were independently associated with level IV metastasis. Race of others (OR = 1.728), N3 status (OR = 1.882), M1 status (OR = 1.609), involvement of levels IV (OR = 2.413), VI (OR = 2.329), and retropharyngeal LNs (OR = 5.222) were independently associated with level V metastasis.

Table 2.

Distribution of cervical lymph node metastases in SEER database.

Distribution of cervical metastases	All cases (n = 2740)		N+ cases (n = 1961)
Distribution of cervical metastases	No.	Accounting for total cases (%)	Accounting for positive cases (%)
I	297	(10.8)	(15.1)
II	1244	(45.4)	(63.4)
III	876	(32)	(44.7)
Retropharyngeal	70	(2.6)	(3.6)
IV	407	(14.9)	(20.8)
V	277	(10.1)	(14.1)
VI	52	(1.9)	(2.7)
VII	24	(0.9)	(1.2)
Facial	7	(0.3)	(0.4)
Parapharyngeal	51	(1.9)	(2.6)
Parotid	23	(0.8)	(1.2)
Suboccipital/retroauricular	10	(0.4)	(0.5)

N+, lymph node metastasis; SEER, Surveillance, Epidemiology, and End Results.

Table 3.

Multivariate analysis of independent correlators for level IV/level V metastasis among patients with N+ status in SEER database.

Variable	Multivariate analysis for level IV			Multivariate analysis for level V
Variable	OR	95% CI	p	OR	95% CI	p
Race
White	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Black	1.381	(1.042–1.831)	0.025	1.214	(0.873–1.687)	0.249
Others	0.899	(0.55–1.47)	0.671	1.728	(1.059–2.822)	0.029
Gender
Female	Ref.	Ref.	Ref.	–	–	–
Male	1.474	(1.045–2.08)	0.027	–	–	–
N status
N1/N2	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
N3	1.482	(1.01–2.194)	0.049	1.882	(1.23–2.878)	0.004
M status
M0	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
M1	1.351	(0.943–1.935)	0.101	1.609	(1.084–2.388)	0.018
Level I involvement
No	–	–	–	Ref.	Ref.	Ref.
Yes	–	–	–	1.376	(0.97–1.953)	0.073
Level III involvement
No	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Yes	3.509	(2.759–4.462)	<0.001	1.019	(0.768–1.353)	0.895
Level IV involvement
No	–	–	–	Ref.	Ref.	Ref.
Yes	–	–	–	2.413	(1.808–3.219)	<0.001
Retropharyngeal nodes involvement
No	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Yes	1.237	(0.698–2.192)	0.467	5.222	(3.042–8.962)	<0.001
Level V involvement
No	Ref.	Ref.	Ref.	–	–	–
Yes	2.42	(1.804–3.245)	<0.001	–	–	–
Level VI involvement
No	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Yes	2.15	(1.137–4.066)	0.018	2.329	(1.19–4.558)	0.014
Level VII involvement
No	–	–	–	Ref.	Ref.	Ref.
Yes	–	–	–	1.983	(0.664–5.962)	0.22
Facial nodes involvement
No	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Yes	0.485	(0.062–3.777)	0.49	/	/	0.999
Parapharyngeal nodes involvement
No	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Yes	0.997	(0.48–2.072)	0.993	1.01	(0.447–2.282)	0.981
Parotid nodes involvement
No	Ref.	Ref.	Ref.	–	–	–
Yes	0.535	(0.114–2.504)	0.427	–	–	–
Suboccipital/retroauricular nodes involvement
No	Ref.	Ref.	Ref.	Ref.	Ref.	Ref.
Yes	3.612	(0.812–16.068)	0.092	2.065	(0.392–10.871)	0.392

p Value in bold statistically significant.

CI, confidence interval; N+, lymph node metastasis; OR, odds ratio; SEER, SEER, Surveillance, Epidemiology, and End Results.

Relationship between level IV/V metastasis and survival rate in the database

Among the entire cohort, patients with level IV metastasis exhibited worse survival outcomes, the 5-year OS and CSS rates were 22.8% and 28%, respectively. Conversely, patients without level IV metastasis demonstrated higher 5-year OS and CSS rates, 30.8% and 39.9%, respectively (p < 0.001). Similarly, those with level V metastasis had a lower survival rate, the 5-year OS and CSS rates were 19.2% and 22.3%, respectively. By contrast, patients without level V metastasis achieved better outcomes, the 5-year OS and CSS rates were 30.8% and 40.1%, respectively (p < 0.001). For a more detailed analysis of survival rates, please refer to Table 4. Multivariate analysis (Table 4) revealed a significant association between OS or CSS and age, race, year of diagnosis, primary subsite, T status, N status, M status, neck dissection, surgery to primary lesion, radiotherapy, chemotherapy, and marital status (p < 0.05). Furthermore, level IV involvement was the sole independent prognostic factor for OS (hazard ratio (HR) = 1.167, p = 0.029) among all metastatic LN regions. In terms of CSS, only level IV involvement (HR = 1.176, p = 0.036) and level V (HR = 1.216, p = 0.021) were independent predictors of prognosis.

Table 4.

Univariate and multivariate analyses predicting OS and CSS for all the patients in the SEER database.

Variables	5-year OS				5-year CSS
Variables	OS (%)	p	Multivariate Cox regression HR(95% CI)	p	CSS (%)	p	Multivariate Cox regression HR(95% CI)	p
Age (years)
⩽62	32.6	<0.001	Reference		40.3	<0.001	Reference
>62	26.6		1.34(1.216–1.477)	<0.001	36.1		1.306(1.172–1.456)	<0.001
Race
White	32.2	<0.001	Reference		40.8	<0.001	Reference
Black	15.7		1.239(1.098–1.398)	<0.001	23.6		1.22(1.068–1.395)	0.003
Others	38.1		0.87(0.709–1.067)	0.181	46.6		0.868(0.69–1.092)	0.227
Gender
Female	30.4	0.908	–	–	40.1	0.659	–	–
Male	29.4		–	–	37.7		–	–
Year of diagnosis
2010–2015	34.9	<0.001	Reference		43.2	<0.001	Reference
2004–2009	26.5		1.177(1.052–1.317)	0.004	34.8		1.156(1.021–1.309)	0.023
Primary subsite
Pyriform sinus	31	<0.001	Reference		40	<0.001	Reference
Postcricoid region	26.8		1.083(0.805–1.457)	0.597	33.1		1.206(0.874–1.665)	0.255
Aryepiglottic fold	36.9		0.942(0.763–1.163)	0.58	47.8		0.919(0.719–1.175)	0.501
Posterior pharyngeal wall	27		1.359(1.125–1.641)	0.001	35.5		1.348(1.088–1.67)	0.006
Overlapping lesion or NOS	26.6		1.141(1.025–1.269)	0.016	34		1.148(1.019–1.293)	0.024
Grade
Well differentiated	27.2	0.186	–	–	32	0.375	–	–
Moderately differentiated	28		–	–	36.7		–	–
Poorly or undifferentiated	30.8		–	–	39.3		–	–
Unknown	31.7		–	–	40.9		–	–
T status
T1	54.1	<0.001	Reference		67	<0.001	Reference
T2	34.4		1.616(1.321–1.976)	<0.001	46.1		1.757(1.372–2.249)	<0.001
T3	29.7		2.004(1.614–2.488)	<0.001	37.3		2.39(1.843–3.099)	<0.001
T4a	19.2		2.582(2.103–3.17)	<0.001	24.2		3.207(2.504–4.109)	<0.001
T4b	16.5		2.495(1.968–3.163)	<0.001	20.6		3.083(2.331–4.078)	<0.001
N status
N0	34.5	<0.001	Reference		45.5	<0.001	Reference
N1	31.9		1.196(1.027–1.392)	0.021	42.2		1.181(0.99–1.408)	0.064
N2	26.7		1.287(1.107–1.498)	0.001	33.4		1.342(1.129–1.594)	<0.001
N3	18.4		1.938(1.523–2.467)	<0.001	22.1		1.96(1.501–2.559)	<0.001
M status
M0	31.8	<0.001	Reference		41	<0.001	Reference
M1	3.9		1.818(1.541–2.145)	<0.001	4.5		1.965(1.649–2.343)	<0.001
Neck dissection
Yes	39.2	<0.001	Reference		45.3	<0.001	Reference
No/unknown	27.6		1.5(1.271–1.772)	<0.001	36.7		1.324(1.1–1.595)	0.003
Surgery to the primary lesion
Yes	36.9	<0.001	Reference		48	<0.001	Reference
No/unknown	28		1.324(1.132–1.549)	<0.001	35.8		1.49(1.242–1.788)	<0.001
Radiotherapy
Yes	33.1	<0.001	Reference		41.6	<0.001	Reference
No/unknown	14.4		2.059(1.812–2.34)	<0.001	21.9		2.061(1.785–2.379)	<0.001
Chemotherapy
Yes	33	<0.001	Reference		39.9	<0.001	Reference
No/unknown	21.9		1.648(1.465–1.854)	<0.001	34.5		1.582(1.384–1.808)	<0.001
Insurance status at diagnosis
Any	32.7	<0.001	Reference		41.7	<0.001	Reference
None/unknown	23.9		1.108(0.988–1.242)	0.079	31.3		1.147(1.009–1.303)	0.035
Marital status at diagnosis
Married	37.4	<0.001	Reference		45.7	<0.001	Reference
Others	23.2		1.299(1.176–1.435)	<0.001	31.7		1.275(1.14–1.426)	<0.001
Level I involvement
No	30.2	0.043	Reference		38.7	0.03	Reference
Yes	25.5		0.975(0.836–1.138)	0.752	34		0.948(0.8–1.123)	0.538
Level II involvement
No	32.1	0.004	Reference		41.8	<0.001	Reference
Yes	26.6		1.106(0.985–1.243)	0.089	33.7		1.12(0.984–1.273)	0.085
Level III involvement
No	31.1	0.003	Reference		40.4	<0.001	Reference
Yes	26.6		1.024(0.909–1.154)	0.698	33.3		0.994(0.871–1.134)	0.929
Retropharyngeal nodes involvement
No	30	0.029	Reference		38.7	0.01	Reference
Yes	15.3		0.926(0.689–1.244)	0.609	18.3		0.901(0.658–1.235)	0.519
Level IV involvement
No	30.8	<0.001	Reference		39.9	<0.001	Reference
Yes	22.8		1.167(1.016–1.341)	0.029	28		1.176(1.01–1.368)	0.036
Level V involvement
No	30.8	<0.001	Reference		40.1	<0.001	Reference
Yes	19.2		1.104(0.943–1.293)	0.218	22.3		1.216(1.03–1.436)	0.021
Level VI involvement
No	29.9	<0.001	Reference		38.5	<0.001	Reference
Yes	13.5		1.38(0.997–1.911)	0.052	19.9		1.134(0.788–1.632)	0.498
Level VII involvement
No	29.8	0.024	Reference		38.4	0.023	Reference
Yes	13		1.077(0.678–1.711)	0.753	15.5		1.03(0.589–1.8)	0.918
Facial nodes involvement
No	29.7	0.018	Reference		38.3	0.023	Reference
Yes	0		1.07(0.406–2.824)	0.891	0		0.93(0.368–2.348)	0.877
Parapharyngeal nodes involvement
No	29.9	0.001	Reference		38.6	<0.001	Reference
Yes	16		1.226(0.868–1.731)	0.248	16.7		1.373(0.988–1.908)	0.059
Parotid nodes involvement
No	29.7	0.019	Reference		38.3	0.021	Reference
Yes	17.7		1.3(0.811–2.085)	0.275	21.8		1.198(0.691–2.077)	0.52
Suboccipital/retroauricular nodes involvement
No	29.7	0.049	Reference		38.2	0.289	–	–
Yes	15		0.673(0.261–1.732)	0.411	29.2		–	–

p value in bold statistically significant.

CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; OS, overall survival; SEER, Surveillance, Epidemiology, and End Results.

The survival rates of patients with level IV/V involvement were compared separately to those without level IV/V metastasis. The 5-year OS and CSS of patients with level IV metastasis (IV+) (Figure 2(a)) were both inferior to those with IV stages N0 to N2 (p < 0.001), but without significant difference compared to patients with N3 (OS: 22.8% vs 19.1%, p = 0.123; CSS: 28% vs 23.4%, p = 0.138). These results indicated that patients with level IV metastasis should be defined as the N3 stage. The survival rates of patients with level V metastasis (V+) consistently demonstrated worse outcomes compared to those with V− stages N0 to N2 (p < 0.001; Figure 2(b)), but without significant difference compared to patients with N3 (p > 0.05). These results suggested that patients with level V metastasis should also be defined as the N3 stage.

Figure 2.

Comparison of overall survival and cancer-specific survival between patients with and without level IV/V metastasis in the SEER database. (a) The survival curves were compared among patients with and without level IV metastasis (IV+ vs IV−), stratified by N staging categories (N0, N1(IV−), N2(IV−), N3(IV−)). (b) The survival curves were compared among patients with and without level V metastasis (V+ vs V−), stratified by N staging categories (N0, N1(V−), N2 (V−), N3(V−)).

To investigate the therapeutic approaches that may enhance the survival outcomes of patients with metastasis in level IV/V, we conducted univariate/multivariate analyses (Supplemental Table 2). The findings demonstrated that the administration of neck dissection (HR = 0.555; HR = 0.582), radiotherapy (HR = 0.492; HR = 0.522), and chemotherapy (HR = 0.412; HR = 0.408) independently and significantly (p < 0.001) improved survival rate.

General clinical data analysis in our center

The staging and LN distribution patterns from the SEER database were predominantly based on clinical diagnosis rather than pathological information. Distant metastasis, LN involvement, and multimodality therapy significantly impact the survival outcomes. To minimize statistical bias and to further validate the impact of level IV/V metastasis, we conducted an evaluation on a cohort of patients from our center.

The general information of the patients is shown in Supplemental Table 3. The study population included 232 men aged 39–74 years. The majority of tumors originated from the pyriform sinus (83.6%), with a moderate differentiation level in pathology (81%), unilateral positive LNs (82.8%), and stage IVA disease (62.9%). ENE/pN3/IVB stage was observed in 49 patients (21.1%).

The distribution of the LN spread is shown in Figure 3. Based on pathologic diagnosis, the LNs metastasis rates to level I–VI, retropharyngeal LNs, and parotid LNs were 5.6%, 82.3%, 76.7%, 35.8%, 16.4%, 7.3%, 9.1%, and 1.3%, respectively. A total of 83 and 38 patients developed metastasis in level IV and level V (Table 5), respectively. Bilateral positive LNs, NPLN ⩾ 3, LN ratio ⩾ 0.138, esophageal invasion, pT3/pT4, pN2/pN3 (ENE), involvement of level III, V, VI, and parotid nodes were more frequent in patients with level IV metastasis than those without (p < 0.05). Bilateral positive LNs, NPLN ⩾ 3, LN ratio ⩾ 0.138, positive margin, perineural invasion, pN3 (ENE), involvement of level I, III, IV, VI, retropharyngeal LNs, and parotid LNs were more frequent in patients with level V metastasis (p < 0.05). The multivariate analysis (Supplemental Table 4) demonstrated that LN ratio ⩾ 0.138, esophageal invasion, pT3/pT4, pN2/pN3 (ENE), and involvement of level V were independently associated with metastasis to level IV. pN3 (ENE) and involvement of level IV were independently associated with metastasis to level V.

Figure 3.

Distribution of LN metastasis among 232 patients with pathologically positive LNs in our center.

Table 5.

The correlation between clinical factors and level IV/level V metastasis for 232 patients with pathologically positive lymph nodes in our center.

Factors	Level IV−	Level IV+	p	Level V−	Level V+	p
Factors	N = 149 (%)	N = 83 (%)	p	N = 194 (%)	N = 38 (%)	p
Age			0.265			0.405
<60	76 (51)	36 (43.4)		96 (49.5)	16 (42.1)
⩾60	73 (49)	47 (56.6)		98 (50.5)	22 (57.9)
Smoking			0.796			0.28
No	18 (12.1)	11 (13.3)		22 (11.3)	7 (18.4)
Yes	131 (87.9)	72 (86.7)		172 (88.7)	31 (81.6)
Alcohol abuse			0.51			0.068
No	22 (14.8)	15 (18.1)		24 (12.4)	9 (23.7)
Yes	127 (85.2)	68 (81.9)		170 (87.6)	29 (76.3)
Primary subsite			0.278			0.871
Pyriform sinus	127 (85.2)	67 (80.7)		163 (84)	31 (81.6)
Postcricoid region	10 (6.7)	4 (4.8)		12 (6.2)	2 (5.3)
Posterior pharyngeal wall	12 (8.1)	12 (14.5)		19 (9.8)	5 (13.2)
Grade			0.925			0.45
Well differentiated	9 (6)	4 (4.8)		10 (5.2)	3 (7.9)
Moderately differentiated	120 (80.5)	68 (81.9)		160 (82.5)	28 (73.7)
Poorly differentiated	20 (13.4)	11 (13.3)		24 (12.4)	7 (18.4)
Unilateral/bilateral positive LNs			0.015			0.002
Unilateral	130 (87.2)	62 (74.7)		167 (86.1)	25 (65.8)
Bilateral	19 (12.8)	21 (25.3)		27 (13.9)	13 (34.2)
NPLN			<0.001			<0.001
⩽2	84 (56.4)	16 (19.3)		96 (49.5)	4 (10.5)
⩾3	65 (43.6)	67 (80.7)		98 (50.5)	34 (89.5)
LN ratio			<0.001			<0.001
<0.138	102 (68.5)	26 (31.3)		118 (60.8)	10 (26.3)
⩾0.138	47 (31.5)	57 (68.7)		76 (39.2)	28 (73.7)
ENE			<0.001			<0.001
No	128 (85.9)	55 (66.3)		165 (85.1)	18 (47.4)
Yes	21 (14.1)	28 (33.7)		29 (14.9)	20 (52.6)
Surgical margin			0.501			0.032
Negative margin	132 (88.6)	71 (85.5)		174 (89.7)	29 (76.3)
Positive margin	17 (11.4)	12 (14.5)		20 (10.3)	9 (23.7)
Esophageal invasion			0.041			0.268
No	137 (91.9)	69 (83.1)		170 (87.6)	36 (94.7)
Yes	12 (8.1)	14 (16.9)		24 (12.4)	2 (5.3)
Cartilage invasion			0.137			0.72
No	125 (83.9)	63 (75.9)		158 (81.4)	30 (78.9)
Yes	24 (16.1)	20 (24.1)		36 (18.6)	8 (21.1)
Perineural invasion			0.357			0.03
No	143 (96)	77 (92.8)		187 (96.4)	33 (86.8)
Yes	6 (4)	6 (7.2)		7 (3.6)	5 (13.2)
Vascular/lymphatic invasion			0.272			0.085
No	130 (87.2)	68 (81.9)		169 (87.1)	29 (76.3)
Yes	19 (12.8)	15 (18.1)		25 (12.9)	9 (23.7)
Pathological T status			0.003			0.734
pT1/T2	65 (43.6)	20 (24.1)		72 (37.1)	13 (34.2)
pT3/T4	84 (56.4)	63 (75.9)		122 (62.9)	25 (65.8)
Pathological N status			<0.001			<0.001
pN1	44 (29.5)	2 (2.4)		46 (23.7)	0 (0)
pN2	84 (56.4)	53 (63.9)		119 (61.3)	18 (47.4)
pN3	21 (14.1)	28 (33.7)		29 (14.9)	20 (52.6)
Level I involvement			0.162			0.003
No	143 (96)	76 (91.6)		187 (96.4)	32 (84.2)
Yes	6 (4)	7 (8.4)		7 (3.6)	6 (15.8)
Level II involvement			0.549			0.207
No	28 (18.8)	13 (15.7)		37 (19.1)	4 (10.5)
Yes	121 (81.2)	70 (84.3)		157 (80.9)	34 (89.5)
Level III involvement			<0.001			<0.001
No	47 (31.5)	7 (8.4)		53 (27.3)	1 (2.6)
Yes	102 (68.5)	76 (91.6)		141 (72.7)	37 (97.4)
Level IV involvement	–	–	–			<0.001
No	–	–	–	145 (74.7)	4 (10.5)
Yes	–	–	–	49 (25.3)	34 (89.5)
Level V involvement			<0.001	–	–	–
No	145 (97.3)	49 (59)		–	–	–
Yes	4 (2.7)	34 (41)		–	–
Level VI involvement			0.039			0.029
No	142 (95.3)	73 (88)		183 (94.3)	32 (84.2)
Yes	7 (4.7)	10 (12)		11 (5.7)	6 (15.8)
Retropharyngeal nodes involvement			0.235			0.028
No	138 (92.6)	73 (88)		180 (92.8)	31 (81.6)
Yes	11 (7.4)	10 (12)		14 (7.2)	7 (18.4)
Parotid nodes involvement			0.045			0.004
No	149 (100)	80 (96.4)		194 (100)	35 (92.1)
Yes	0 (0)	3 (3.6)		0 (0)	3 (7.9)

p value in bold, statistically significant.

ENE, extranodal extension; LN, lymph node; NPLN, the number of positive lymph nodes.

Survival outcomes and the prognostic factors

As indicated in Supplemental Table 3, local recurrence, regional recurrence, and distant metastases were observed in 61, 63, and 69 patients, respectively. Among the patients with distant metastasis, 43 had lung/mediastinum-specific metastases, while the remaining 26 had metastases involving multiple organs or organs other than lungs/mediastinum. Interestingly, level V involvement increased the risk of distant metastasis to multiple organs or non-lung/mediastinum organs (54.2% vs 28.9%, p = 0.039, Supplemental Table 5). The 5-year LRFS rate of patients with and without level IV disease was 24.4% versus 74.4% (p < 0.001) and the 5-year DMFS was 37.5% versus 80.5% (p < 0.001; Supplemental Table 6). The 5-year LRFS rate of patients with and without level V involvement was 20.7% versus 64.3% (p < 0.001) and the 5-year DMFS rate was 25.2% versus 74.8% (p < 0.001, Supplemental Table 6). The multivariate analyses (Table 6) in predicting LRFS showed that postcricoid region (HR = 2.762), bilateral positive LNs (HR = 1.667), positive margin (HR = 1.706), level IV (HR = 4.687), and retropharyngeal nodes involvement (HR = 1.984) were significantly correlated with worse outcomes (p < 0.05). Bilateral positive LNs (HR = 1.803), ENE (HR = 4.026), level IV (HR = 2.569), and level V (HR = 1.875) lymphadenopathy were independently correlated with poorer DMFS (p < 0.05).

Table 6.

Multivariate Cox regression analyses predicting OS, CSS, LRFS, and DMFS for 232 patients with pathologically positive lymph nodes in our center.

Variable	OS		CSS		LRFS		DMFS
Variable	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p
Primary subsite							Not included
Pyriform sinus	R		R		R
Postcricoid region	3.072(1.619–5.826)	<0.001	3.319(1.741–6.325)	<0.001	2.762(1.303–5.855)	0.008
Posterior pharyngeal wall	0.872(0.467–1.627)	0.667	0.865(0.45–1.662)	0.663	1.169(0.638–2.144)	0.613
Unilateral/bilateral positive LNs
Unilateral	R		R		R		R
Bilateral	2.067(1.328–3.218)	0.001	2.154(1.366–3.396)	<0.001	1.667(1.017–2.734)	0.043	1.803(1.039–3.13)	0.036
NPLN
⩽2	R		R		R		R
⩾3	0.892(0.57–1.398)	0.619	0.957(0.532–1.721)	0.883	0.905(0.551–1.486)	0.693	1.054(0.507–2.189)	0.888
LN ratio					Not included
<0.138	R		R				R
⩾0.138	1.01(0.626–1.627)	0.969	0.909(0.594–1.391)	0.661			1.246(0.731–2.124)	0.419
ENE
No	R		R		R		R
Yes	1.087(0.659–1.793)	0.743	1.165(0.489–2.777)	0.731	0.819(0.477–1.407)	0.47	4.026(1.118–14.492)	0.033
Surgical margin	Not included
Negative margin			R		R		R
Positive margin			1.412(0.838–2.38)	0.195	1.706(1.01–2.881)	0.046	1.408(0.755–2.627)	0.282
Esophageal invasion					Not included		Not included
No	R		R
Yes	1.233(0.678–2.244)	0.493	1.411(0.767–2.595)	0.268
Perineural invasion			Not included		Not included		Not included
No	R
Yes	0.941(0.413–2.144)	0.886
Vascular/lymphatic invasion					Not included		Not included
No	R		R
Yes	2.076(1.305–3.303)	0.002	2.017(1.242–3.276)	0.005
Pathological T status	Not included
pT1/T2			R		R		R
pT3/T4			1.056(0.655–1.703)	0.823	1.182(0.735–1.899)	0.491	1.286(0.731–2.264)	0.383
Pathological N status
pN1	R		R		R		R
pN2	1.024(0.501–2.094)	0.948	1.171(0.558–2.457)	0.677	0.944(0.435–2.049)	0.884	3.199(0.956–10.709)	0.059
pN3	As ENE	–	As ENE		As ENE		As ENE
Level I involvement					Not included
No	R		R				R
Yes	1.539(0.684–3.461)	0.297	1.392(0.58–3.338)	0.459			1.321(0.52–3.359)	0.558
Level III involvement	Not included		Not included		Not included
No							R
Yes							1.439(0.616–3.364)	0.401
Level IV involvement
No	R		R		R		R
Yes	4.634(3.147–6.825)	<0.001	4.687(3.12–7.04)	<0.001	4.687(3.033–7.243)	<0.001	2.569(1.436–4.595)	0.001
Level V involvement
No	R		R		R		R
Yes	1.22(0.75–1.985)	0.423	1.253(0.757–2.075)	0.38	0.987(0.539–1.805)	0.965	1.875(1.019–3.452)	0.043
Level VI involvement							Not included
No	R		R		R
Yes	1.329(0.746–2.371)	0.335	1.264(0.689–2.316)	0.449	1.293(0.672–2.487)	0.442
Retropharyngeal nodes involvement
No	R		R		R		R
Yes	1.847(1.066–3.199)	0.029	2.028(1.165–3.529)	0.012	1.984(1.13–3.481)	0.017	1.769(0.892–3.507)	0.102
Parotid nodes involvement
No	R		R		R		R
Yes	0.86(0.236–3.137)	0.82	0.742(0.202–2.724)	0.653	0.918(0.255–3.295)	0.895	1.609(0.417–6.212)	0.49

p value in bold, statistically significant.

CI, confidence interval; CSS, cancer-specific survival; DMFS, distant metastasis-free survival; ENE, extranodal extension; HR, hazard ratio; LN, lymph node; LRFS, locoregional relapse-free survival; NPLN, the number of positive lymph nodes; OS, overall survival; R, reference.

By the end of the last follow-up, 116 patients had died, with 106 (91.4%) deaths caused by the progression of HPSCC, while 10 patients (8.6%) died from secondary primary cancer or cardiovascular disease. Both level IV and V lymphadenopathy had a significantly adverse impact on the 5-year OS (level IV: 18.4% vs 70.6%; level V: 18% vs 59%) and CSS rate (level IV: 20.9% vs 73.6%; level V: 18.8% vs 62.6%; p < 0.001, Supplemental Table 6). The multivariate analyses of factors to predict OS and CSS showed that postcricoid region (HR = 3.072; HR = 3.319), bilateral positive LNs (HR = 2.067; HR = 2.154), vascular/lymphatic invasion (HR = 2.076; HR = 2.017), level IV (HR = 4.634; HR = 4.687), and retropharyngeal nodes involvement (HR = 1.847; HR = 2.028) significantly correlated with inferior outcomes (p < 0.05, Table 6).

Relationship between level IV/V metastasis and N stage

Among the whole cohort, patients with level IV/V metastasis exhibited the worst survival outcomes (p < 0.001, Figure 4(a) and (b)). The 5-year OS, CSS, LRFS, and DMFS rates were significantly lower in patients with level IV or level V metastasis compared to those without level IV or level V metastasis, regardless of N stage (N1 to N3, p < 0.001). Our results indicated that patients with level IV or V metastasis should be defined as more than the N3 stage. Subsequently, a separate analysis was conducted to investigate the impact of level IV/V lymphadenopathy on survival outcomes in the N3 stage. Surprisingly, even at the N3 stage, patients with level IV/V involvement demonstrated significantly worse 5-year OS, CSS, and LRFS (p < 0.05) compared to those without level IV/V disease (Figure 5(a) and (b)).

Figure 4.

Comparison of overall survival, cancer-specific survival, locoregional relapse-free survival, and distant metastasis-free survival between patients with and without level IV/V metastasis in our center. (a) The survival curves were compared among patients with and without level IV metastasis (IV+ vs IV−), stratified by N staging categories (N1(IV−), N2(IV−), N3(IV−)). (b) The survival curves were compared among patients with and without level V metastasis (V+ vs V−), stratified by N staging categories (N1, N2(V−), N3(V−)).

Figure 5.

At the N3 stage, a comparison was conducted to assess overall survival, cancer-specific survival, locoregional relapse-free survival, and distant metastasis-free survival between patients with and without level IV/V metastasis in our center. (a) Level IV− versus level IV+. (b) Level V− versus level V+.

The role of CCRT

Despite the lack of a significant benefit from CCRT compared to radiotherapy alone (Supplemental Table 6) in the entire cohort, a different scenario emerged when we analyzed two subgroups based on the involvement of level IV/V. The patients with level IV metastasis who received CCRT after surgery had a significantly better 5-year LRFS (34.7% vs 10.6%, p = 0.033) compared to those who received radiotherapy alone (Figure 6(a)). On the contrary, CCRT did not present an advantage over radiotherapy alone in patients without level IV metastasis (Figure 6(b)). Moreover, the patients with level V metastasis who received CCRT had a significantly better 5-year OS (28.6% vs 0%, p = 0.007) and CSS (28.6% vs 0%, p = 0.014) compared to those who received radiotherapy alone (Figure 7(a)). However, CCRT did not contribute a significant advantage over radiotherapy alone in patients without level V lymphadenopathy (Figure 7(b)).

Figure 6.

Overall survival, cancer-specific survival, locoregional relapse-free survival, and distant metastasis-free survival curves according to patients’ postoperative treatment modality (CCRT vs RT alone). (a) Patients with level IV metastasis (IV+). (b) Patients without level IV metastasis (IV−).

Figure 7.

Overall survival, cancer-specific survival, locoregional relapse-free survival, and distant metastasis-free survival according to patients’ postoperative treatment modality (CCRT vs RT alone). (a) Patients with level V metastasis (V+). (b) Patients without level V metastasis (V−).

Discussion

The presence of LN metastasis is considered one of the most significant prognostic factors, leading to the classification of patients as stage III or IV disease for HNSCC.² Notably, N2 stage, ENE, multiple pN+, LN ratio, as well as lymphatic invasion have been correlated with unfavorable clinical outcomes.^9,13–15 However, evidence is lacking in terms of whether the location of the involved LN might impact the prognosis of HPSCC. For the first time, our study demonstrated that the presence of level IV/V lymphadenopathy significantly outweighs other parameters associated with LNs in predicting the prognosis for HPSCC.

The current research on the distribution of LN metastasis and its impact on prognosis remains limited in patients with HPSCC. The patterns of LN spread in 244 newly diagnosed HPSCC patients were assessed using pre-treatment MRI.¹⁶ The overall lymph node metastasis (LNM) rates to levels II–VI and retropharyngeal LNs were 59.0%, 52.9%, 14.3%, 1.6%, 2.9%, and 16.4%, respectively. However, it should be noted that clinical diagnosis may not necessarily align with pathological diagnosis, especially regarding the rate of cervical LN involvement, potentially leading to an underestimation of metastasis rate in level IV/V. The metastatic pattern of LNs in HPSCC was investigated in another study, which assessed 75 dissected lateral neck specimens. The study found that the order of metastatic ratio was level II (90.5%), level III (76.2%), level IV (41.3%), level V (15.9%), level I (7.9%), and level VI (3.2%).¹⁷ These findings were in close accordance with our real-world study. It is generally believed that level IV/V metastasis in HPSCC occurs secondarily to level II–III involvement.^11,18,19 Consequently, the vast majority of patients exhibiting metastasis in the level IV/V also presented with multiple LN involvement within the regional LNs.^7,20–22 In our study, a higher N stage was identified as a significant risk factor for level IV/V metastasis, which was consistent with previous reports of oral cancer.^23,24 More significantly, our research has revealed a close correlation between level IV/V metastasis and ENE, thereby indicating an unfavorable prognosis for level IV/V lymphadenopathy.^6,23,24

The NCCN guidelines for HNSCC specifically address the risk of level IV/V metastasis related to oral and oropharyngeal cancer, where it is regarded as an intermediate risk factor for recurrence. Therefore, postoperative radiotherapy or CCRT is recommended for such cases.^2,9 The presence of level IV/V metastases in oral cancer was associated with an elevated risk of neck recurrence and signifies an unfavorable prognosis.^23–26 In our study, only level IV and level V among all metastatic LN regions were found to be independent predictors of prognosis in the SEER database. More importantly, cases with level IV/V involvement have worse outcomes in the subgroups of patients with pN1-N3 disease in our center. Studies of oral cancer have revealed that even in patients with ENE/pN3b, there remains considerable variation in prognosis.^6,27 Notably, individuals with metastasis to the IV/V region exhibited the worst prognosis and should therefore be classified as high risk within the N3b population.^6,27 Following neck LN dissection, the presence of IV/V metastasis still remains a significant risk factor for regional recurrence.^24,28 Level IV/V represents a critical LN region, and the presence of level IV/V lymphadenopathy is indicative of an elevated risk for occult metastases in the subsequent lymphatic drainage pathway and distant metastasis.⁶

It is widely acknowledged that a high frequency of distant metastases occurs predominantly in patients with advanced LN involvement.^29–31 The study of 111 patients with HNSCC³² revealed through univariate and multivariate analyses that level IV lymphadenopathy had an independent impact on pulmonary metastases. The currently accepted theory suggests a sequential metastasis through the locoregional lymphatics into the bloodstream.^32–34 In our study, level IV/V involvement was significantly associated with distant metastasis at initial presentation and after treatment. It has been observed that the involvement of level V increases the likelihood of distant metastasis to multiple organs. Thus, if level V lymphadenopathy was detected, the cancer should be considered highly aggressive.⁶ Due to the high risk of regional recurrence and distant metastasis associated with IV/V involvement in HPSCC, patients diagnosed as pN1 or pN2 after surgery should still be considered at an elevated risk level. An aggressive and intensified therapeutic approach might be suitable for these patients.

Unlike oral cancer or oropharyngeal cancer, the NCCN guidelines do not provide specific recommendations for patients with level IV/V metastasis in HPSCC. The SEER database demonstrated that patients who underwent neck dissection exhibit a better prognosis compared to those who did not receive neck dissection. A consensus has yet to be reached regarding the application of postoperative adjuvant therapy. Our previous research indicated that patients with an NPLN of 3 or higher who underwent postoperative CCRT exhibited significantly improved OS, CSS, and LRFS compared to those who received radiotherapy alone,⁵ which was consistent with other relevant studies on HNSCC.³⁵ Those findings suggested that LN metastasis burden seemed to be an appropriate selection criterion for CCRT. Li analyzed patients with HNSCC who underwent surgical treatment, specifically focusing on those with LN metastasis but without positive margins or ENE.³⁵ In patients with levels IV/V involvement, adding chemotherapy to postoperative radiotherapy resulted in a 24% reduction in recurrence risk and a 20% decrease in mortality risk. In our study, postoperative CCRT significantly improved the rates of LRFS and OS in patients with level IV/V metastasis. The administration of CCRT, however, did not yield a significant improvement in DMFS. The poor survival of the patients with level IV/V involvement may be explained by the high incidence of distant metastasis (level IV: 50.6%; level V: 63.2%). It is worthwhile to explore other potential adjuvant therapies to decrease the rate of distant metastasis.

It is important to acknowledge the limitations of our current study. The first point is that our study was retrospective, and not all patients underwent nodal dissections ranging from level I to level VI. The second point was radiation dose, 54–70 Gy was delivered to the neck based on pathologic information and also at the discretion of the supervising physician. Whether different dose levels might impact OS, DMFS, and LRFS needs to be explored in the future.

Conclusion

To our knowledge, this study is the first to demonstrate that metastasis to level IV/V was significantly associated with a poorer prognosis in HPSCC patients. Therefore, adjuvant therapy (radiotherapy or CCRT) is strongly recommended following surgery for patients presenting with level IV/V metastasis. We suggest taking into account the location of lymphadenopathy for the staging system in the future. Our results indicated that patients with level IV or V metastasis should be defined as ⩾N3 stage.

Supplemental Material

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Supplemental material, sj-docx-4-tam-10.1177_17588359241312079 for The association between level IV/V metastasis and the recurrence, distant metastasis, and survival outcomes in hypopharyngeal squamous cell carcinoma by Ruichen Li, Qi Wang, Siyuan Ma, Ji Li, Yang Zhao and Xiaoshen Wang in Therapeutic Advances in Medical Oncology

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sj-docx-6-tam-10.1177_17588359241312079 – Supplemental material for The association between level IV/V metastasis and the recurrence, distant metastasis, and survival outcomes in hypopharyngeal squamous cell carcinoma

Supplemental material, sj-docx-6-tam-10.1177_17588359241312079 for The association between level IV/V metastasis and the recurrence, distant metastasis, and survival outcomes in hypopharyngeal squamous cell carcinoma by Ruichen Li, Qi Wang, Siyuan Ma, Ji Li, Yang Zhao and Xiaoshen Wang in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-pdf-7-tam-10.1177_17588359241312079 – Supplemental material for The association between level IV/V metastasis and the recurrence, distant metastasis, and survival outcomes in hypopharyngeal squamous cell carcinoma

Supplemental material, sj-pdf-7-tam-10.1177_17588359241312079 for The association between level IV/V metastasis and the recurrence, distant metastasis, and survival outcomes in hypopharyngeal squamous cell carcinoma by Ruichen Li, Qi Wang, Siyuan Ma, Ji Li, Yang Zhao and Xiaoshen Wang in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Ruichen Li

Supplemental material

Supplemental material for this article is available online.

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