Introduction: The presence of cervical lymph node metastases is an unfavorable prognostic factor in head and neck squamous cell carcinoma (HNSCC) and a potential cause of treatment failure. Occult lymph node metastasis occurs in approximately 15–20% of HNSCC patients with a clinically negative neck (cN0), greatly impacting on their prognosis. The present study aimed to investigate the role of pre-treatment peripheral blood markers in predicting clinically occult cervical lymph node metastasis. Methods: This multicenter, retrospective study was performed in a cohort of 472 patients diagnosed with cN0 HNSCC who underwent up-front surgery. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory marker (SIM), and systemic immune-inflammation index (SII) were calculated from available blood parameters. Results: Oro-hypopharyngeal and oral cancers, locally advanced stage, moderately (G2), and poorly (G3) differentiated grade were associated with an increased risk of pathological lymph node involvement. NLR, LMR, PLR, SIM, and SII were significantly associated at multivariable analysis. NLR >2.12 was the most reliable at predicting occult lymph node metastasis (OR = 5.22; 95% CI: 2.14–12.75). We describe a predictive score integrating cancer site, local stage, and NLR which is effective at predicting positive lymph node pathological status. Conclusions: The present study provides evidence that pre-treatment peripheral blood markers, in particular NLR, represent reliable predictors of clinically occult cervical lymph node metastasis in cN0 HNSCC. Therefore, the present study provides a novel useful predictive score for directing the elective management of the neck in patients with cN0 HNSCC.

1.
Ferlito
A
,
Rinaldo
A
,
Devaney
KO
,
MacLennan
K
,
Myers
JN
,
Petruzzelli
GJ
et al
.
Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes
.
Oral Oncol
.
2002
;
38
(
8
):
747
51
.
2.
de Bondt
RBJ
,
Nelemans
PJ
,
Hofman
PAM
,
Casselman
JW
,
Kremer
B
,
van Engelshoven
JMA
et al
.
Detection of lymph node metastases in head and neck cancer: a meta-analysis comparing US, USgFNAC, CT and MR imaging
.
Eur J Radiol
.
2007
;
64
(
2
):
266
72
.
3.
Ferlito
A
,
Shaha
AR
,
Rinaldo
A
.
The incidence of lymph node micrometastases in patients pathologically staged N0 in cancer of oral cavity and oropharynx
.
Oral Oncol
.
2002
;
38
(
1
):
3
5
.
4.
Wei
WI
,
Ferlito
A
,
Rinaldo
A
,
Gourin
CG
,
Lowry
J
,
Ho
WK
et al
.
Management of the N0 neck: reference or preference
.
Oral Oncol
.
2006
;
42
(
2
):
115
22
.
5.
Sanabria
A
,
Shah
JP
,
Medina
JE
,
Olsen
KD
,
Robbins
KT
,
Silver
CE
et al
.
Incidence of occult lymph node metastasis in primary larynx squamous cell carcinoma, by subsite, t classification and neck level: a systematic review
.
Cancers
.
2020
;
12
(
4
):
1059
.
6.
van den Brekel
MWM
,
Castelijns
JA
,
Stel
HV
,
Golding
RP
,
Meyer
CJL
,
Snow
GB
.
Modern imaging techniques and ultrasound-guided aspiration cytology for the assessment of neck node metastases: a prospective comparative study
.
Eur Arch Oto-Rhino-Laryngol
.
1993
;
250
(
1
):
11
7
.
7.
Mascarella
MA
,
Mannard
E
,
Silva
SD
,
Zeitouni
A
.
Neutrophil-to-lymphocyte ratio in head and neck cancer prognosis: a systematic review and meta-analysis
.
Head Neck
.
2018
;
40
(
5
):
1091
100
.
8.
Wang
L
,
Simons
DL
,
Lu
X
,
Tu
TY
,
Avalos
C
,
Chang
AY
et al
.
Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes
.
EBioMedicine
.
2020
;
52
:
102631
.
9.
Liang
W
,
Ferrara
N
.
The complex role of Neutrophils in tumor angiogenesis and metastasis
.
Cancer Immunol Res
.
2016
;
4
(
2
):
83
91
.
10.
Chen
L
,
Zhang
F
,
Sheng
XG
,
Zhang
SQ
,
Chen
YT
,
Liu
BW
.
Peripheral platelet/lymphocyte ratio predicts lymph node metastasis and acts as a superior prognostic factor for cervical cancer when combined with neutrophil: lymphocyte
.
Medicine
.
2016
;
95
(
32
):
e4381
.
11.
Chen
MF
,
Tsai
MS
,
Chen
WC
,
Chen
PT
.
Predictive value of the pretreatment neutrophil-to-lymphocyte ratio in head and neck squamous cell carcinoma
.
J Clin Med
.
2018
;
7
(
10
):
294
.
12.
Szilasi
Z
,
Jósa
V
,
Zrubka
Z
,
Mezei
T
,
Vass
T
,
Merkel
K
et al
.
Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as prognostic markers of survival in patients with head and neck tumours – results of a retrospective multicentric study
.
Int J Environ Res Public Health
.
2020
;
17
(
5
):
1742
.
13.
Yang
L
,
Huang
Y
,
Zhou
L
,
Dai
Y
,
Hu
G
.
High pretreatment neutrophil-to-lymphocyte ratio as a predictor of poor survival prognosis in head and neck squamous cell carcinoma: systematic review and meta-analysis
.
Head Neck
.
2019
;
41
(
5
):
1525
35
.
14.
De Felice
F
,
Tombolini
M
,
Abate
G
,
Salerno
F
,
Bulzonetti
N
,
Tombolini
V
et al
.
Prognostic significance of the neutrophil/lymphocyte ratio in patients with non-human papilloma virus-related oropharyngeal cancer: a retrospective cohort study
.
Oncology
.
2019
;
96
(
1
):
8
13
.
15.
Abbate
V
,
Dell’Aversana Orabona
G
,
Salzano
G
,
Bonavolontà
P
,
Maglitto
F
,
Romano
A
et al
.
Pre-treatment Neutrophil-to-Lymphocyte Ratio as a predictor for occult cervical metastasis in early stage (T1-T2 cN0) squamous cell carcinoma of the oral tongue
.
Surg Oncol
.
2018
;
27
(
3
):
503
7
.
16.
Li
Y
,
Liu
K
,
Ke
Y
,
Zeng
Y
,
Chen
M
,
Li
W
et al
.
Risk factors analysis of pathologically confirmed cervical lymph nodes metastasis in oral squamous cell carcinoma patients with clinically negative cervical lymph node: results from a cancer center of central China
.
J Cancer
.
2019
;
10
(
13
):
3062
9
.
17.
Salzano
G
,
Perri
F
,
Maglitto
F
,
Togo
G
,
De Fazio
GR
,
Apolito
M
et al
.
Pre-treatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of occult cervical metastasis in clinically negative neck supraglottic and glottic cancer
.
J Pers Med
.
2021
;
11
(
12
):
1252
.
18.
Ventura
E
,
Barros
J
,
Salgado
I
,
Millán
A
,
Vilares
M
,
Zagalo
C
et al
.
Pretreatment blood markers in the prediction of occult neck metastasis: a 10-year retrospective study
.
Cureus
.
2021
;
13
(
7
):
e16641
.
19.
Kano
S
,
Homma
A
,
Hatakeyama
H
,
Mizumachi
T
,
Sakashita
T
,
Kakizaki
T
et al
.
Pretreatment lymphocyte-to-monocyte ratio as an independent prognostic factor for head and neck cancer
.
Head Neck
.
2017
;
39
(
2
):
247
53
.
20.
Zhou
S
,
Yuan
H
,
Wang
J
,
Hu
X
,
Liu
F
,
Zhang
Y
et al
.
Prognostic value of systemic inflammatory marker in patients with head and neck squamous cell carcinoma undergoing surgical resection
.
Future Oncol
.
2020
;
16
(
10
):
559
71
.
21.
Diao
P
,
Wu
Y
,
Li
J
,
Zhang
W
,
Huang
R
,
Zhou
C
et al
.
Preoperative systemic immune-inflammation index predicts prognosis of patients with oral squamous cell carcinoma after curative resection
.
J Transl Med
.
2018
;
16
(
1
):
365
.
22.
Hong
W
,
Lillemoe
KD
,
Pan
S
,
Zimmer
V
,
Kontopantelis
E
,
Stock
S
et al
.
Development and validation of a risk prediction score for severe acute pancreatitis
.
J Transl Med
.
2019
;
17
(
1
):
146
.
23.
Bhattacharya
K
,
Mahajan
A
,
Vaish
R
,
Rane
S
,
Shukla
S
,
D’Cruz
AK
.
Imaging of neck nodes in head and neck cancers – a comprehensive update
.
Clin Oncol
.
2023
;
35
(
7
):
429
45
.
24.
Welsh
LW
,
Welsh
JJ
,
Rizzo
TA
.
Laryngeal spaces and lymphatics: current anatomic concepts
.
Ann Otol Rhinol Laryngol Suppl
.
1983
;
105
:
19
31
.
25.
Valero
C
,
Pardo
L
,
López
M
,
García
J
,
Camacho
M
,
Quer
M
et al
.
Pretreatment count of peripheral neutrophils, monocytes, and lymphocytes as independent prognostic factor in patients with head and neck cancer
.
Head Neck
.
2017
;
39
(
2
):
219
26
.
26.
Pereira
ER
,
Jones
D
,
Jung
K
,
Padera
TP
.
The lymph node microenvironment and its role in the progression of metastatic cancer
.
Semin Cell Dev Biol
.
2015
;
38
:
98
105
.
27.
Deng
L
,
Zhang
H
,
Luan
Y
,
Zhang
J
,
Xing
Q
,
Dong
S
et al
.
Accumulation of Foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients
.
Clin Cancer Res
.
2010
;
16
(
16
):
4105
12
.
You do not currently have access to this content.