Prognostic Value and Staging Classification of

Retropharyngeal Lymph Node Metastasis in

Nasopharyngeal Carcinoma Patients Treated with
Intensity-modulated Radiotherapy
1.

1.

Ling-Long Tang , Rui Guo , Guanqun Zhou , Ying Sun , Li-Zhi Liu , Ai-Hua Lin , Haiqiang Mai , Jianyong
5

Shao , Li Li , Jun Ma *

1 Department of Radiation oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer
Medicine, Guangzhou, Guangdong, Peoples Republic of China, 2 Imaging Diagnosis and Interventional Center, State Key Laboratory of Oncology in South China, Sun Yatsen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, Peoples Republic of China, 3 Department of Medical
Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, Peoples Republic of China, 4 Department of Nasopharyngeal
Carcinoma, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, Peoples Republic of China,

5 Department of Molecular Diagnostics, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation
Center for Cancer Medicine, Guangzhou, Guangdong, Peoples Republic of China

Abstract

Background: The development of intensity-modulated radiotherapy (IMRT) has revolutionized the management of
nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the prognostic value and classification of TNM
stage system for retropharyngeal lymph node (RLN) metastasis in NPC in the IMRT era.

Material and Methods: We retrospectively reviewed data from 749 patients with biopsy-proven, non-metastatic NPC. All
patients received IMRT as the primary treatment. Chemotherapy was administered to 86.2% (424/492) of the patients with
stage III or IV disease.

Results: The incidence of RLN metastasis was 64.2% (481/749). Significant differences were observed in the 5-year
disease-free survival (DFS; 70.6% vs. 85.4%, P,0.001) and distant metastasis-free survival (DMFS; 79.2% vs. 90.1%,
P,0.001) rates of patients with and without RLN metastasis. In multivariate analysis, RLN metastasis was an independent
prognostic factor for disease failure and distant failure (P = 0.005 and P = 0.026, respectively), but not for locoregional
recurrence. Necrotic RLN metastases have a negative effect on disease failure, distant failure and locoregional recurrence in
NPC with RLN metastasis (P = 0.003, P = 0.018 and P = 0.005, respectively). Survival curves demonstrated a significant
difference in DFS between patients with N0 disease and N1 disease with only RLN metastasis (P = 0.020), and marginally
statistically significant differences in DMFS and DFS between N1 disease with only RLN metastasis and other N1 disease (P
= 0.058 and P = 0.091, respectively). In N1 disease, no significant differences in DFS were observed between unilateral and
bilateral RLN metastasis (P = 0.994).

Conclusions: In the IMRT era, RLN metastasis remains an independent prognostic factor for DFS and DMFS in NPC. It is still
reasonable for RLN metastasis to be classified in the N1 disease, regardless of laterality. However, there is a need to investigate the
feasibility of classifying RLN metastasis as N1a disease in future by a larger cohort study.

Citation: Tang L-L, Guo R, Zhou G, Sun Y, Liu L-Z, et al. (2014) Prognostic Value and Staging Classification of Retropharyngeal Lymph Node Metastasis in Nasopharyngeal
Carcinoma Patients Treated with Intensity-modulated Radiotherapy. PLoS ONE 9(10): e108375. doi:10.1371/journal.pone.0108375

Editor: Masaru Katoh, National Cancer Center, Japan

Received June 23, 2014; Accepted August 19, 2014; Published October 10, 2014

Copyright: 2014 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All data files are available from the figshare
database (DOI:10.6084/m9.figshare.1120584).

Funding: This work was supported by grants from the China Scholarship Council (No. 201308440052, the National Natural Science Foundation of China (No.
81101695 and No. 81071836), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2010), and the Innovation Team
Development Plan of the Ministry of Education (IRT1297). The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

* Email: majun2@mail.sysu.edu.cn

. These authors contributed equally to this work.

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October 2014 | Volume 9 | Issue 10 | e108375

Introduction

Although nasopharyngeal carcinoma (NPC) is rare in most regions of

the world, it is endemic in certain regions, especially Southeast Asia.
The incidence of NPC is approximately 3080 per 100,000 per year
in Southern China [1]. The nasopharynx contains a well-developed
network of lymph nodes, and the retropharyngeal lymph nodes (RLN)
are regarded as one of the key lymph nodes in NPC [2]. Due to the
limitations of CT imaging, RLN metastases are isodense and
contiguous with the primary tumor, and can be difficult to identify as
a separate mass on CT scans; therefore, the true incidence of RLN
metastasis was previously underestimated [35]. However, due the
superior soft tissue contrast and multiplanar capacity of MRI, the
incidence of RLN metastasis in NPC is currently approximately 70%
[5,6], and RLN metastasis has received increasing attention in recent
years.

The recent seventh edition of the International Union against

Cancer/American Joint Committee on Cancer (UICC/AJCC)
staging system for NPC incorporated RLN metastasis into the
tumor-node-metastasis (TNM) classification, and classified it as
N1 disease regardless of laterality [7,8]. However, this revision
was based on patients treated with a two-dimensional
conventional radiotherapy technique. Intensity-modulated
radiotherapy (IMRT) offers an improved tumor target conformity,
allows safer dose escalations and yields superior results in NPC
compared to 2D-CRT, primarily by achieving a higher local tumor
control rate [9]. IMRT has gradually replaced two-dimensional
conventional radiotherapy as the primary radiotherapy modality
for the treatment of NPC; however, the introduction of new
therapeutic technologies may require a revaluation of the
prognostic value and appropriate classification of TNM staging
system for RLN metastasis in NPC.

In this study, we analyzed the outcomes of patients with NPC

staged by MRI prior to treatment who subsequently received
IMRT and the current standard systemic treatments, to investigate
whether it is still reasonable to classify RLN metastasis in NPC as
N1 disease in the IMRT era.

Methods and Materials

Patient characteristics

Approval for retrospective analysis of the patient data was

obtained from the ethics committee of Sun Yat-sen University
Cancer Center. Written consent was waived, while oral consent

from the patients was obtained via telephone and documented by

telephone recording. All 749 patients with newly diagnosed,
biopsy-proven, non-metastatic NPC who were treated at Sun YatSen University Cancer Center using IMRT between January 2003
and December 2007 were retrospectively reviewed. The clinicopathologic characteristics of the patients are shown in Table 1.

All patients completed a pre-treatment evaluation including

complete patient history, physical examination, hematology and
biochemistry profiles, neck and nasopharyngeal MRI, chest
radiography, abdominal sonography and a single photon emission
computed tomography (SPECT) whole body bone scan. 18-Ffluorodeoxyglucose (FDG)-positron emission tomography (PET)CT was performed on 162/749 patients (21.6%). All patients were
retrospectively re-staged according to the 7th edition of UICC/
AJCC staging system. The distribution of disease stages was:
stage I, 10.4%; stage II, 23.9%; stage III, 37.7% and stage IVab,
28.0% (Table 1).

Classification of RLN Metastasis in NPC

MRI techniques and criteria for retropharyngeal lymph

node and other cervical lymph node metastasis

All patients underwent MRI scans using a 1.5-T system (Signa,

General Electric, CV/i; General Electric Healthcare, Chalfont St.
Giles, United Kingdom). The area from the suprasellar cistern to
the inferior margin of the sternal end of clavicle was examined
with a head and neck combined coil. T1-weighted fast spin-echo
images in the axial, coronal and sagittal planes (repetition time of
500600 ms and echo time of 1020 ms), and T2-weighted fast
spin-echo MR images in the axial plane (repetition time of 4000
6000 ms and echo time of 95110 ms) were obtained before
injection of contrast material. After intravenous injection of GdDTPA at a dose of 0.1 mmol/kg body weight, spin-echo T1weighted axial and sagittal sequences, and spin-echo T1-weighted
fat-suppressed coronal sequences were performed sequentially
using parameters similar to those used before injection of
contrast. The section thickness for the axial plane was 5 mm with
a 1 mm interslice gap, and 6 mm with a 1 mm interslice gap for
the coronal and sagittal planes.

Two radiologists specializing in head and neck cancers evaluated

all of the scans independently. Any disagreements were resolved
by consensus. The diagnostic MRI criteria for metastatic
lymphadenopathy included: 1) lateral RLN with a minimal axial
diameter of $5 mm and any node seen in the median
retropharyngeal group, or lymph nodes with a minimal axial
diameter $11 mm in the diagastric region or $10 mm for all other
cervical nodes except the retropharyngeal group; 2) lymph nodes
of any size with central necrosis or a contrast-enhanced rim; and
3) nodal grouping: the presence of three or more contiguous and
confluent lymph nodes, each of which should have a minimal
axial diameter of 810 mm [1012]. The criteria for extranodal
neoplastic spread (ENS) in RLN was the presence of indistinct
nodal margins, irregular nodal capsular enhancement or infiltration into the adjacent fat or muscle [13].

Treatment

All patients received IMRT as the primary treatment. The patients

were immobilized in supine position by a thermoplastic mask.
After administration of intravenous contrast material, 3-mm CT
slices, depicting the area of the head until 2 cm below the sternoclavicular joint, were acquired. The primary tumor and the upperneck area above the caudal edge of the cricoid cartilage were
treated by IMRT. Target volumes were in agreement with the

International Commission on Radiation Units and Measure-ments

Reports 50 and 62. The contoured images were transferred to an
integrated IMRT planning and delivery system (Peacock, Corvus
3.0, NOMOS Corporation, Sewickley, Pa). The pre-scribed
radiation dose was defined as follows: a total dose of 68 Gy in 30
fractions at 2.27 Gy per fraction to the planning target volume
(PTV) of the primary gross tumor volume (GTV-P), 60 to 64 Gy
to the PTV of nodal gross tumor volume (GTV-N), 60 Gy to the
PTV of CTV-1 (i.e., high-risk regions), and 54 Gy to the PTV of
CTV-2 (i.e., low-risk regions) and CTV-N (i.e., neck nodal
regions). The treatment was delivered by a dynamic, multileaf,
intensitymodulating collimator (called MIMiC). For the lower
neck, an anterior cervical field was used. All patients were treated
with one fraction daily over 5 days per week.

Chemotherapy was administered to 86.2% (424/492) of the

patients with stage III or IV disease. The chemotherapy regimens
included concurrent chemotherapy alone, concurrent chemotherapy combined with induction chemotherapy and/or adjuvant
chemotherapy in conjunction with a platinum-based therapeutic
clinical trial. Reasons for deviation from institutional guidelines
included patients refusal, age ($70 years), organ severe dysfunc-

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Classification of RLN Metastasis in NPC

Table 1. The clinicpathological characters of 749 patients in this study.

Characteristic
N
Column (%)

Age

.50
553
73.8

#50
196
26.2
Gender

Male
580
77.4
Female
169
22.6

Histologic type

WHO II/III
744
99.3

WHO I
5
0.7
T category

T1
177
23.6
T2

140
18.7

T3
264
35.2
T4
168
22.4

N category

N0
184
24.6

N1
409
54.6
N2
106
14.2

N3
50
6.7

Stage

I
78
10.4
II
179
23.9

III
282
37.7
Iva-b
210
28.0

Chemotherapy

No
214
28.6

Concurrent

233
33.5
Concurrent + Induction
246
32.8

Concurrent + Adjuvant
46
6.1
PET-CT

Yes
162
21.6
No
587
78.4

doi:10.1371/journal.pone.0108375.t001

Follow-up
tion (diabetes, cardiac dysfunction, renal insufficiency, liver
insufficiency, et al) that would suggest intolerance to chemotherapy. When possible, salvage treatments such as intracavitary
brachytherapy, surgery and chemotherapy were provided in the
event of documented relapse or persistent disease.

Median follow-up was 81 months (range, 3127 months). Each

patient was assessed weekly during treatment for treatment
response and toxicity, and every 23 months during the first 2
years and every 36 months during years 35 after radiotherapy.
Endoscopy, CT or MRI scans of the head and neck were
performed every 3 months during the first year and annually

during years 25. Patients with residual or recurrent local disease

underwent biopsy to confirm malignancy. Additional tests were
ordered when indicated to evaluate for local or distant failure.

from the start of treatment to the first defining event) were

estimated: locoregional relapse-free survival (LRRFS), local
relapse-free survival (LRFS), and nodal relapse-free survival
(NRFS), DMFS, disease-free survival (DFS) and overall survival
(OS).

Statistical analysis

All analyses were performed using SPSS version 20.0 (IBM

Corporation, Armonk, NY, USA). Actuarial rates were estimated
by the Kaplan-Meier method; survival curves were compared
using the log-rank test [14]. The following endpoints (measured

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Multivariate analyses with the Cox proportional hazards model

were used to test for independent significance by backward
elimination of insignificant explanatory variables [15]. The Cox
proportional hazards model was used to calculate hazard ratios
(HRs). Two-tailed P values ,0.05 were considered statistically
significant.

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Classification of RLN Metastasis in NPC

Figure 1. Survival curves for nasopharyngeal carcinoma (NPC) patients with and without retropharyngeal lymph node (RLN) metastasis.
RLN (-): NPC patients without RLN metastasis; RLN (+): NPC patients with RLN metastasis.
doi:10.1371/journal.pone.0108375.g001

Results

bilateral involvement. The mean minimal and maximal axial

diameters of the RLN metastases were 9.6164.31 mm (range, 5
28 mm) and 12.6665.61 mm (range, 536 mm). The incidence of
RLN necrosis was 13.3% (64/481) and the incidence of ENS was
21.8% (105/481).

Incidence of RLN metastasis

Prognostic value of RLN metastasis
In this study, no patient had a metastatic median RLN, and the
incidence of lateral RLN metastasis in the current study was
64.2% (481/749 patients). Thirty-two percent (154/481) of
patients with RLN metastasis had no evidence of cervical lymph
node (CLN) metastasis, and 79.6% (327/411) patients with CLN
metastasis had evidence of RLN involvement.

Of 481 the patients with RLN metastasis, 63.2% (304/481) had

unilateral RLN involvement, whereas 36.8% (177 of 481) had

There were 56/749 (7.5%) patients developed recurrence,

including 34 patients (4.5%) with isolated local recurrences, 15
patients (2.0%) with isolated regional nodal recurrences, and 7
patients (0.9%) with both local and regional nodal recurrence. In
addition, there were 129 (17.2%) patients developed distant
metastases and 149 (19.9%) died. The 5-year survival rates were:
LRRFS, 92.9%; DMFS, 83.1%; DFS, 75.9% and OS, 83.9%.

Significant differences were observed in the 5-year DFS (70.6% vs.

85.4%, P,0.001), DMFS (79.2% vs. 90.1%, P,0.001) and LRRFS
(90.5% vs. 97.0%, P = 0.010) rates of patients with and without RLN
metastasis (Figure 1). Multivariate analysis was performed to adjust
for various prognostic factors; the following known important

prognostic variables were included in the Cox proportional hazards

model: age (#50 vs..50 years), gender, T-classification, chemotherapy
(yes vs. no), bilateral CLN metastasis (yes vs. no), dimension of CLN
metastases (#6 vs..6 cm) and the

Table 2. Summary of multivariate analysis of prognostic factors in 749 patients with nasopharyngeal carcinoma.

Endpoint
Variable
B
P*
HR
95% CI for HR

Distant failure
Retropharyngeal lymph node (yes vs. no)
0.520
0.026
1.682
1.0652.655

Age (#50 vs. 50 years)

0.406
0.040
1.501
1.0192.211

T-classification
0.451
,0.001
1.570
1.3071.887

CLN dimension (#6 vs. . 6 cm)

1.268
,0.001
3.555
1.9656.434

CLN location (with SCLN vs. without SCLN)

0.896
0.003
2.450
1.3514.443

Bilateral CLN (yes vs. no)

0.511
0.013
1.668
1.1142.497

Disease failure
Retropharyngeal lymph node (yes vs. no)
0.509
0.005
1.663
1.1692.365

Age (#50 vs. 50 years)

0.656
,0.001
1.927
1.4272.602

T classification
0.435
,0.001
1.544
1.3351.787

CLN dimension (#6 vs. .6 cm)

1.068
,0.001
2.908
1.6915.001

CLN location (with SCLN vs. without SCLN)

0.818
0.002
2.266
1.3423.826

Bilateral CLN (yes vs. no)

0.362
0.040
1.436
1.0162.029

Locoregional recurrence
Retropharyngeal lymph node (yes vs. no)
NS

T-classification
0.438
0.001
1.550
1.1832.031

Bilateral CLN (yes vs. no)

0.681
0.022
1.975
1.1053.530

Abbreviations: CI = confidence interval; HR = hazard ratio; CLN = cervical lymph nodes; NS = not significant; SCLN = Supraclavicular lymph node.

*P values were calculated using an adjusted Cox proportional-hazards model. The following known important prognostic variables were included in the Cox
proportional hazards model: age (#50 vs. .50 years), gender, T-classification, chemotherapy (yes vs. no), bilateral CLN metastasis (yes vs. no), dimension of
CLN metastases (#6 vs. .6 cm), CLN location (with SCLN vs. without SCLN) and RLN metastasis (yes vs. no).

doi:10.1371/journal.pone.0108375.t002

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retropharyngeal

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*P
0.001
0.002

0.019

neoplastic spread

Yes

70.3
58.1

85.2

nodes metastasis according to the

Extranodal

Bilateral

characteristics of

NoP

73.6

0.032

81.6

65.5

0.054

74.1

88.9

0.310

92.0

Size (minimal axial diameters)

Yes

Laterality

UnilateralP

,0.001

82.5

,0.001

73.6

,80.0 0.001

Necrosis

91.5

Abbreviations: DFS = disease-free survival; DMFS = Distant metastasis-free survival; LRRFS = Locoregional relapse-free
survival.*Pvalueswerecalculatedbytheunadjustedlog-ranktest.doi:10.1371/journal.pone.0108375.t003

Table 3. Five-year survival rates for 481

nasopharyngeal carcinoma patients with
retropharyngeal lymphlymphnodemetastasis.

62.8
53.1

10 mm

10 mm

,86.571.90.001

81.6

,78.362.90.001

73.3

LRRFS
92.0

93.5

No,$P

87.3

0.017

DMFS

Classification of RLN Metastasis in NPC

DFS

location of CLN metastasis (with supraclavicular lymph nodes

metastasis vs. without supraclavicular lymph nodes metastasis).
Dimension of CLN metastases (#6 vs..6 cm) was measured based
on maximal diameter by palpation. RLN metastasis was an
independent prognostic factor for disease failure and distant
failure (HR = 1.663, 95% CI: 1.1692.365, P = 0.005, and HR =
1.682, 95% CI: 1.0652.655, P = 0.026, respectively), but not for
locoregional recurrence (Table 2).

All of the MRI-determined nodal variables were analyzed in the

481 patients with RLN metastasis using univariate analyses and
multivariate analyses. The RLN variables were categorized as
follows: minimal axial diameters (,10 vs. $10 mm MID), necrosis
(no vs. yes), laterality (unilateral vs. bilateral) and ENS (no vs.
yes). Univariate analysis revealed that necrosis had significant
prog-nostic value for DMFS, DFS and LRRFS (P,0.001, P,0.001
and P,0.001; Table 3). After adjusting for various prognostic
factors including age, sex, T-classification, N-classification and
chemotherapy, necrosis remained significant for disease failure,
distant failure and locoregional recurrence (HR = 1.795, 95%CI:
1.2142.654, P = 0.003; HR = 1.752, 95%CI:1.1002.790, P =
0.018 and HR = 2.614, 95%CI: 1.3395.103, P = 0.005; Table 4).

Survival according to N classification

According to the seventh edition of AJCC staging system, RLN is

included as a criterion for N1 disease, and 154 (20.6%) N0
patients would be upgraded to N1 disease (N1 with RLN only).
All 749 patients were divided into five groups: N0 disease, N1
disease with retropharyngeal lymph node metastasis and without
CLN metastasis (N1 with RLN only), N1 disease with CLN
metastasis (N1 with CLN), N2 disease, and N3 disease. The
survival curves demonstrated a significant difference in DFS
between patients with N0 disease and N1 with RLN only (P =
0.020). The differences in DMFS and DFS between N1 with RLN
only and N1 with CLN were marginally statistically significant (P
= 0.058 and P = 0.091, respectively; Fig. 2).

In the N1 disease group, no significant differences were observed

in the DFS, MDFS, LRFS or NRFS rates of patients with
unilateral and bilateral RLN metastasis (P = 0.994, P = 0.752, P
= 0.398 and P = 0.08 respectively).

Discussion

The TNM staging system is crucial for

predicting prognosis, guiding treatment
strategy for different risk groups, and
facilitating the exchange of information
between oncology centers [8,16]. The
TNM staging system is continually
being modified to account for new
developments in diagnostic and
therapeutic techniques. There is little
controversy that IMRT is the treatment
of choice for NPC, as dosimetric studies
have demonstrated the clear advantages
of IMRT in terms of improving the dose
conformity for complex tumor targets

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and better protecting the adjacent organs at risk [17,18]. This is

the first study to demonstrate that it is reasonable for RLN
metastasis in NPC to be classified as N1 disease in the IMRT era.

Prognostic value of RLN metastasis

Several studies have reported that neck lymph node involve-ment

in NPC spreads in an orderly manner down the neck [19,20].
RLN metastasis is very common in NPC, as the RLNs are the first
echelon lymph node [21]. When treated with two-dimensional
conventional radiotherapy, patients with NPC and RLN metastasis
had a poor prognosis [7]. In this study of patients treated with
IMRT, RLN metastasis remained an independent

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Classification of RLN Metastasis in NPC

Table 4. Summary of multivariate analysis of prognostic factors in 481 nasopharyngeal carcinoma patients with
retropharyngeal lymph node metastasis (RLN) metastasis.

Endpoint

Variable
B
P*
HR
95% CI for HR

Disease failure
Age (#50 vs. 50)
0.659
,0.001
1.933
1.3742.721

T-classification
0.330
,0.001
1.391
1.1671.658

N-classification
0.349
,0.001
1.417
1.2031.670

Necrosis
0.585
0.003
1.795
1.2142.654

MID (,10 vs. $10 mm)

0.329
0.063
1.389
0.9831.964
Distant failure
Age (#50 vs. 50 years)
0.412
0.064
1.510
0.9762.335

T-classification
0.318
0.004
1.374
1.1071.706

N-classification

0.413
,0.001
1.511
1.2491.828

Necrosis
0.561
0.018
1.752
1.1002.790

MID (,10 vs. $10 mm)

0.490
0.026
1.632
1.0592.515

Locoregional recurrence
Necrosis
0.961
0.005
2.614
1.3395.103

MID (,10 vs. $10 mm)

0.570
0.083
1.767
0.9293.364

Abbreviations: CI = confidence interval, MID = minimal axial diameters.

*P values were calculated using an adjusted Cox proportional-hazards model. The following known important prognostic variables were included in the Cox
proportional hazards model: minimal axial diameters of RLN (,10 vs. $10 mm MID), necrosis of RLN (no vs. yes), laterality of RLN (unilateral vs. bilateral) and
extra nodal neoplastic spread of RLN (no vs. yes), age (#50 vs. 50), sex, T-classification, N-classification and chemotherapy (no vs. yes).

doi:10.1371/journal.pone.0108375.t004

prognostic factor for DFS and DMFS, even after adjustment for
various prognostic factors. It is possible that conventional twodimensional and three-dimensional conformal radiotherapy and

IMRT do not have a significantly different effect on DMFS in

patients with RLN metastasis. A number of studies have confirmed
that IMRT has improved local control, but not distant control, in
NPC [9,17,22]. In this study, the DMFS rate was only 83.1%,
indicating that distant failure remains a challenge in patients with

RLN metastasis. Therefore, the inclusion of RLN metastasis in the

UICC/AJCC staging system would be useful to guide treatment
planning, and additional therapeutic improvements are required to
achieve a favorable outcome in patients with RLN metastasis.

Central necrosis is considered to be a late event in the biological

evolution of tumor metastases within lymph nodes [23]. It has been
confirmed that central necrosis primarily occurs in lymph nodes

approximately 20.0 mm or larger, and it appears that central necrosis

characteristically occurs after massive tumor infiltration [24]. There
are few reports about the prognostic value of necrosis in RLN
metastases in NPC. In this study, we found that necrosis of RLN
metastases had a negative effect on survival in NPC. Tumor necrosis
is believed to represent the endpoint of severe, chronic hypoxia in
tissues distal to functional blood vessels. Tumor hypoxia may be one
factor accounting for the poor prognosis of patients with necrotic
RLN metastases [25]. Although IMRT offers improved tumor target
coverage, the lack of oxygen

th

Figure 2. Survival curves for patients with nasopharyngeal carcinoma (NPC) stratified by the N classification of the 7 edition of the
UICC/AJCC staging system for NPC. N1 + RLN only: N1 disease with retropharyngeal lymph node metastasis and without cervical lymph
node metastasis; N1 + CLN: N1 disease with cervical lymph node metastasis.
doi:10.1371/journal.pone.0108375.g002

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October 2014 | Volume 9 | Issue 10 | e108375

Sham JST, Choy D, Wei WI (1990) Nasopharyngeal carcinoma: orderly neck node
spread. Int J Radiat Oncol Biol Phys 19: 929933.

in areas of hypoxia not only makes the tissues less susceptible to

radiotherapy, but also induces the transcription of a variety of
genes which promote tumor progression and increase tumor
aggressiveness compared to non-hypoxic tumors [26,27], which
may explain why necrosis had significant prognostic value for all
endpoints (DFS, DMFS and LRRFS). We propose that RLN
necrosis should be adopted as a factor to enhance individualized
NPC patient prognostication and clinical decision making,
especially as it is simple to assess and could easily be
incorporated into routine histopathological examinations.

Classification for RLN metastasis

Due to the limited diagnostic capabilities prior to the era of MRI

imaging, consistent guidelines for the designation of RLN
metastasis could not be identified in previous TNM staging
systems; RLN metastasis was only incorporated into the TNM
classification of the most recent 7th edition of the UICC/AJCC
staging system for NPC. Evidence from two retrospective studies
indicated that patients with RLN alone, regardless of laterality,
have a similar risk of distant metastasis (DM) as patients with N1
disease [7,28]. However, all of the patients in one of these
studies [7] underwent conventional radiotherapy, and in the other
study [28], only 12.7% of the patients underwent IMRT and there
were no stratification analyses according to the radiation
technique. IMRT achieves a significantly higher survival rate in
NPC than CRT [9]; therefore, it was necessary to reevaluate
whether it is still reasonable for RLN metastasis to be classified
as N1 disease in the IMRT era.

This study, in which all patients received IMRT as the primary

treatment, demonstrates that it is still reasonable for RLN metastasis
in NPC to be classified as N1 disease, regardless of laterality. There
are a number of reasons for this suggestion: Firstly, it is well
recognized that the RLNs are the first echelon node in NPC. In most
cases, and unlike CT, MRI can discriminate the RLNs from the
primary tumor, so RLN metastasis should be classified in the Nclassification, not the T-classification. Secondly,

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In conclusion, in the IMRT era, RLN metastasis remains an

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Author Contributions

Conceived and designed the experiments: JM LT. Performed the

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LT. Contributed reagents/materials/analysis tools: LT RG GZ YS L. Liu
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