ORIGINAL ARTICLE
Lymph node density—Prognostic value in head and neck cancer
Sonali Rudra, MD,1* Michael T. Spiotto, MD, PhD,1 Mary Ellyn Witt, RN,1 Elizabeth A. Blair, MD,2 Kerstin Stenson, MD,2 Daniel J. Haraf, MD1
1
Department of Radiation and Cellular Oncology, The University of Chicago Medical Center, Chicago, Illinois, 2Section of Otolaryngology/Head and Neck Surgery,
The University of Chicago Medical Center, Chicago, Illinois.
Accepted 29 January 2013
Published online 14 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23299
ABSTRACT: Background. The purpose of this study was to determine
the prognostic value of lymph node density in head and neck cancer.
Methods. We utilized a prospective, multicenter database of 223
patients with head and neck cancer to identify patients who underwent
lymph node dissection before chemoradiation to assess the prognostic
significance of lymph node density.
Results. In 38 patients who met study criteria, lymph node density
0.20 predicted for improved overall survival (OS; 79% vs 50%; p ¼
.04). Lymph node density was also associated with a trend toward
improved 3-year locoregional control (96% vs 79%; p ¼ .14) and distant
metastasis–free survival (93% vs 78%; p ¼ .13). In the patients with
INTRODUCTION
Head and neck cancer is a common site of malignancy
with an estimated 52,140 cases and 11,460 deaths in
2011.1 Despite advances in diagnosis, the majority of
patients present with stage III/IV disease2 and require
treatment with a combination of chemotherapy, radiation
therapy, and/or surgery.
The current American Joint Committee on Cancer
guidelines stage all patients with lymph node involvement
as having stage III or stage IV disease. However, there is
significant heterogeneity in outcomes between patients
within each stage or even nodal group, which makes
prognosis difficult to estimate. Some studies have shown
that the nodal stage does not stratify well with tumor control.3,4 Therefore, previous investigators have tried to
characterize other features of lymph node involvement
that can further stratify patients with nodal involvement,
such as the total number of lymph nodes, location in the
neck (eg, upper vs lower neck), or presence of extracapsular extension.5,6
Recently, the lymph node density has been advocated
to guide prognosis in other disease sites including breast,
treatment failure distantly or locoregionally, that failure was earlier in
patients with lymph node density >0.20 than in patients with lymph
node density 0.20 (median, 12.7 months vs 5.2 months; p ¼ .004).
Conclusion. Our data suggest that lymph node density predicts for OS in
patients with head and neck cancer and that the difference in OS may
C 2013 Wiley Periodicals,
be because of differences in time to failure. V
Inc. Head Neck 36: 266–272, 2014
KEY WORDS: head and neck, radiation, lymph node density, surgery,
prognosis
bladder, and gastrointestinal malignancies.7–11 The lymph
node density, sometimes referred to as the lymph node ratio, is defined as the total number of positive lymph
nodes to the total number of lymph nodes dissected and
assessed. Using the ratio can minimize differences in surgical and pathologic techniques. In head and neck cancer,
retrospective studies have suggested that the lymph node
density may be prognostic in oral cavity squamous cell
carcinoma (SCC).12–15 However, the prognostic effect of
the lymph node density in head and neck cancer has not
yet been validated in prospective studies or studied in
other head and neck sites. Additionally, the majority of
patients in the previous oral cavity SCC studies were
treated with surgery alone or surgery followed by adjuvant radiation, rather than with adjuvant chemoradiation.
In this study, we retrospectively reviewed a large, multicenter prospective database of patients with head and
neck cancer to assess the prognostic significance of the
lymph node density. The analysis focuses on the subset
of pathologically node-positive patients who underwent
lymph node dissection with or without resection of the
primary lesion before chemotherapy and radiation.
MATERIALS AND METHODS
Patient population
*Corresponding author: S. Rudra, Department of Radiation and Cellular
Oncology, University of Chicago Hospitals, 5758 S. Maryland Ave, MC 9006,
Chicago, IL 60637. E-mail: [email protected]
Contract grant sponsor: This study was supported in part by the Robert and
Valda Svendsen Memorial.
This work was presented at the 53rd Annual Meeting of the American Society for
Therapeutic Radiology and Oncology, Miami, Florida, 2011.
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FEBRUARY 2014
Between February 1996 and January 2005, 223 consecutive patients with locoregionally advanced nonmetastatic
SCC and poorly differentiated head and neck carcinoma
were enrolled on 3 sequential multi-institutional phase II
chemoradiotherapy (CRT) trials (Protocols 7929, 8626,
and 19A).16–18 Patients were recruited onto these trials
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from the University of Chicago Hospital, University of
Illinois, Northwestern Memorial Hospital, Evanston Hospital, and Lakeland Hospital. The protocols were
reviewed and approved by the institutional review boards
of all institutions. Informed consent was obtained from all
patients. From this cohort, patients who underwent lymph
node dissection with or without surgery to the primary
lesion before chemoradiation were identified for this analysis. Patients who did not undergo neck dissection or who
underwent dissection after definitive chemoradiation were
excluded. Patients with pathologically negative lymph
nodes were also excluded from the analysis. Our study
cohort was selected from this database of patients enrolled on phase II trials because these patients had follow-up data collected in a prospective manner that was
available for analysis. Details of these protocols have
been published previously.16–18 Before any therapy,
patients were evaluated with a complete history and physical, radiographic assessment of the primary tumor, neck,
and chest, bone scan, panendoscopy, dental evaluation,
and speech and swallowing evaluation. Review of patient
data for this analysis was approved by the Institutional
Review Board protocol #12-1555.
Treatment
Surgery. The type and extent of surgery was dependent on
the primary site, the surgeon’s clinical judgment, and the
patient’s willingness to undergo resection. The primary
goal of surgical resection was to preserve cosmetic and
functional outcome without compromising locoregional
control. Patients underwent radical neck dissection, modified radical neck dissection, or selective neck dissection
per the treating physician’s discretion.
Concurrent chemoradiotherapy. CRT was administered on
days 1 to 5 (d1–5) of each cycle followed by a 9-day
break without chemotherapy or radiotherapy. Cycles were
repeated every 14 days until the completion of CRT.
CRT consisted of paclitaxel (20 mg/m2/day on d1–5 from
1996 to 2000 or 100 mg/m2 on d1 after 2000), oral
hydroxyurea (500 mg prescribed orally every 12 hours on
d1–5 of each cycle, given 2 hours before each fraction),
continuous-infusion 5-fluorouracil (5-FU; 600 mg/m2/day
on d1–5), and 1.5 Gy twice a day radiation, administered
as previously described.16–18 Patients treated on protocol
19A received chemotherapy with 2 cycles of paclitaxel
(100 mg/m2 days 1, 8, and 15) and carboplatin (area
under the curve of 6, day 1) before CRT. Concurrent
CRT, scheduled to begin 1 to 2 weeks after the last dose
of paclitaxel, consisted of 4 to 5 cycles of hydroxyurea,
5-FU, gefitinib, and 1.5 Gy of radiation twice per day.
Gefitinib (250 mg every day orally) was begun on the
first day of radiotherapy and continued for a maximum of
2 years.
Radiation therapy. All patients underwent CT-based treatment planning and risk-defined volumes were contoured
by the attending radiation oncologist. Patients receiving
chemotherapy before chemoradiation underwent 2 CT
simulations both before and after administration of chemotherapy alone. The gross tumor volume included all
known areas of gross disease detected on physical or
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radiographic examination before the administration of
chemotherapy. The highest risk volume, planning target
volume 1 (PTV1), included the gross tumor volume (or
resection bed) expanded by 1.5 cm. PTV2 included PTV1
plus the first echelon of uninvolved lymph nodes, and
PTV3 included PTV2 plus the second echelon of uninvolved lymph nodes. Volumes were modified to avoid
spinal cord overlap or extension beyond the skin. Radiotherapy was delivered via 6-MV photons using twicedaily 1.5-Gy fractions with a minimum 6-hour interfractional interval. Patients who underwent complete
resection were prescribed doses of 60 to 66 Gy. All gross
disease was prescribed doses of 70 to 75 Gy.
Statistical analysis
Estimates of the probability of locoregional control
(LRC), distant metastasis-free survival, relapse-free survival (RFS), and overall survival (OS) were calculated
using the Kaplan–Meier method. Time to event was
measured from the start of chemoradiation. RFS was calculated to the date of local or distant failure. Patient follow-up was reported up to the date last seen in the clinic
or identified through the Social Security Death Index.
The effect of the lymph node density and pN (pathologic nodal) classification on the endpoints in our study
was assessed using the log-rank test. Various previously
published cutoffs for the lymph node density were
assessed, including 0.06, 0.13, and 0.20. A univariate
analysis was performed for OS and RFS using a log-rank
test for dichotomous variables. The following factors
were assessed for prognostic effect on OS and RFS on
univariate analysis: age greater than the median (54
years vs >54), lymph node density (0.20 vs >0.20),
number of lymph nodes assessed greater than or less than
the median (26 vs >26), Tx/1/2 versus T3/4 disease,
pN (pN1 vs pN2 vs pN3), the use of chemotherapy before
chemoradiation, and resection of primary and lymph node
dissection versus lymph node dissection alone. These variables were selected based on a literature review of factors commonly associated with OS in head and neck cancer or other malignancies.19–23 Given the overall young
age of the patients, age was also assessed as a continuous
variable. We also assessed the type of neck dissection
(radical/modified radical vs selective neck dissection).
Factors that were statistically significant or near statistical
significance (p .10) on univariate analysis were entered
into a multivariate Cox regression analysis for OS and
RFS. A separate analysis was done in the patients who
had local or distant failure to analyze if the lymph node
density was predictive of time to failure or OS. Statistics
were performed with JMP, version 9 (Cary, NC). Power
calculations were done using STATA, version 12 (College Station, TX).
RESULTS
Of the 223 patients treated on 3 protocols, 41 patients
underwent lymph node dissection before CRT. Of these
patients, 3 patients were excluded because they were
found to be pN0. Therefore, a total of 38 patients were
identified and analyzed for this study. Patient, tumor, and
treatment characteristics are summarized in Table 1. The
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RUDRA ET AL.
TABLE 1. Patient, tumor, and treatment characteristics.
Characteristics
Age, y
Median
Range
Sex
Male
Female
Primary site
Oropharynx
Oral cavity
CUP
Larynx/hypopharynx
Stage
III
IVA
IVB
cT-classification
Tx (CUP)
T1–2
T3–4
cN-classification
N1
N2a
N2b
N2c
N3
RT dose, Gy
Median
Range
Chemotherapy regimen
Paclitaxel, 5-FU, hydroxyurea
Carboplatin þ paclitaxel!gefitinib,
5-FU, Hydoxyurea!gefitinib
Surgery
Neck only
Primary and neck
Bilateral vs unilateral dissection
Bilateral neck
Unilateral neck
Type of neck dissection (45 total necks)
Radical neck
Modified radical neck
Selective
Unknown
No. of patients
(%)
54
34–75
29 (76)
9 (24)
17 (44)
12 (32)
6 (16)
3 (8)
1 (3)
34 (89)
3 (8)
6 (16)
18 (47)
14 (37)
2 (5)
1(3)
27 (71)
5 (13)
3 (8)
60.5 Gy
30–75 Gy
24 (63)
14 (37)
22 (58)
16 (42)
7 (18)
31 (82)
4 (9)
19 (42)
18 (40)
4 (9)
TABLE 2. Locoregional control, distant metastasis-free survival,
relapse-free survival, and overall survival based on pathologic nodal
classification.
3-y LRC
3-y DMFS
3-y RFS
3-y OS
pN1 (n ¼ 5)
pN2 (n ¼ 30)
pN3 (n ¼ 3)
75%
100%
75%
75%
93%
86%
83%
70%
100%; p ¼ .64
100%; p ¼ .64
100%; p ¼ .77
67%; p ¼ .89
Abbreviations: pN classification, pathologic nodal classification; LRC, locoregional control;
DMFS, distant metastasis-free survival; RFS, relapse-free survival; OS, overall survival.
lymph nodes involved, and 1 patient had undergone simple tonsillectomy. Fifteen patients received chemotherapy
before chemoradiation, and none received chemotherapy
before lymph node dissection. A total of 45 necks were
dissected in 38 patients. The type of lymph node dissection is listed in Table 1.
Locoregional control, distant control, and
overall survival
Overall, 3-year actuarial LRC, distant metastasis–free
survival, and RFS was 91.7%, 88.5%, and 83%, respectively. The 3-year OS was 71%.
The pathologic N classification was not found to be
associated with 3-year LRC, distant metastasis-free survival, RFS, or OS based on log-rank analysis (Table 2).
However, density of lymph nodes involved 0.20 was
associated with an improvement in OS (3-year OS 79%
vs 50%; p ¼ .04; Figure 1). There was also a trend toward improved LRC (96% vs 79%; p ¼ .14), distant metastasis-free survival (93% vs 78%; p ¼ .13), and RFS
(89% vs 68%; p ¼ .10) in patients with a lymph node
density 0.20 compared to those with a higher lymph
node density.
Other studies in the head and neck literature have demonstrated an association of other thresholds (lymph node
density >0.06 or >0.13) with outcomes.12–15 In our
cohort, there was no statistically significant difference in
LRC, distant metastasis-free survival, RFS, or OS when a
Abbreviations: CUP, cancer of unknown primary; cT-classification, clinical T classification;
cN-classification, clinical N classification; RT, radiation therapy; Gy, gray; 5-FU, 5fluorouracil.
median follow-up was 52 months. The median patient age
was 54 years and the majority of patients were men
(76%). The majority of patients had stage IVA disease (n
¼ 34), 8% had stage IVB (n ¼ 3), and 3% had stage III
disease (n ¼ 1). The most common primary sites were
oropharynx (44%), oral cavity (32%), and cancer of
unknown primary (16%). Twenty-two patients (58%)
underwent lymph node dissection alone before chemoradiation and the remaining patients also underwent resection of the primary. Of the patients who underwent surgical excision of the primary, 9 patients underwent adjuvant
chemoradiation for positive or close margins, 2 patients
had evidence of extracapsular extension, 1 patient had
invasion of the skeletal muscle, 3 patients had multiple
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FIGURE 1. The overall survival (OS) rates are shown for patients
who had a lymph node density 0.20 (solid line) at the time of
dissection versus >0.20 lymph nodes involved (dashed line).
Three-year OS ¼ 79% versus 50%, p ¼ .04.
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TABLE 3. Locoregional control, distant metastasis-free survival, relapsefree survival, and overall survival based on alternate lymph node
density cutoffs.
3-y LRC
3-y DMFS
3-y RFS
3-y OS
LND 0.13 vs LND >0.13
LND 0.06 vs LND >0.06
95% vs 89%; p ¼ .84
89% vs 88%; p ¼ .82
84% vs 83%; p ¼ .68
79% vs 63%; p ¼ .77
89% vs 93%; p ¼ .30
100% vs 85%; p ¼ .74
89% vs 81%; p ¼ .51
89% vs 65%; p ¼ .48
Abbreviations: LND, lymph node density; LRC, locoregional control; DMFS, distant metastasis-free survival; RFS, relapse-free survival; OS, overall survival.
lymph node density cutoff of 0.06 or 0.13 was used.
These results are shown in Table 3.
Univariate/multivariate analysis
On univariate analysis, the following factors were
assessed for prognostic effect on OS: age greater than the
median age (54 years vs >54), lymph node density
(0.20 vs >0.20), number of lymph nodes assessed
greater than or less than the median (26 vs >26), Tx/1/
2 versus T3/4 disease, pN (pN1 vs pN2 vs pN3), the use
of chemotherapy before chemoradiation, and resection of
primary and lymph node dissection versus lymph node
dissection alone. We also assessed the type of neck dissection (radical/modified radical vs selective neck dissection). Only age >54 years and lymph node density >0.20
were associated with worse OS. When age was assessed
as a continuous variable, it was also found to be significant on univariate analysis (p ¼ .01). Notably, pN classification was not found to correlate with OS on univariate
analysis (p ¼ .89). On multivariate analysis, both age
>54 years (hazard ratio [HR] ¼ 5.92; 95% confidence
interval [CI] ¼ 1.86–26.3; p ¼ .002) and lymph node
density >0.20 (HR ¼ 4.19; 95% CI ¼ 1.17–14.3; p ¼
.03) were significant (Table 4).
A univariate analysis was also done to determine factors associated with RFS. The same factors listed above
were tested. Only age >54 was found to be statistically
significant (p ¼ .01), whereas lymph node density >0.20
and number of lymph nodes dissected >26 reached borderline significance (p ¼ .10 for both). In multivariate
analysis, all 3 of these factors were found to be statistically significant (Table 4). Given the limited number of
locoregional or distant failures, a multivariate analysis
was not performed for these endpoints.
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Patterns of failure
Eight patients had documented progression of disease.
The site of progression was locoregional alone in 3
patients, distant and locoregional in 1 patient, and distant
alone in 4 patients. Of the 3 patients who recurred locoregionally first, all received salvage surgery and 1 patient
was recommended to undergo adjuvant reirradiation
because of positive margins. The median time to locoregional failure in these 3 patients was 9.7 months. Of the
5 patients who had distant failure as a component of first
failure, 2 failed in the lung, 1 failed in the lung and liver,
1 failed with dermal metastasis, and 1 failed extensively
in the chest, pericardium, liver, bone, and brain. The median time to distant failure in these 5 patients was 9.2
months. In patients who had either distant or locoregional
failure, the 3-year OS was 25% compared 83% in those
who did not fail (p ¼ .001; Figure 2). There was no difference in OS between patients who failed locoregionally
alone compared with those who had a component of distant failure (p ¼ .44).
The time to failure (local or distant) was analyzed
based on the lymph node density in these 8 patients. The
median time to failure in patients with a lymph node density >0.20 was 5.2 months compared with 12.7 months in
those patients with a lymph node density 0.20 (p ¼
.004; Figure 3A). The median OS was also worse in these
8 patients when they had a higher lymph node density.
The median OS in patients with lymph node density
>0.20 was 8.7 months compared with 23 months in
patients with a lymph node density 0.20 (p ¼ .004;
Figure 3B).
DISCUSSION
In this study, a multicenter prospective database of
patients with head and neck cancer was analyzed to
investigate the prognostic value of the lymph node density in locally advanced head and neck cancer. We found
that the lymph node density 0.20 was predictive for
improved OS (79% vs 50%; p ¼ .04). The lymph node
density was also associated with a trend toward improved
LRC (96% vs 79%; p ¼ .14), distant metastasis-free survival (93% vs 78%; p ¼ .13), and RFS (89% vs 68%; p
¼ .10). In our cohort, the prognostic value of using a
lymph node density cutoff of 0.06 or 0.13 was not
observed. Additionally, the analysis did not demonstrate a
prognostic value of the pathologic nodal stage for LRC,
distant metastasis-free survival, RFS, or OS. In the subset
TABLE 4. Univariate and multivariate analysis for overall survival and relapse-free survival.
Age >54 vs 54
LND >0.20 vs 0.20
Lymph node dissected >26 vs 26
Tx/1/2 vs T3/4
pN1 vs pN2 vs pN3
Chemo before CRT vs CRT alone
Resection of primary þ LND vs LND only
Dissection type (radical vs selective)
OS (univariate)
OS (multivariate)
RFS (univariate)
RFS (multivariate)
p ¼ .008
p ¼ .04
p ¼ .68
p ¼ .38
p ¼ .89
p ¼ .61
p ¼ .70
p ¼ .19
p ¼ .002
p ¼ .03
p ¼ .01
p ¼ .10
p ¼ .10
p ¼ .41
p ¼ .77
p ¼ .64
p ¼ .88
p ¼ .52
p ¼ .001
p ¼ .02
p ¼ .02
Abbreviations: OS, overall survival; RFS, relapse-free survival; LND, lymph node density; pN, pathologic nodal classification; Chemo, chemotherapy; CRT, chemoradiation.
The figures in boldface represent factors that were found to be statistically significant.
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RUDRA ET AL.
FIGURE 2. The overall survival (OS) rates are shown for patients
who did not experience a failure (solid line) versus those who did
experience a failure (dashed line). Three-year OS ¼ 83% versus
25%; p ¼ .001.
of patients who failed either locally or distantly, higher
lymph node density was associated with shorter median
time to failure (12.7 months with lymph node density
0.20 vs 5.2 months with lymph node density >0.20;
p ¼ .004), as well as shorter OS (23 months vs 8.7
months; p ¼ .004). This may suggest that a larger burden
of nodal disease predicts for a shorter time to failure and
may explain the differences seen in OS based on the
lymph node density.
On univariate and multivariate analysis, age >54 and
lymph node density >0.20 were statistically significant
for OS. For RFS, age was found to be statistically significant, whereas lymph node density >0.20 and number of
lymph nodes dissected >26 reached borderline significance on univariate analysis. However, all 3 factors were
found to be statistically significant on multivariate analysis. Age has been shown to be prognostic in many studies. Most notably, a meta-analysis by Pignon et al24
revealed that age >71 predicted for no improvement in
OS with the addition of chemotherapy. Because only 2 of
our patients were above the age of 70 years, we did not
analyze if age >70 was prognostic in our study, but
instead analyzed age as both a continuous variable and
using a threshold of the median age in our cohort.
There are several limitations in our study. Although
this study is a multi-institutional study, our institutional
preference is to treat the majority of patients with locally
advanced head and neck cancer with definitive CRT to
try to achieve organ preservation. Most institutions treat
oral cavity tumors with surgical resection 6 adjuvant
therapy. However, 7 of the 12 patients with oral cavity
SCC underwent definitive chemoradiation alone.
Although these patients were treated on protocol, even
off-protocol, patients with oral cavity SCC are treated at
University of Chicago with definitive chemoradiation
with good control rates (5-year PFS ¼ 66.9%).25 Because
of these differences in treatment regimens, our study population may vary from those at other institutions, which
may limit generalizability. Additionally, there were a limited number of events (locoregional failures and distant
failures) which precluded a multivariate analysis for LRC
or distant metastasis-free survival. However, we did perform a multivariate analysis for OS because there were
17 events for this analysis. Additionally, power calculations revealed that our study was underpowered to detect
differences in the LRC, distant metastasis–free survival,
and RFS using a lymph node density threshold of 0.20.
Additionally, the study was underpowered to detect differences in any of the outcomes (LRC, distant metastasis–free survival, RFS, and OS) using lower lymph node
density thresholds of 0.13 or 0.06 (data not shown).
Major strengths of this study include its multi-institutional
setting and prospective collection of patient information.
Despite the limitations, our data still suggest the prognostic value of the lymph node density on OS.
In this study, the pN classification was not predictive
for LRC, distant metastasis-free survival, or OS. This
may be partially explained by the relative prevalence of
patients with pN2 disease in our cohort (13% pN1, 79%
pN2, and 8% pN3), which may have limited statistical
power. However, the prevalence of pN2 disease in locally
advanced head and neck cancer that we observed reflects
what is often seen in practice.26,27 This suggests that the
lymph node density may have greater prognostic significance for node-positive patients than traditional pN classification. Using the pN staging, there was a trend toward
decreased OS with higher pN classification, but this was
FIGURE 3. (A) The time to failure (TTF) rates are shown for patients with lymph node density 0.20 (solid line) versus those with lymph node
density >0.20 (dashed line) in the patients who failed either locally or distantly. (B) The overall survival (OS) rates are shown for patients with
lymph node density 0.20 (solid line) versus those with lymph node density >0.20 (dashed line) in patients with either local or distant failure.
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not observed with LRC, distant metastasis–free survival,
or RFS. In comparison, using the lymph node density,
worse LRC, distant metastasis–free survival, RFS, and OS
were observed with increasing burden of disease. Another
advantage of the lymph node density over pN classification clinically is that the use of the lymph node density
may help standardize against variability in either the
number of lymph nodes removed by the surgeon or the
number of lymph nodes assessed by the pathologist. In
our study, the median number of lymph nodes assessed
was 26, but the range of lymph nodes assessed was 4 to
76. Therefore, using the lymph node density can adjust
for differences in pathologist and surgeon preferences.
In our study, a lymph node density cutoff of 0.20 was
found to be an important threshold, which is supported by
multiple studies in the literature. Van der Wal et al7
assessed the prognostic effect of the lymph node density
in a retrospective series in breast cancer. In women with
positive lymph nodes, they found that having a lymph
node density >0.20 predicted for worse 10-year OS (73%
vs 52%; p < .0001) and distant metastasis-free survival
(HR ¼ 3.56; 95% CI ¼ 1.63–7.77). A recent study utilizing the Geneva Cancer Registry also supports the importance of the lymph node density in breast cancer. In this
study, patients with node-positive breast cancer were divided into low (0.20), intermediate (>0.20–0.65), and
high-risk (>0.65) lymph node density groups, which correlated with a difference in the 10-year disease-specific
survival (DSS) rates.8 In patients with gastric cancer, a
study by Siewert et al10 also showed that the lymph node
density was the most important prognostic factor for survival. The authors found that the relative risk of death
was 1.8 in patients with lymph node density 0.20 and
2.8 in patients with lymph node density >0.20 compared
to node-negative patients (p < .0001). Additionally, in a
series of 182 patients with pancreatic cancer treated with
surgical resection, lymph node density 0.20 was predictive for survival with 5-year OS of 6% (lymph node density 0.20) versus 19% (lymph node density <0.20; p ¼
.003).11 In head and neck cancer, a study from Australia
analyzed 313 patients with oral cavity SCC and revealed
that the lymph node density was a predictor of regional
failure, DSS, and OS. The authors then divided the
patients into 3 groups (lymph node density ¼
0.025–0.075, 0.075–0.20, and >0.20) and found that the
relative risk of death from oral cavity SCC was 2.6, 3.7,
and 4.4 times that of patients with a lymph node density
<0.025, showing that the patients with lymph node density >0.2 were in the highest risk group.12
This study also adds to the growing body of literature
demonstrating that the lymph node density can be used as
a prognostic indicator in head and neck cancer.12–15 To
our knowledge, all of the studies published thus far have
been in oral cavity SCC. A study from Memorial
Sloan–Kettering reported the value of the lymph node
density in comparison to conventional staging in patients
undergoing neck dissection for oral cavity SCC. In their
population, stratifying patients with a lymph node density
of >0.06 or 0.06 was the most important prognostic
factor, compared with T classification, presence of extracapsular spread, overall stage, and number of positive
lymph nodes.13 A study from the Princess Margaret Hospital analyzing patients with oral cavity SCC also found
NODE DENSITY AS PROGNOSTIC
the lymph node density to be the most important predictor
of both DSS and OS. They were able to stratify these
patients further based on the lymph node density into low
(<0.06), intermediate (0.06–0.13), and high-risk groups
(>0.13) with 5-year OS rates of 54.1%, 44.7%, and
16.1%, respectively.14 In aggregate, these studies show
the importance of incorporating the lymph node density
to predict a patient’s prognosis. We assessed these lower
thresholds in our cohort and did not find it to be statistically significant, but did find a higher threshold (lymph
node density >0.20) to be a statistically significant predictor of OS.
CONCLUSIONS
Our findings demonstrate the prognostic value of the
lymph node density (using a cutoff of 0.20) for OS. Using
the lymph node density may be important in determining
the appropriate treatment strategy for patients undergoing
lymph node dissection before adjuvant treatment or definitive chemoradiation. Currently, the main indications for
postoperative chemoradiation include extracapsular extension and positive surgical margins,28 whereas some institutions will also include patients with lymphovascular
invasion, perineural invasion, or multiple lymph nodes
involved.2 Using the lymph node density may provide
additional prognostic information that could be useful in
determining if adjuvant treatment is required. Future studies should validate these findings in other clinical settings
and prospectively evaluate the clinical utility of the
lymph node density.
Acknowledgments
We thank Dr. Sydeaka Watson, PhD, for providing statistical consultation.
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