European Journal of Endocrinology (2013) 168 219–225 ISSN 0804-4643

CLINICAL STUDY

The prognostic value of the metastatic lymph node ratio and

maximal metastatic tumor size in pathological N1a papillary
thyroid carcinoma
Min Ji Jeon1, Jong Ho Yoon2, Ji Min Han1, Ji Hye Yim1, Suck Joon Hong2, Dong Eun Song3, Jin-Sook Ryu4,
Tae Yong Kim1, Young Kee Shong1 and Won Bae Kim1
Departments of 1Internal Medicine, 2Surgery, 3Pathology and 4Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine,
388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Republic of Korea
(Correspondence should be addressed to W B Kim; Email: kimwb@amc.seoul.kr)

Abstract
Objective: The presence of central neck lymph node (LN) metastases (defined as pN1a according to
Tumor Node Metastasis classification) in papillary thyroid cancer (PTC) is known as an independent
risk factor for recurrence. Extent of LN metastasis and the completeness of removal of metastatic LN
must have an impact on prognosis but they are not easy to measure. Moreover, the significance of
the size of metastatic tumors in LNs has not been clarified. This study was to evaluate the impact of
the extent of LN metastasis and size of metastatic tumors on the recurrence in pathological N1a PTC.
Design: This retrospective observational cohort study enrolled 292 PTC patients who underwent total
thyroidectomy with central neck dissection from 1999 to 2005. LN ratio was defined as the number
of metastatic LNs divided by the number of removed LNs, which was regarded as variable reflecting
both extent of LN metastasis and completeness of resection, and LN size as the maximal diameter of
tumor in metastatic LN.
Results: The significant risk factors for recurrence in univariate analysis were large primary tumor
size (defined as larger than 2 cm), high LN ratio (defined as higher than 0.4), and presence of
macrometastasis (defined as larger than 0.2 cm). Age, sex, clinical node status, and microscopic
perithyroidal extension had no effect on recurrence. In multivariate analysis, high LN ratio and
presence of macrometastasis were independent risk factors for recurrence.
Conclusion: LN ratio and size of metastatic nodes had a significant prognostic value in pathological N1a
PTC. We suggest that risk stratification of pathological N1a PTC according to the pattern of LN
metastasis such as LN ratio and size would give valuable information to clinicians.

European Journal of Endocrinology 168 219–225

Introduction as gastric, breast, and colorectal cancers. Complete

surgical removal of the involved LN may lead to
Regional neck lymph node (LN) metastases are found in clearly better prognosis even with the large number
up to 70% of cases of papillary thyroid carcinoma (PTC) of involved LNs (5, 6, 7). In breast cancers, LN size is
and the presence of neck LN metastases has been also an important prognostic factor. The term ‘micro-
identified as an independent risk factor for recurrence metastases’ was arbitrarily defined in the breast cancer
(1, 2, 3, 4). American Joint Committee on Cancer staging system in 1971 on the basis of 0.2 cm and
(AJCC) classification system based on pathological it subclassifies N1 disease (8, 9).
tumor node metastasis (TNM) parameters and age Several studies also suggested that larger size or
categorizes nodal status into N1a and N1b according higher number of metastatic LNs in PTC is associated
to the compartment of neck nodes but the prognosis of with poorer outcomes (1, 10, 11, 12, 13). A recent
PTC patients with pathological N1a are quite variable review suggested new risk factors that modify standard
(3). It is difficult to clarify the prognostic factors and to N1 risk of recurrence such as clinical status, size,
find optimal management strategies for PTCs because number, or presence of extranodal extension of
of its indolent clinical course (4). metastatic lesions in LNs (14).
LN ratio after lymphadenectomy has been known Here, we evaluated the prognostic value of meta-
as a prognostic variable in nonthyroidal cancers such static LN ratio and maximal metastatic tumor size

q 2013 European Society of Endocrinology DOI: 10.1530/EJE-12-0744

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220 M J Jeon and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 168

in pathological N1a PTC patients who underwent during surgery. Clinical N0 (cN0) was defined as the
operation in a single tertiary referral hospital absence of suspicion for LN involvement.
with postoperative radioactive iodine (RAI) ablation All the patients eligible for analysis received central
therapy. neck node dissection (by the inclusion criteria regarding
the number of removed nodes). We divided patients
into two groups according to clinical node status. Thus,
Materials and methods a group of patients with cN1 was defined as ‘therapeutic
dissection group’, and the other group of patients with
Patients cN0 was defined as ‘prophylactic dissection group’.
Pathological N1a (pN1a) was defined as the presence of
Between 1999 and 2005, 602 conventional PTC metastatic LN among four or more removed LNs from
patients who underwent total thyroidectomy, routine central neck and pathological N0 (pN0) was defined as
central neck dissection by a single surgeon (S J H),
the absence of metastasis in pathological examination.
and subsequent RAI ablation therapy according to
LN ratio was defined as the number of metastatic LNs
a protocol established by the Endocrinology Division of
divided by the number of removed LNs. It represented the
the Asan Medical Center (Seoul, Korea) were retrieved
extent of LN involvement and completeness of LN dis-
(15). The median dose of administered radioiodine
section. Receiver Operating Characteristic curve (ROC)
was 5.6 GBq. Among them, we only included patients
with four or more removed central LNs and with the curve analysis showed that 0.38 is the appropriate cutoff
maximal diameter of primary tumor O1 cm. Patients point of LN ratio (data are not shown). So, we defined
with lateral neck LN involvement or distant metastasis, low LN ratio as %0.4 and high LN ratio as O0.4.
gross invasion, or resection margin involvement by LN size, which means the maximal tumor diameter
tumor were excluded. Finally, 292 patients were eligible in the metastatic LNs, was classified into two groups
for analysis (Fig. 1). This study was approved by the on the basis of the largest LN among metastatic LN
institutional review board. using the concept of micrometastasis in breast cancer
(8, 9, 16): micrometastasis, %0.2 cm; macrometastasis,
O0.2 cm.
Definitions The patients were classified into three groups by
Clinical node status was defined as follows: clinical N1 the LN ratio and LN size: Low, low LN ratio with
(cN1) was defined as the presence of suspicious central micrometastasis; Intermediate, low LN ratio with
neck LNs identified by preoperative physical exami- macrometastasis or high LN ratio with micrometastasis;
nation, preoperative imaging and/or gross inspection and High, high LN ratio with macrometastasis.

Total thyroidectomy and central neck dissection by single surgeon Pathological examination
and underwent radioactive iodine ablation (n =602)
The entire specimen from the operation was submitted
Primary tumor sized ≤1 cm (n=151)
for histological analysis to find LN metastasis and the
Patient with primary tumor sized larger than 1.0 cm (n =451) maximal tumor diameter in the metastatic LN was
recorded. For this study, an experienced pathologist
Gross invasion and/or positive resection margin (n =73)
(D E S) reviewed the pathological slides and measured
Laternal neck involvement and/or distant metastasis (n =66)
the size of metastatic foci in each LN.
Number of removed lymph nodes less than four (n =10)

Eligible patients for analysis (n =292)

Follow-up protocol to detect recurrence
Pre-Op Abnormal Normal Normal After remnant ablation, all patients were regularly
Intra-Op Any Abnormal Normal followed with physical examination and serum Tg
measurement every 6–12 months. Neck ultrasono-
n =4 n =104
graphic examinations were done in all patients during
Therapeutic dissection group Prophylactic dissection group the entire follow-up periods at 6- to 12-month
(n =108) (n =184) intervals. Additional diagnostic imaging studies, such
as diagnostic radioiodine whole-body scan, computed
tomography, magnetic resonance scan, or whole-body
pN0 (n =40) pN1 (n =68) pN0 (n =101) pN1 (n =83) fluorodeoxyglucose-positron emission tomography
scan, were also performed in some patients. Clinical
Figure 1 Description of study cohort. This algorithm demonstrated recurrence was defined as the structural disease
how the final enrolled patients were retrieved. A total of 292 patients
were classified into therapeutic dissection group and prophylactic recurrence; reappearance of pathologically proven
dissection group according to preoperative physical examination, malignant tissue and/or appearance of metastatic
ultrasonograpy, and surgical findings. lesions in other organs by imaging studies.

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 168 LN ratio and size in pathological N1a PTC 221

Table 1 Univariate analysis of risk factors of recurrence. of these variables on recurrence in each dissection
group. All P values were two sided, with P!0.05
Classification n (%) Hazard ratio (95% CI) P value considered statistically significant.
Age (years)
!45 150 (51) Ref
R45 142 (49) 0.75 (0.39 to 1.45) 0.393
Sex Results
Male 28 (10) Ref
Female 264 (90) 0.60 (0.23 to 1.53) 0.283 Baseline characteristics of patients and LNs
Tumor size (cm)
%2.0 180 (62) Ref A total of 292 patients were evaluated in this study,
O2.0 112 (39) 2.71 (1.38 to 5.29) 0.004 and they were followed for a median of 8 years
Perithyroidal extension (IQR 5.8–10.0). Median age of the patients was 44.4
Absent 116 (40) Ref
Present 176 (60) 1.23 (0.62 to 2.46) 0.558 years (IQR 35.1–54.2) and 264 (90%) patients were
Clinical status female. Median primary tumor size was 1.8 cm (IQR
cN0 184 (63) Ref 1.5–2.5). Of 292 patients, 108 (37%) were therapeutic
cN1 108 (37) 1.84 (0.96 to 3.54) 0.068 dissection group and 184 (63%) were prophylactic dis-
Metastasis to LN
pN0 141 (48) Refa
section group. Among 108 patients in the therapeutic
pN1a 151 (52) 8.22 (2.91 to 23.25) !0.001 dissection group, four had enlarged LNs in preoperative
LN ratio physical examination or preoperative ultrasonography
Low (%0.4) 89 (59) 3.22 (0.97 to 10.71) 0.056 and 104 in intra-operative gross inspection (Fig. 1).
High (O0.4) 62 (41) 17.14 (5.94 to 49.46) !0.001 Using TNM system (a classification system of the
LN size
Micrometastasis 59 (39) 4.12 (1.21 to 14.08) 0.024 AJCC, 6th ed., 2002), 172 (59%) patients were stage I,
(%0.2 cm) seven (2%) were stage II, and 113 (39%) were stage III.
Macrometastasis 92 (61) 11.42 (3.97 to 32.83) !0.001 The median number of resected LN per patient was
(O0.2 cm) 9 (IQR 6–13). Of the 292 patients, 151 (52%) showed
Patient’s group
Low 46 (31) 2.23 (0.50 to 9.95) 0.295
metastases to central neck and the median number of
Intermediate 56 (37) 6.07 (1.87 to 19.70) 0.003 metastatic LN was 3 (IQR 2–5.5). Patients with high LN
High 49 (32) 19.08 (6.51 to 55.93) !0.001 ratio were 62 (41%) and those with low LN ratio were
89 (59%). The mean metastatic LN size was 0.3 cm
CI, confidence interval; Ref, reference; LN ratio, metastatic LNs/removed
LNs; patient group according to the ratio and size of LN.
(IQR 0.2–0.5). Among patients with LN metastasis, 92
a
pN0 is a reference group to compare risk of recurrence in LN ratio, LN size, (61%) showed macrometastasis and 59 (39%) showed
and patient group. micrometastasis. Group Low included 46 (31%), group
Intermediate included 56 (37%), and group High
included 49 (32%) patients (Table 1).
Thirty-six (12%) events of recurrence had occurred
Statistical analysis during the follow-up period. Thirty-three (92%) of them
were lateral neck recurrences, two were recurrences at
Statistics were calculated by R version 2.13 and R operation bed, and one was metastasis to mediastinal
libraries survival, car and Cairo were used to analyze LN. Most of the recurrences (34, 94%) were treated by
the data and draw graphs (R Foundation for Statistical
Computing, Vienna, Austria, http://www.R-project. Table 2 Multivariate analysis of risk factors of recurrence.
org). We also used SPSS software (version 18.0.1;
Classification Hazard ratio (95% CI) P value
SPSS, Inc.) for ROC curve analysis. Continuous variables
were presented as medians with interquartile range Model A
(IQR) and categorical variables were presented as Tumor size O2.0 cm 1.82 (0.93 to 3.60) 0.083
LN ratio Low (%0.4) 2.92 (0.88 to 9.76) 0.081
numbers with percentages. Cox proportional hazard High (O0.4) 14.83 (5.07 to 43.35) !0.001
model was used to evaluate the risk of recurrence. Model B
Univariate analyses were performed on age, sex, tumor Tumor size O2.0 cm 1.91 (0.97 to 3.77) 0.061
size, microscopic extrathyroidal extension (ETE), clinical LN size Micrometastasis 3.74 (1.09 to 12.84) 0.036
(%0.2 cm)
node status, LN size, LN ratio, and patient group. Macrometastasis 9.86 (3.39 to 28.68) !0.001
Multivariate analyses included the variables that were (O0.2 cm)
significant in the univariate analysis. Because LN size, Model C
LN ratio, and patient group were closely related, they Tumor size O2.0 cm 1.82 (0.92 to 3.58) 0.085
Patient Low 2.07 (0.46 to 9.28) 0.341
were separately analyzed in multivariate analysis. group Intermediate 5.31 (1.62 to 17.43) 0.006
Recurrence-free survival curves were constructed High 16.55 (5.58 to 49.11) !0.001
using Kaplan–Meier method and log rank tests were
Model A analyzed tumor size and LN ratio; Model B analyzed tumor size and
used to evaluate differences of recurrence-free survival LN size; Model C analyzed tumor size and patient group; LN ratio, metastatic
between patient groups. We also analyzed the impact LNs/removed LNs; Patient group according to the ratio and size of LN.

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222 M J Jeon and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 168

recurrence. We subdivided pN1a group on the basis of

100 pN0 (n =141) LN ratio and LN size. High LN ratio showed a higher
Low (n =46) hazard ratio compared with the pN0 group. Not only
Recurrence-free survival (%)

90 macrometastasis but also micrometastasis of LN was

Intermediate (n =56) associated with higher risk of recurrence than pN0
group. In consideration of both LN ratio and LN size,
80
group Low did not show any significant impact on
prognosis (Table 1).
70 Multivariate analysis on tumor size, LN size, LN
ratio, and patient’s group, which were significant
factors associated with recurrences in univariate
60
High (n =49) analysis, revealed that high LN ratio and presence of
macrometastasis were independently associated with
recurrence. Micrometastasis also carries a risk higher
0 2 4 6 8 10 12 14 than pathological N0 but lower than macrometastatic
Duration of follow-up (year) disease after adjusting for tumor size. Group Low
showed higher risk of recurrence when compared
Figure 2 Recurrence-free survival according to the patient groups with pN0 but it was not statistically significant
classified by both LN ratio and size: Low, low LN ratio with
micrometastasis; Intermediate, low LN ratio with macrometastasis
(hazard ratio 2.07, 95% confidence interval (CI)
or high LN ratio with micrometastasis; and High, high LN ratio with 0.46 to 9.28, PZ0.341) after adjusting for tumor
macrometastasis. Recurrence-free survival rate of each group size. This result suggests that LN ratio has a more
were 96.5% in pN0, 90.9% in group Low, 81.5% in group distinct effect on prognosis than LN size. Patients in
Intermediate and 54.8% in group High. There was significant
difference in recurrence-free survival among patient groups.
group Intermediate and group High showed signi-
(Log rank statisticsZ60.9, P!0.001). ficantly higher risk of recurrence (hazard ratio 5.31,
95% CI 1.62 to 17.43, PZ0.006 in Intermediate
surgical excision, two with lateral neck recurrences by group; hazard ratio 16.55, 95% CI 5.58 to 49.11,
RAI, one with lateral neck recurrences by ethanol P!0.001 in High group) (Table 2). Kaplan–Meier
injection, and one with mediastinal metastasis by curves for recurrence-free survival according to the
radiotherapy. There were three mortality events includ- patient groups is shown in Fig. 2, and there was a
ing one of disease-specific mortality from patients with clear association between prognosis and patient
lateral neck recurrence. groups (c2Z60.9, P!0.001).

Impact of LN ratio and LN size on recurrence Impact of LN ratio and LN size on recurrence
in each dissection group
In univariate analysis of risk factors for recurrence,
primary tumor of O2 cm and pN1a compared with pN0 Of 108 patients in therapeutic dissection group,
were significantly associated with recurrence of PTC. 40 patients (37%) were pN0 even though they had
Age, sex, presence of microscopic perithyroidal exten- cN1 disease. Higher LN ratio and larger LN size were
sion, and clinical node status were not risk factors for also significant risk factors in this group. However, the
Table 3 Impact of LN ratio, LN size, and patient group on recurrence in each dissection group.

Therapeutic dissection group Prophylactic dissection group

Classification n (%) Hazard ratio (95% CI) P value n (%) Hazard ratio (95% CI) P value

Metastasis to LN
pN0 40 (37) Refa 101 (55) Ref
pN1a 68 (63) 3.78 (1.10 to 12.97) 0.035 83 (45) 20.98 (2.78 to 158.30) 0.003
LN ratio
Low (%0.4) 39 (57) 1.15 (0.23 to 5.69) 0.866 50 (60) 10.14 (1.18 to 86.90) 0.034
High (O0.4) 29 (43) 40.80 (2.31 to 28.70) 0.001 33 (40) 40.80 (5.26 to 316.30) !0.001
LN size
Micrometastasis (%0.2 cm) 16 (24) 1.70 (0.28 to 10.15) 0.563 43 (52) 11.54 (1.35 to 98.79) 0.026
Macrometastasis (O0.2 cm) 52 (76) 4.59 (1.32 to 15.98) 0.017 40 (48) 33.76 (4.35 to 262.21) !0.001
Patient group
Low 14 (20) 0.00 (K0.00 to NA) 0.998 32 (39) 9.26 (0.96 to 89.01) 0.054
Intermediate 27 (40) 2.97 (0.07 to 12.43) 0.136 29 (35) 14.46 (1.61 to 129.57) 0.017
High 27 (40) 7.45 (2.07 to 26.79) 0.002 22 (27) 56.72 (7.16 to 449.11) !0.001

CI, confidence interval; Ref, reference; NA, not available; LN ratio, metastatic LNs/removed LNs; Patient group according to the ratio and size of LN.
a
pN0 is a reference group to compare risk of recurrence in LN ratio, LN size, and patient group.

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 168 LN ratio and size in pathological N1a PTC 223

analysis for patient group according to LN ratio and Discussion

size showed poorer prognosis in pN0 group than Low
group (Table 3 and Fig. 3). One possible reason is We showed the prognostic values of LN ratio and
the failure to detect clinically apparent LNs during metastatic LN size on recurrence of PTC by comparing
operation. Alternatively, enlarged LNs caused by inflam- the risk of recurrences in pN0 and pN1a patients. To
matory change may have led surgeons to make no precisely assess the impact of metastatic pattern in
further efforts to find other suspicious metastatic LNs. central neck LN on prognosis, we only selected patients
Of 184 patients in the prophylactic dissection group, with primary tumor O1 cm and without metastases to
83 patients (45%) were pN1. LN ratio and size were lateral neck or to distant organs. As only one disease-
also significant risk factors in this group. The patient specific mortality event occurred during the follow-up
groups according to LN ratio and size were well period of median 8 years, we could not evaluate the
correlated with prognosis (c 2Z43.9, P!0.001) influence of prognostic factors on overall survival.
(Table 3 and Fig. 3). This study demonstrated that both high LN ratio and
large LN size were positively associated with recurrence
A
and LN ratio has a more prominent effect. As shown in
100 Fig. 2, patient groups according to LN ratio and LN size
Low (n =14) were highly associated with prognosis. However,
patients in group Low did not show a statistically
Recurrence-free survival (%)

90 significant increased risk of recurrence compared with

pN0 (n =40)
those without pathologically proven metastatic LN.
The others had poorer prognosis that was statistically
80 significant and among them, group High, which had
Intermediate (n =27) both high LN ratio and large metastatic LN, showed the
lowest recurrence-free survival rate at 54.8%.
70 Moreover, we found that older age at diagnosis
and presence of microscopic perithyroidal extension
did not have prognostic values on recurrence. Size of
60
High (n =27) primary tumor, which was well known as an important
prognostic factor for PTC, also showed no significant
effect on recurrence in this study. Recurrence-free
0 2 4 6 8 10 12 14
survival rate according to pathological T stage was
96.7% in T1, 76.5% in T2, and 84.6% in T3, and it
Duration of follow-up (year)
seems that pathological T staging is not enough to
B predict prognosis (hazard ratio 1.53, 95% CI 0.94
100 to 2.51, PZ0.090). This is not consistent with the
pN0 (n =101) previous data (1, 10, 11, 12) and we think that
patient selection bias might have led to this conclusion,
Recurrence-free survival (%)

90 Low (n =32) as only those with tumor size O1 cm were analyzed.

Patients with tumor size !1 cm showed overall
Intermediate (n =29)
excellent prognosis and it was not meaningful to
80
analyze the impact of central neck LN metastases. We
also excluded patients with gross invasion or resection
70
margin involvement, which were associated with poorer
prognosis (4).
Postoperative staging is important to assess the risk
60 for disease recurrence, to make decisions on the
High (n =22) frequency and intensity of follow-up and on post-
operative adjunctive therapy. TNM classification is
generally applied for differentiated thyroid cancer
0 2 4 6 8 10 12 14 staging, but it was developed to predict risk for mortality
Duration of follow-up (year) and may not be appropriate for predicting recurrence in
patients (4). TNM classification distinguishes central LN
Figure 3 Recurrence-free survival according to the patient metastases from lateral neck metastases but does not
group classified by both LN ratio and size in each dissection group. take into consideration the extent of metastatic LN (1).
(A) Kaplan–Meier curves for the therapeutic dissection group. The American Thyroid Association risk of recurrence
These show poorer prognosis in the pN0 group than in the Low
group. (B) Kaplan–Meier curves for the prophylactic dissection group. system also did not use other characteristics of the LN
These show close correlation of recurrence with patient group metastases such as size or number of metastatic LNs (4).
according to LN ratio and size (Log rank statisticsZ43.9, P!0.001). All patients with central neck metastases were treated

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224 M J Jeon and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 168

in the same way, but we showed that their prognosis Declaration of interest
was extremely different according to LN ratio and to The authors declare that there is no conflict of interest that could be
metastatic LN size. These results proved the need for perceived as prejudicing the impartiality of the research reported.
new staging systems to predict accurate risk of
recurrence of pN1 patients. This is consistent with the
previous studies which showed that increased number Funding
of central LN metastases and LN size of larger than 3 cm This study was supported by a Grant (2012-289) from the Asan
were associated with poorer prognosis (1, 3, 10, 12, 13, Institute for Life Sciences, Seoul, Korea.
14, 17). Lang et al. (11) also revealed that higher
metastatic central LN ratio (over 33.34%) was an
independent factor for short-term outcomes estimated
by postablative stimulated serum thyroglobulin. References
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