ORIGINAL ARTICLE
Number of central lymph node metastasis for predicting lateral lymph node metastasis in
papillary thyroid microcarcinoma
Rui-chao Zeng, MD, Wei Zhang, MD, Er-li Gao, MD, Pu Cheng, MD, Guan-li Huang, MD, Xiao-hua Zhang, MD,* Quan Li, MD
Department of Oncology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou City, Zhejiang Province, People’s Republic of China.
Accepted 22 January 2013
Published online 30 July 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.23270
ABSTRACT: Background. The purpose of this study was to present our
evaluation of the relationship between the number of positive central
lymph nodes and lateral lymph node metastasis in patients with papillary
thyroid microcarcinoma (PTMC).
Methods. Up to 141 patients with PTMC were divided into 3 groups
according to different positive central lymph node classifications as
follows: group A, no positive central lymph node; group B, 1 positive
central lymph node; and group C, 2 or more positive central lymph
nodes.
Results. Incidence of lateral lymph node metastasis was 30.5% (43 of
141). It was significantly high in group C compared with groups A and B,
although there was no significant difference between groups A and B.
Number of positive central lymph node 2, underlying Hashimoto
thyroiditis, and extrathyroidal extension were the independent predictive
factors for lateral lymph node metastasis on multivariate analysis.
Conclusion. Lateral lymph node metastasis was mainly observed in patients
with 2 positive central lymph nodes, which is an independent predictive
factor for lateral lymph node metastasis. Therefore, 2 positive central
lymph nodes may be valuable in predicting lateral lymph node metastasis.
C 2013 Wiley Periodicals, Inc. Head Neck 36: 101–106, 2014
V
INTRODUCTION
number of positive central lymph nodes to lateral lymph
node metastasis in patients with PTMC. The present study
was designed to investigate the importance of the number
of positive central lymph nodes in predicting lateral node
involvement.
Papillary thyroid microcarcinoma (PTMC) is the most
common histological type of thyroid malignancy, which
has a rapidly increasing incidence worldwide.1 With
advances in ultrasonographic screening and ultrasonography-guided fine-needle aspiration biopsy, more patients
with PTMC have been discovered in China.2 Fortunately,
PTMC rarely becomes life threatening and patients
generally have excellent clinical outcomes after surgical
intervention. However, a subgroup of low-risk PTMC is
aggressive and shows easier recurrence or distant metastasis resulting from lymph node metastasis.3–6 The recurrence of PTMC may not be associated with increased
mortality, but repeated surgery increases the incidence of
complications, such as damage to the laryngeal nerve,
hypoparathyroidism, and so on. In the last decades, the
lymphatic drainage pattern of the thyroid has been extensively investigated. Lymph node metastasis was found to
occur usually in the paratracheal and pretracheal nodes in
the central compartment (level VI) and spreads to the
ipsilateral lateral neck nodes. Previous studies have
proven that the status of the central neck lymph nodes is
valuable in predicting lateral lymph node metastasis.7–10
However, few reports focused on the relevance of the
*Corresponding author: X.-h. Zhang, Department of Oncology, The First Affiliated
Hospital of Wenzhou Medical College, No. 2, Fu Xue Road, 325000, WenZhou City,
Zhejiang Province, People’s Republic of China. E-mail: [email protected]
KEY WORDS: papillary thyroid microcarcinoma, lymph node, central
lymph node metastasis, number of positive central lymph node,
lateral lymph node metastasis
MATERIALS AND METHODS
Between March 2004 and August 2011, 645 patients
underwent unilateral central lymph node dissection with
or without lateral lymph node dissection at our hospital.
All patients were confirmed with PTMC by final histological examination and were subjected to high-resolution
ultrasonography before surgery. Patients were enrolled if
they satisfied all of the selection criteria as follows: (1)
the patients had no history of thyroid or neck surgery; (2)
the patients had histopathologically proven PTMC, but
without other head and neck cancers; and (3) the patients
underwent total thyroidectomy with ipsilateral central and
lateral neck dissection. Based on these criteria, 142
patients with PTMC with other accompanying head and
neck cancers (most of them were papillary thyroid carcinoma cases) were excluded from this study. Of the
remaining 362 patients, 52 patients had a history of thyroid surgery, 187 patients underwent selective lateral
lymph node dissection, and 123 patients had only central
lymph node dissection. Finally, 141 patients were enrolled
in our study, of which 77 (54.6%) had ultrasonographydetectable lateral lymph node metastasis. Ultrasonography-detectable lateral lymph node metastasis was not
considered an exclusion criterion in our study. This study
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ZENG ET AL.
TABLE 1. Clinicopathological characteristics of 141 patients.
Characteristics
No. of patients
Mean age at diagnosis (range)
<45 y
45 y
Sex
Female
Male
Pathologic tumor size, mm (range)
Underlying Hashimoto thyroiditis
Multifocality
Extrathyroidal extension
Lateral lymph node metastasis
Central lymph node metastasis
The nonparametric data with continuous variables were
compared by the Mann–Whitney U test. The continuous
data were compared by independent 2-sample t test. Logistic regression analysis was performed to estimate the odds
ratios (ORs) of certain parameters. Results were presented
as OR with 95% confidence interval and p value. Any p
value < .05 was considered statistically significant.
Value
141
44.0 6 10.5 (17–72)
74 (52.5%)
67 (47.5%)
RESULTS
104 (73.8%)
37 (26.2%)
7.9 6 2.1 (2–10)
28 (19.9%)
41 (29.1%)
37 (26.2%)
43 (30.5%)
85 (57.4%)
Note: Data are expressed as mean 6 SD and number (%).
was approved by the Institutional Review Board of
Wenzhou Medical University.
Lateral lymph node dissection was performed if the
patients satisfied at least one of the selection criteria as
follows: there was a positive or suspicious radiographic
finding in the lateral lymph nodes and multiple metastatic
central lymph nodes were identified from the frozen
biopsy after unilateral central lymph node dissection,
even if the lateral lymph nodes were clinically negative.
Unilateral central lymph node dissection, which includes
dissection of the pretracheal, prelaryngeal, and ipsilateral
paratracheal lymph nodes, was performed in all patients.
As for the lateral lymph node dissection, levels II, III,
IV, and V were routinely dissected. The specimens were
sent to the laboratory for confirmation of lateral lymph
node metastasis and quantitative histopathologic
evaluation of the positive central lymph nodes from the
unilateral central compartment. The lymph nodes were
identified quantitatively and the histological reports from
all procedures were reviewed.
The data were retrospectively analyzed with respect to
age, sex, tumor size, multifocality, extrathyroidal extension, lateral lymph node metastasis, underlying Hashimoto thyroiditis, and number of positive central lymph
nodes. When multiple PTMCs were found in the specimen, the largest tumor or the most suspicious dominant
nodule was analyzed.
Statistical analysis
Categorical data were compared by chi-square and
Fisher exact tests and adjusted with the Bonferroni
correction for multiple comparisons. The data without normal distribution were tested by the Kruskal–Wallis test.
The clinicopathological characteristics of the 141
patients enrolled in this study are shown in Table 1. A
total of 90 patients (63.8%) were proven to have lymph
node metastasis by final histopathological examination,
38 patients had lymph node metastasis in both the central
and lateral compartment, 47 patients had only central
lymph node metastasis, and 5 patients had lateral but no
central lymph node metastasis. The overall rate of lateral
lymph node metastasis was 43 of 141 patients (30.5%).
Of 77 patients with ultrasonography-detectable lateral
lymph node metastasis, 31 patients had lateral lymph
node metastasis, as shown by histopathologic examination. The lateral lymph node statuses of the 141 patients
are listed in Table 2. The patients were divided into
groups according to the different numbers of positive
central lymph nodes. The incidence of lateral lymph node
metastasis evidently increased with the number of positive central lymph nodes as follows: 8.9% in patients
without positive central lymph node, 16.7% in patients
with 1 positive central lymph node, and 40% to 80% in
patients with 2 or more positive central lymph nodes.
The relationship between lateral lymph node metastasis
and number of positive central lymph nodes was further
analyzed by grouping the patients according to the number of positive central lymph nodes. First, we hypothesized that there may be a significant difference between
the patients with and without lateral lymph node metastasis. Second, 1.5 positive central lymph nodes was the
cutoff number for differentiating patients with or without
lateral lymph node metastasis by using the receiveroperating characteristic curve test. Therefore, we divided
the patients into 3 groups: group A, which had no positive central lymph node; group B, which had 1 positive
central lymph node; and group C, which had 2 or more
positive central lymph nodes. The relationship between
the 3 groups and the presence of lateral lymph node metastasis are shown in Table 3. The mean numbers of the
removed lateral lymph nodes and positive lateral lymph
nodes in the 3 groups had no significant statistical difference when only the patients with positive lateral lymph
nodes in the 3 groups were compared by Kruskal–Wallis
test (p ¼ .546 and p ¼ .500). The incidence of lateral
lymph node metastasis was significantly higher in group
TABLE 2. Lateral lymph node metastasis grouped by the number of positive central lymph node.
No. of positive central lymph nodes
Parameter
No. of patients (n ¼ 141)
No. of patients with lateral lymph node metastasis (n ¼ 43)
Incidence of patients with lateral lymph node metastasis (%)
102
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0
1
2
3
4
5
6
7
56
5
8.9
30
5
16.7
18
10
55.6
10
5
50.0
5
2
40.0
5
3
60.0
5
4
80.0
12
9
75.0
PREDICTING
LATERAL LYMPH NODE METASTASIS
TABLE 3. Relationship between number of positive central lymph node and lateral lymph node metastasis.
Parameter
No. of patients
Lateral lymph node metastasis
Negative
Positive
Mean no. of lateral lymph node
removed (range)||
Mean no. of lateral positive lymph
node removed (range)||
p value*
p value†
p value‡
.475
< .001§
< .001§
Group A
Group B
Group C
p value
56
30
55
51 (91.1%)
5 (8.9%)
16.8 (6–24)
25 (83.3%)
5 (16.7%)
14.8 (6–30)
22 (40.0%)
33 (60.0%)
13.7 (3–28)
.546
1.4 (1–3)
2.0 (1–5)
2.4 (1–11)
.500
Note: Group A had no positive central lymph node, group B had 1 positive central lymph node, and group C had at or more than 2 positive central lymph nodes.
* p value between Group A and Group B;
†
p value between group A and group C.
‡
p value between group B and group C, Bonferroni corrected a ¼ 0.0167.
§
Statistically significant (p < .05).
||
Patients with lateral lymph node positive, p value using Kruskal–Wallis test.
2, and other clinicopathologic features by univariate and
multivariate analysis. As shown in Table 4, lateral lymph
node metastasis was significantly associated with multifocality, extrathyroidal extension, underlying Hashimoto
thyroiditis, and number of positive central lymph nodes
2 on univariate analysis. None of the remaining parameters was significantly associated with lateral lymph node
metastasis. We used multivariate logistic regression analysis to confirm the independently predictive value of number of positive central lymph node 2 for lateral lymph
node metastasis. The age at diagnosis, sex, and tumor
size are associated with the clinical outcomes in thyroid
cancer.11–13 After adjusting for the established clinicopathological prognostic factors and the remaining statistically significant factors, the number of positive central
C than in groups A and B (p < .001; Bonferroni corrected a ¼ 0.0167) and had no significant difference
between groups A and B (p ¼ .475; Bonferroni corrected
a ¼ 0.0167). Approximately 80% of the lateral lymph
node metastasis was found in patients with 2 positive
central lymph nodes. Therefore, we hypothesized that 2
positive central lymph nodes is valuable in predicting
lateral lymph node metastasis.
Independent relationship between the number of
positive central lymph nodes 2 and lateral lymph
node metastasis
We examined the relationship among lateral lymph
node metastasis, number of positive central lymph node
TABLE 4. Univariable and multivariate analysis of clinicopathologic features for lateral lymph node metastasis.
Lateral lymphatic status
Characteristics
No. of patients
Age at diagnosis*
<45 y
45 y
Sex
Female
Male
Pathologic tumor size, mm†
<5
5
Multifocality
Yes
No
Underlying Hashimoto thyroiditis
Yes
No
Extrathyroidal extension
Yes
No
No. of positive central lymph nodes 2
Yes
No
Logistic regression analysis
Positive
Negative
p value
OR (95% CI)
p value
43
42.6 6 10.2
25 (58.1%)
18 (41.9%)
98
44.6 6 10.5
49 (50.0%)
49 (50.0%)
.301
.373
31 (72.1%)
12 (27.9%)
8.4 6 1.8
2
41
73 (74.5%)
25 (25.5%)
7.7 6 2.2
10
88
.009‡
19 (44.2%)
24 (55.8%)
22 (22.4%)
76 (77.6%)
2.143 (0.796–5.768)
.131
15 (34.9%)
28 (65.1%)
13 (13.3%)
85 (86.7%)
.003‡
4.340 (1.393–13.519)
.011‡
.017‡
2.838 (1.048–7.687)
.040‡
< .001‡
11.282 (4.309–29.540)
< .001‡
.766
17 (39.5%)
26 (60.5%)
33 (76.7%)
10 (23.3%)
20 (20.4%)
78 (79.6%)
.071
.447
22 (22.4%)
76 (77.6%)
Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval.
* p value using independent 2-sample t test.
†
p value using the Mann–Whitney U test; other p value using chi-square test or Fisher exact test.
‡
Statistically significant (p < .05).Note: Data are expressed as mean 6 SD and number (%).
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ZENG ET AL.
lymph nodes 2, underlying Hashimoto thyroiditis, and
extrathyroidal extension were found to be the independent
predictive factors for lateral lymph node metastasis with
ORs of 11.282, 4.340, and 2.838, respectively (p < .05).
The number of positive central lymph nodes 2 may
strongly predict the presence of lateral lymph node
metastasis based on a significantly high OR.
Of the 141 patients in this study, transient hypocalcemia (serum calcium level <2 mmol/L) developed in 33
patients (23.4%) but resolved within 6 months. No patient
had persistent hypocalcemia. Vocal cord palsy developed
in 5 patients (3.5%), among whom 4 recovered in 1
month to 4 months and 1 (0.7%) had permanent vocal
cord palsy. Chyle leakage was observed in 5 of those 141
patients (3.5%) and stopped within 30 days after surgery.
Two patients (1.4%) developed hematoma postoperatively. No other serious complications occurred (such as
Horner syndrome, major nerve injury, or motion limitation of the shoulder).
The mean duration of follow-up was 61 months (range,
10–83 months). In our study, neck recurrence was diagnosed in 6 patients (4.3%): 3 recurrences were detected
in the contralateral central compartment, 1 in the ipsilateral central compartment, and 2 in the lateral compartment (no one had a recurrence in the thyroidal bed). Two
patients (1.4%) developed distant metastasis in the lung.
Two patients died of breast cancer and cardiac disease.
All other patients were currently free of disease.
DISCUSSION
Central lymph node metastasis is common in patients
with PTMC and occurs in about 41% to 64%.14–19 The
number of regional lymph node metastases is regarded as
a prognostic factor that guides the choice of treatment
modalities in a number of human cancers, such as breast
and gastric cancers, but not in PTMC.20,21 Although the
prognostic implication of central lymph node metastasis
has been tackled in many studies, the significance of the
number of positive central lymph nodes has not been
well understood. Cervical lymph node metastasis occurs
first in the lymph nodes in the central compartment and
subsequently to those in the lateral neck compartment in
patients with thyroid cancer.7,22 Skip metastasis occurs in
a minority of patients with PTMC and has no obvious
risk factor.23 Routine unilateral central lymph node dissection is a subject of debate. In recent years, several
studies have shown that routine unilateral central lymph
node dissection does not cause increased risk of complications, helps determine the central lymph node status,
and provides a more accurate cancer staging.24,25 Therefore, more surgeons support the routine use of unilateral
central lymph node dissection. Central lymph node dissection includes unilateral and bilateral central lymph
node dissection. In this study, all the patients underwent
unilateral central lymph node dissection. Although unilateral central lymph node dissection cannot determine the
status of contralateral central compartment, the extent of
central lymph node dissection may not affect the results
of this study inasmuch as there is generally no lymph
node metastasis in the central compartment contralateral
to the primary tumor in PTMC.15,26 Unilateral central
lymph node dissection could be routinely performed
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during thyroid surgery, so we focused on lateral lymph
node involvement in this study. Our hypothesis was that
the number of positive central lymph nodes is valuable in
predicting the presence of lateral lymph node metastasis.
The central and lateral compartments are the most common sites of metastasis in PTMC. Several reports have
shown that central lymph node metastasis is an important
independent factor for lateral lymph node metastasis.7–10
In our study, the incidence of lateral lymph node metastasis significantly increased with the number of positive
central lymph node. Similar results were found in 2 other
reports.18,19 Therefore, we divided the 141 patients
enrolled in this study into 3 groups according to the different numbers of positive central lymph nodes. Finally,
we found that the incidence of lateral lymph node metastasis in patients with 2 or more positive central lymph
nodes was significantly higher than in those with 1 positive central lymph node or with no positive central lymph
node. Although the incidence of lateral lymph node
metastasis in patients with 1 positive central lymph node
(16.7%) was nearly twice that of patients with no positive
central lymph node (8.9%), this difference had no
statistical significance (p ¼ .475; Bonferroni corrected a
¼ 0.0167). To avoid the influence from the different incidents of lateral lymph node metastasis in the 3 groups,
we only analyzed the mean numbers of the lateral lymph
nodes and the lateral positive lymph nodes in patients
with lateral lymph node metastasis in each of the 3
groups. The mean number of the removed lateral lymph
nodes had no difference in the 3 groups, indicating that it
had no affect on the mean number of lateral positive
lymph nodes. There was an increasing trend among the
mean numbers of positive lateral lymph nodes among the
3 groups (group A ¼ 1.4; group B ¼ 2.0; and group C ¼
2.4), but had no statistically significant difference, similar
to the findings of a previous study.19 However, we may
have more accurate information on the number of lateral
positive lymph nodes because of the extent of lateral
lymph node dissection in this study. From these data, our
hypothesis was that the presence of 2 or more positive
central lymph nodes may be valuable in predicting the
presence of lateral lymph node metastasis. This study was
not the first to investigate the relationship between the
number of positive central lymph nodes and lateral lymph
node metastasis. Lim et al18 showed that the number of
bilateral positive central lymph nodes is an independent
risk factor for lateral lymph node metastasis. Xiao and
Gao19 suggested that the presence of 2 or more positive
central lymph nodes in patients subjected to unilateral
central lymph node dissection may be valuable in predicting lateral lymph node metastasis. Lee et al17 reported
that further treatment for the lateral neck should be considered if the number of positive central lymph node is
>2 in patients who undergo bilateral central lymph node
dissection. All the patients enrolled in these 3 previous
studies had papillary thyroid carcinoma, whereas those in
our study had PTMC.
To further confirm the independently predictive value
of number of positive central lymph node 2 for lateral
lymph node metastasis, we regarded it as a clinicopathological feature to investigate the relationship between
lateral lymph node metastasis and the clinicopathological
PREDICTING
features of our patients by univariate and multivariate
analysis. Several studies have shown that multifocality is
a predictive parameter for lymph node metastasis.27–29
The association between Hashimoto thyroiditis and lymph
node metastasis remains controversial. Kim et al30 suggested that coexisting Hashimoto thyroiditis in patients
with thyroid cancer is a negative independent predictive
factor for central lymph node metastasis. However, lateral
lymph node metastasis with Hashimoto thyroiditis was
more often found in patients with PTMC in another
study.31 Extrathyroidal extension proved to be an
independent factor for the presence of lymph node metastasis.29 In our study, lateral lymph node metastasis was
significantly associated with number of positive central
lymph nodes 2, multifocality, underlying Hashimoto
thyroiditis, and extrathyroidal extension on univariate
analysis. We performed a multivariate analysis with
adjustment for the established clinicopathological prognostic factors and the remaining 4 statistically significant
predictive factors. Number of positive central lymph node
2 (OR, 11.282), underlying Hashimoto thyroiditis (OR,
4.340), and extrathyroidal extension (OR, 2.838) were
independent predictive factors for lateral lymph node metastasis based on the multivariate analysis. Furthermore,
number of positive central lymph node 2, which had the
highest OR value, was a key factor in predicting lateral
lymph node metastasis. Multifocality was significantly
associated with lateral lymph node metastasis on univariable analysis, but failed to be a predictive factor on multivariate analysis.
Wada et al32 studied 259 patients with PTMC, among
whom 24 with palpable nodes underwent therapeutic
neck dissection; the others underwent prophylactic neck
dissection. They posited that therapeutic neck dissection
should be performed and that prophylactic neck dissection may not be beneficial in PTMC. In our study, all
the patients enrolled had routine unilateral central lymph
node dissection. In this study, we did not divide the
patients based on acceptance of lateral compartment surgery (including therapeutic or prophylactic lateral lymph
node dissection). We considered that the number of unilateral positive central lymph nodes may be valuable in
predicting lateral lymph node metastasis. Patients with
evidently suspicious lateral lymph node metastasis seen
via ultrasonography or physical examination are more
likely to have histopathologic lateral lymph node metastasis in therapeutic lateral lymph node dissection. However, some of those patients have no lateral lymph node
metastasis. Therefore, we believe that paying more
attention to the number of positive central lymph nodes
as an important variable may help prevent possibly
unnecessary therapeutic lateral compartment lymph node
dissection. Lim et al18 showed that the specimens dissected from the central compartment could be analyzed
by frozen section for the confirmation of central lymph
node metastasis and for the quantitative determination of
positive central lymph nodes in less than 30 minutes.
Therefore, we believe it will be helpful for surgeons in
deciding whether further treatment for the lateral compartment is necessary if the number of positive central
lymph nodes could be analyzed by intraoperative frozen
sections with accurate diagnosis.
LATERAL LYMPH NODE METASTASIS
The surgical treatment in this study has limited postoperative complications. Most patients in this article developed transient postoperative complications and recovered.
Only 1 patient had permanent complication (vocal cord
palsy). The survival rate is proved to be excellent for
patients with thyroid cancer in many studies.33,34 In our
study, 2 patients died because of other diseases and no
one died of PTMC. We observed neck recurrence in 6
patients (not one in the thyroidal bed) and distant metastasis in 2 patients. Some studies reported that patients
treated by lobectomy alone have a 5% to 10% recurrence
rate in the opposite thyroid lobe, whereas 1% recurrence
rate after total thyroidectomy and I131 therapy.33,35,36
Therefore, we consider that the treatment in our study
may not be associated with decreased mortality, but
decreased the incidence of recurrence in residual thyroid.
When total thyroidectomy with unilateral central neck
dissection and lateral neck dissection is necessary for the
treatment of PTMC, the procedure can be performed
safely with acceptable morbidity.
There are several potential limitations in this study. Lee
et al17 suggested that the number of positive central
lymph nodes is significantly associated with tumor size,
and patients with number of positive central lymph node
3 are more likely to have extrathyroidal extension. Our
study only investigated lateral lymph node metastasis; we
did not provide data on other clinicopathological features
or long-term follow-up results, such as disease recurrence,
postoperative radioiodine studies, thyroglobulin levels,
and disease-free survival, which may be associated with
the number of positive central lymph nodes. We are currently collecting full clinicopathological data and longterm follow-up results for a consecutive report to confirm
whether the number of positive central lymph nodes is
associated with other clinicopathological factors and longterm follow-up results.
CONCLUSIONS
Patients with PTMC, having 2 or more positive central
lymph nodes, are more likely to have lateral lymph node
metastasis. The number of positive central lymph nodes
2 is an important independent factor for lateral lymph
node metastasis. Therefore, number of positive central
lymph nodes 2 may be valuable in predicting lateral
lymph node metastasis in patients with PTMC and can
help determine the type of surgical intervention needed.
Acknowledgments
This work was supported by Wenzhou Science and Technology Planning Project (NO. Y20120190).
REFERENCES
1. Leenhardt L, Grosclaude P, Cherie–Challine L; Thyroid Cancer Committee. Increased incidence of thyroid carcinoma in France: a true epidemic or
thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid 2004;14:1056–1060.
2. Xiang J, Wu Y, Li DS, et al. New clinical features of thyroid cancer in
eastern China. J Visc Surg 2010;147:e53–e56.
3. Wang Y, Ji M, Wang W, et al. Association of the T1799A BRAF mutation
with tumor extrathyroidal invasion, higher peripheral platelet counts, and
over-expression of platelet-derived growth factor-B in papillary thyroid
cancer. Endocr Relat Cancer 2008;15:183–190.
4. Patron V, Bedfert C, Le Clech G, Aubry K, Jegoux F. Pattern of lateral neck
metastases in N0 papillary thyroid carcinoma. BMC Cancer 2011;11:8.
HEAD & NECK—DOI 10.1002/HED
JANUARY 2014
105
ZENG ET AL.
5. Mercante G, Frasoldati A, Pedroni C, et al. Prognostic factors affecting
neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid 2009;19:
707–716.
6. Ito Y, Tomoda C, Uruno T, et al. Preoperative ultrasonographic examination for lymph node metastasis: usefulness when designing lymph node
dissection for papillary microcarcinoma of the thyroid. World J Surg
2004;28:498–501.
7. Goropoulos A, Karamoshos K, Christodoulou A, et al. Value of the cervical compartments in the surgical treatment of papillary thyroid carcinoma.
World J Surg 2004;28:1275–1281.
8. Roh JL, Kim JM, Park CI. Lateral cervical lymph node metastases from
papillary thyroid carcinoma: pattern of nodal metastases and optimal strategy for neck dissection. Ann Surg Oncol 2008;15:1177–1182.
9. Kwak JY, Kim EK, Kim MJ, et al. Papillary microcarcinoma of the thyroid: predicting factors of lateral neck node metastasis. Ann Surg Oncol
2009;16:1348–1355.
10. Lin KL, Wang OC, Zhang XH, Dai XX, Hu XQ, Qu JM. The BRAF mutation is predictive of aggressive clinicopathological characteristics in papillary thyroid microcarcinoma. Ann Surg Oncol 2010;17:3294–3300.
11. Lin JD, Chao TC, Weng HF, Ho YS. Prognostic variables of papillary thyroid carcinomas with local invasion. Endocr J 1999;46:91–98.
12. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting
outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one
institution during 1940 through 1989. Surgery 1993;114:1050–1057; discussion 1057–1058.
13. Fonseca E, Soares P, Rossi S, Sobrinho–Simões M. Prognostic factors in
thyroid carcinomas. Verh Dtsch Ges Pathol 1997;81:82–96.
14. Kutler DI, Crummey AD, Kuhel WI. Routine central compartment lymph
node dissection for patients with papillary thyroid carcinoma. Head Neck
2012;34:260–263.
15. Moo TA, Umunna B, Kato M, et al. Ipsilateral versus bilateral central
neck lymph node dissection in papillary thyroid carcinoma. Ann Surg
2009;250:403–408.
16. Sadowski BM, Snyder SK, Lairmore TC. Routine bilateral central lymph
node clearance for papillary thyroid cancer. Surgery 2009;146:696–703;
discussion 703–705.
17. Lee YS, Lim YS, Lee JC, Wang SG, Kim IJ, Lee BJ. Clinical implication
of the number of central lymph node metastasis in papillary thyroid carcinoma: preliminary report. World J Surg 2010;34:2558–2563.
18. Lim YS, Lee JC, Lee YS, et al. Lateral cervical lymph node metastases
from papillary thyroid carcinoma: predictive factors of nodal metastasis.
Surgery 2011;150:116–121.
19. Xiao GZ, Gao L. Central lymph node metastasis: is it a reliable indicator
of lateral node involvement in papillary thyroid carcinoma? World J Surg
2010;34:237–241.
106
HEAD & NECK—DOI 10.1002/HED
JANUARY 2014
20. Camp RL, Rimm EB, Rimm DL. A high number of tumor free axillary
lymph nodes from patients with lymph node negative breast carcinoma is
associated with poor outcome. Cancer 2000;88:108–113.
21. Huang CM, Lin BJ, Lu HS, Zhang XF, Li P, Xie JW. Prognostic impact of
metastatic lymph node ratio in advanced gastric cancer from cardia and
fundus. World J Gastroenterol 2008;14:4383–4388.
22. Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin
North Am 1998;31:823–831.
23. Chung YS, Kim JY, Bae JS, et al. Lateral lymph node metastasis in papillary thyroid carcinoma: results of therapeutic lymph node dissection. Thyroid 2009;19:241–246.
24. Giordano D, Valcavi R, Thompson GB, et al. Complications of central
neck dissection in patients with papillary thyroid carcinoma: results of a
study on 1087 patients and review of the literature. Thyroid 2012;22:
911–917.
25. Caliskan M, Park JH, Jeong JS, et al. Role of prophylactic ipsilateral central compartment lymph node dissection in papillary thyroid microcarcinoma. Endocr J 2012;59:305–311.
26. Roh JL, Kim JM, Park CI. Central cervical nodal metastasis from papillary
thyroid microcarcinoma: pattern and factors predictive of nodal metastasis. Ann Surg Oncol 2008;15:2482–2486.
27. Cho JK, Kim JY, Jeong CY, et al. Clinical features and prognostic factors
in papillary thyroid microcarcinoma depends on age. J Korean Surg Soc
2012;82:281–287.
28. Kim TY, Hong SJ, Kim JM, et al. Prognostic parameters for recurrence of
papillary thyroid microcarcinoma. BMC Cancer 2008;8:296.
29. So YK, Son YI, Hong SD, et al. Subclinical lymph node metastasis in papillary thyroid microcarcinoma: a study of 551 resections. Surgery 2010;
148:526–531.
30. Kim SS, Lee BJ, Lee JC, et al. Coexistence of Hashimoto’s thyroiditis
with papillary thyroid carcinoma: the influence of lymph node metastasis.
Head Neck 2011;33:1272–1277.
31. Kim HS, Choi YJ, Yun JS. Features of papillary thyroid microcarcinoma
in the presence and absence of lymphocytic thyroiditis. Endocr Pathol
2010;21:149–153.
32. Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003;237:
399–407.
33. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:
418–428.
34. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis.
Head Neck 1996;18:127–132.
35. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med
1993;328:553–559.
36. Mazzaferri EL. Treating differentiated thyroid carcinoma: where do we
draw the line? Mayo Clin Proc 1991;66:105–111.