Keywords
thyroid neoplasms - recurrence - ultrasonography - computed tomography - X-ray
Introduction
The overall increase in the incidence of thyroid cancer over the last 2 decades can
largely be attributed to increases in the incidence of papillary thyroid cancer (PTC).
In 2010, there were an estimated 44,670 new cases of thyroid cancer and 1,690 deaths
in the United States.[1] PTC and its follicular variant account for 80 to 90% of all primary thyroid cancers.
Furthermore, follicular thyroid cancer and Hurthle cell cancers comprise 5 to 10%,
medullary thyroid cancer comprises 5%, and anaplastic cancer comprises less than 1%
of all thyroid malignancies.[2]
[3] Differentiated thyroid cancer (DTC) can occur at any age but the median age at diagnosis
is 49 years, and the prevalence in women is 3 times greater than that in men.[4]
Cervical recurrence of PTC following thyroidectomy occurs primarily as regional lymph
node (LN) metastasis, which occurs in up to 20% of patients with low-risk disease
(men ≤ 40 years old; women ≤ 50 years old) and 59% of patients with high-risk disease
(older patients).[3]
[5]
[6]
[7] This type of locoregional cervical LN recurs within the first 10 years following
an initial diagnosis in 15 to 30% of patients.[6]
[8] Current surveillance strategies to identify locoregional or nodal recurrence primarily
rely on serial serum thyroglobulin measurements assessed in combination with cervical
ultrasonography (US) and image-guided fine needle aspiration cytology (FNAC) of suspicious
lesions.[9]
[10]
[11] Recently, certain number of antibodies have been developed against antigen to improve
morphologic diagnostic performances.[12]
Several tumor-staging systems have been developed for DTC in an attempt to include
factors with prognostic value to guide the appropriate intensity of treatment and
surveillance. The most relevant factors include patient age, tumor size and extent,
locoregional nodal involvement, and distant metastases,[4] but there are few studies discussing preoperative factors that could predict nodal
recurrence. Factors that may decrease recurrence rates include a more comprehensive
surgery, better tumor definition afforded by more sensitive US techniques, and the
use of routine cervical lymphadenectomy to remove LNs that could cause recurrence.[13] Innovations in serology, histopathology, immunochemistry, and diagnosis through
radiologic investigations provide us with better understanding to plan the management
and follow-up of well-differentiated thyroid cancer.
The objective of the current study was to evaluate the accuracy of preoperative radiologic
investigations of nodal status in determining the postoperative risk of locoregional
nodal recurrence in patients with DTC.
Materials and Methods
Patient Screening
Following the hospital ethics committee approval, the prospectively maintained database
from our tertiary hospital was reviewed. Ninety-eight patients met the inclusion criteria,
which were as follows: (1) well-differentiated thyroid cancer, (2) preoperative radiologic
investigations performed in our hospital, (3) patient operative report, and (4) a
minimum follow-up of 12 months. Demographic data, preoperative and postoperative US
and/or computed tomography (CT) scans, FNAC findings, and surgical pathology were
evaluated. The operative and pathology reports were reviewed, and all patients were
staged according to the current American Joint Committee on Cancer (AJCC) staging
system according to the documented histopathologic findings.[14] The clinical course was determined, and all patients who presented with recurrent
disease were identified. Follow-up evaluation included a physical examination, a neck
US examination, measurement of serum thyroglobulin levels, and the selective use of
neck CT scanning, total body radioactive iodine (RAI) scanning, FNAC, and histopathology
reports. Patients were considered to have cervical recurrence if they had any of the
following: nodal disease on clinical examination; detection of recurrence by FNAC;
or an interval increase in activity on serial RAI imaging that prompted treatment
with RAI,[13] and positive FNAC was considered as most definitive end point of nodal recurrence.
Diagnostic Imaging Modalities
US of the soft tissue of the neck was performed using a high-resolution scanner. The
preoperative and postoperative status of central and lateral neck compartments was
determined according to the sonographic appearance of the thyroid, a description of
the lesion, and the appearance of the LNs. Sonographic features suggestive of abnormal
metastatic LNs include loss of the fatty hilus, a rounded rather than oval shape,
hypoechogenicity, cystic change, calcifications, and peripheral vascularity. Some
patients underwent contrast-enhanced CT with a multidetector scanner with a reconstructed
slice thickness of 3 mm for axial and coronal images. A 90-mL dose of iodinated contrast
medium was administered intravenously at a rate of 3 mL/s using an automated injector.
A 3-mL/s flush of normal saline solution was injected immediately after administration
of the contrast medium to reduce artifacts induced in the subclavian vein. The scan
delay was 40 to 60 seconds. Due to different treating surgical teams and collecting
of data retrospectively, different patients received different radiologic investigation.
Therefore, we divided the patients into different groups: patients who received US
pre- and postoperatively and patients who received CT scan pre- and postoperatively.
Operative Procedures
Total thyroidectomy was performed in cases diagnosed with DTC by FNAC. In most cases,
a prophylactic central node dissection (CND) was performed in patients with PTC and
clinical stage N0 neck. A therapeutic CND and/or lateral neck dissection was performed
in patients with evidence of central and/or lateral neck LN metastasis at the time
of the surgery. After surgery, all patients underwent thyroid-stimulating hormone
suppression treatment with oral thyroxin for 6 weeks, followed by RAI therapy to improve
outcome and tumor control.
Statistical Analyses
All statistical tests were performed using SPSS version 16 (IBM). Univariate statistical
analysis and cross-tabulation were performed to determine the significance of each
factor in predicting cervical recurrence in DTC. The chi-square test was used to calculate
p values, and p < 0.05 was considered statistically significant.
Results
Between January 2006 and December 2012, 98 patients underwent total thyroidectomy
for a diagnosis of well-differentiated thyroid cancer. Patient demographics are shown
in [Table 1]. The median age at diagnosis was 43 years. The median follow-up was 21 months from
the time of the index operation. Cervical recurrence was defined as metastatic involvement
of any cervical LN developing ≥6 months after surgery. Cases of cervical recurrences
were mainly isolated LNs. Of the 98 patients, 71 (72%) patients underwent preoperative
US, and 35 (36%) underwent preoperative CT; 8 patients underwent both studies. Fifty-six
patients had postoperative US, and 42 had postoperative CT scans.
Table 1
Patient demographics
|
Characteristics
|
Number of patients (%)
|
|
Sex
|
|
|
Male
|
24 (24.5)
|
|
Female
|
74 (75.5)
|
|
Age (y)
|
|
|
<60
|
76 (77.6)
|
|
≥60
|
22 (22.4)
|
|
Histopathology
|
|
|
Papillary thyroid cancer
|
68 (70)
|
|
Follicular cancer
|
30 (30)
|
|
Tumor size (cm)
|
|
|
≤2
|
45 (46)
|
|
>2
|
53 (54)
|
|
Lymph node size (cm)
|
|
|
No nodal involvement
|
35 (36)
|
|
≤2
|
47(48)
|
|
>2
|
16 (16)
|
|
Recurrence
|
29 (30)
|
|
Death
|
4 (4)
|
An analysis of factors predicting local recurrence is shown in [Table 2]. Positive LN recurrence was higher in men compared with women, although the difference
did not reach statistical significance (p = 0.784). In addition, age, tumor size, and LN size were not significant risk factors
for local recurrence (p = 0.608, p = 0.385, p = 0.875, respectively).
Table 2
Risk factors correlated with recurrence
|
Risk factors
|
No. of patients with recurrence (%)
|
p Value
|
|
Sex
|
|
|
|
Male (n = 18)
|
8 (44.4)
|
0.784
|
|
Female (n = 56)
|
22 (39.3)
|
|
Age (y)
|
|
|
|
≤60 (n = 58)
|
22 (37.9)
|
0.538
|
|
>60 (n = 16)
|
8 (50)
|
|
Tumor size (cm)
|
|
|
|
≤2 (n = 38)
|
18 (47.4)
|
0.385
|
|
>2 (n = 36)
|
12 (33.3)
|
|
Lymph node size (cm)
|
|
|
|
No nodal involvement (n = 26)
|
10 (38.5)
|
0.875
|
|
≤2 (n = 36)
|
14 (38.9)
|
|
>2 (n = 12)
|
6 (50)
|
a The chi-square test was used to measure p values (p < 0.05 was considered significant by Fisher's exact tests).
Positive LN status on US was not correlated with the prediction of recurrence. In
contrast, positive or negative LN status as detected by CT was significantly correlated
with postoperative locoregional recurrence (p = 0.01; [Table 3]). The US and CT analyses demonstrated similar efficacy at detecting thyroid nodules,
but differed significantly in their ability to accurately evaluate cervical LN involvement
in recurrence, with CT outperforming US ([Table 4]).
Table 3
Correlation of the preoperative lymph node status with recurrence risk
|
Preoperative radiologic investigation
|
No. of patients with recurrence (%)
|
p Value
|
|
Negative LN status on US (n = 20)
|
6 (30)
|
0.778
|
|
Positive LN status on US (n = 34)
|
12 (35.3)
|
|
Negative LN status on CT (n = 15)
|
1 (6.67)
|
0.01
|
|
Positive LN status on CT (n = 14)
|
10 (62.5)
|
Abbreviations: CT, computed tomography; LN, lymph node; US, ultrasonography.
a The chi-square test was used to measure p values (p < 0.05 was considered significant by Fisher's exact tests).
Table 4
A comparison of the prognostic accuracy of radiologic modalities for predicting recurrence
|
Modality
|
Sensitivity (%)
|
Specificity (%)
|
Accuracy (%)
|
PPV (%)
|
NPV (%)
|
|
US
|
66.67
|
77.78
|
74
|
60
|
82.35
|
|
CT
|
80
|
90
|
86.6
|
80
|
90
|
Abbreviations: CT, computed tomography; NPV, negative predictive value; PPV, positive
predictive value; US, ultrasonography.
Discussion
PTC is the most common endocrine neoplasia with a tendency for local and regional
metastasis.[15] The prognostic impact of cervical LN involvement has been investigated in many studies,
but remains a controversial issue.[16]
[17]
[18] Initial studies suggested that the presence of nodal metastasis had no effect in
overall or disease-free survival, but this notion has been recently refuted.[19] Patients with PTC with cervical LN metastasis at initial presentation are more susceptible
to recurrence than those without LN involvement.[16]
[17]
[18] The preoperative LN metastasis rate in our series was 64%, which was higher than
the published 23%.[19] The recurrence rate in our series (30%) was higher than that previously reported
in published studies (10 to 20%),[18]
[20] which can mostly likely be attributed to differences in surgical techniques and
treatments between different surgeons. However, the surgical management of malignant
thyroid nodule was based on FNAC and frozen section evaluation, with the FNAC being
more sensitive and cost-effective.[21]
In this study, we evaluated age, sex, tumor size, LN size, and US and CT findings
preoperatively to determine the relationship of these factors with nodal recurrence.
Univariate analysis has been used, due to small sample, although it was insufficient
in comparison with multivariate analysis. Age and sex are considered prognostic factors
(2010 AJCC staging system),[17]
[22] but these factors were not associated with cervical recurrence in our study.
In addition, tumor size and LN size were not predictive of cervical recurrence. Preoperative
LN metastasis was associated with locoregional recurrence, as has been described for
other studies.[18]
[23] In 560 Japanese patients with thyroid cancer who underwent total thyroidectomy,
those with US-detectable metastasis had a significantly worse relapse-free survival
than those with negative US findings.[24] Hay et al[25] and Spires et al[26] showed that LN metastasis was related to a higher recurrence rate but did not adversely
influence survival.
Our study and those mentioned previously would indicate that positive preoperative
US findings for LN metastasis could indicate a more aggressive disease course and
strongly predict the need for additional surgery in the future, whereas negative preoperative
US LN findings indicate a lower risk with patients less likely to need future surgery.[26] However, most importantly, we determined that preoperative detection of LN metastases
with CT-based detection was significantly more specific, sensitive, and accurate than
US-based detection; all patients who had negative preoperative CT LN metastasis findings
remained recurrence-free, whereas 30% of the patients with negative US LN metastases
findings went on to develop locoregional recurrence. This strongly suggests that preoperative
CT detection of LN metastases is a better modality for predicting locoregional recurrence
in patients with DTC. On the other hand, the sensitivity and specificity of positive
LN status on US in this study were less than those in other published studies.[15]
[27]
[28]
Conclusions
According to this study, patients with thyroid cancer with positive radiologic investigations
(either US or CT) for LN metastasis have an increased risk of regional node recurrence
after total thyroidectomy. CT was superior to US at detecting metastatic LN involvement,
and, therefore, on the basis of our data, we suggest that CT should be further studied
and considered as a more suitable alternative to US for preoperative evaluation and
postoperative follow-up investigations.
