Methods
Clinical data
A total of 315 patients with PTC who were admitted to Jinan Military General Hospital from January 2009 to July 2013, including 66 male patients and 249 female patients, were recruited. The male to female ratio was 1:3.8. Ages ranged from 20 years to 78 years, and the median age was 48 years. The diameter of most tumors was less than 2 cm, the proportion of which was 47.1 % in the recurrent group and 85.8 % in the non-recurrent group. Moreover, 10.5 % (33 cases) of the patients presented extrathyroid invasion, and 42.2 % (133 cases) of the patients were found with lymph node metastases at the time of initial surgery. The tumors of 44.4 % (140 cases) of the patients showed multifocality, and 25.1 % (79 cases) of the patients had Hashimoto's thyroiditis (HT) (Table
1). This study received the approval of the ethics committee of the General Hospital of Jinan Military Command (No. 2013ZD01).
Table 1
Clinicopathological features of patients with recurrent and non-recurrent PTC
Age/year | | | 0.32 | 0.574 |
<45 | 14 | 130 | | |
≥45 | 20 | 151 | | |
Gender | | | 3.11 | 0.078 |
Male | 11 | 55 | | |
Female | 23 | 226 | | |
Tumor size | | | 34.76 | <0.001 |
<1 | 3 | 130 | | |
≥1- < 2 | 13 | 111 | | |
≥2 | 18 | 40 | | |
Initial surgery approach | | | 11.39 | 0.003 |
First type | 16 | 62 | | |
Second type | 14 | 137 | | |
Third type | 4 | 82 | | |
Extra thyroidal invasion | | | 22.15 | <0.001 |
Yes | 12 | 21 | | |
No | 22 | 260 | | |
Coexistent Hashimoto’s thyroiditis | | | 0.38 | 0.537 |
Yes | 10 | 69 | | |
No | 24 | 212 | | |
Lymphatic metastasis | | | 10.10 | 0.001 |
Yes | 23 | 110 | | |
No | 11 | 171 | | |
Multifocality | | | 0.00 | 0.968 |
Yes | 15 | 125 | | |
No | 19 | 156 | | |
Pathological subtype | | | 34.45 | <0.001 |
Group 1 | 11 | 17 | | |
Group 2 | 20 | 134 | | |
Group 3 | 3 | 130 | | |
Pathological subtype of PTC
Recruited PTC patients were divided into three groups. Patients with the tall cell, columnar cell, diffuse sclerosing, and oncocytic variants with higher invasiveness, higher probability of recurrence, and metastases were classified into Group 1. Patients with the follicular, clear cell, and conventional papillary carcinoma variants with similar prognosis were classified into Group 2. Patients with papillary microcarcinoma were classified into Group 3.
Initial surgery approach
The methods of primary lesion dissection used in this research included thyroid lobectomy with or without isthmectomy and total/near-total thyroidectomy. The methods of lymph node dissection included central compartment node dissection, selective neck dissection, modified neck dissection, and radical neck dissection. During statistical analysis, thyroid lobectomy with or without isthmectomy and total/near-total thyroidectomy were classified as the first type of surgical approach. Surgical approaches belonging to the first type combined with central compartment node dissection, selective neck dissection, and wide dissection of metastatic lesions were classified as the second type of surgical approach. Finally, approaches combining modified neck dissection and radical dissection were classified as the third type of surgical approach.
Statistical analysis
SPSS 17.0 software was used for statistical analysis. In addition, χ
2-test and multivariate analysis using Cox proportional hazards modeling were carried out. Factors that may be related to PTC recurrence, including gender, age, tumor size, initial surgery approach, lymph node metastasis, number of lesions, complication with HT, extrathyroid invasion, and pathological subtype, were evaluated. P < 0.05 was considered statistically significant difference.
Discussion
PTC is the most common but least aggressive histological subtype of thyroid cancer. Most patients with PTC have excellent prognosis. However, recent studies have demonstrated increasing incidence of recurrent PTC [
2,
3]. Many factors can affect thyroid cancer recurrence, but final conclusions have not been reached. The results of some studies show that the pathological type, staging, degree of extrathyroid invasion, lymph node metastatic rate, age, and initial surgery approach are related to thyroid cancer recurrence [
4,
5]. Our research showed that tumor size, extrathyroid invasion, initial surgery approach, lymph node metastasis, and pathological subtype demonstrate statistically significant differences between the recurrent and non-recurrent groups. By contrast, factors such as age, gender, complication with HT, and number of lesions are not correlated with tumor recurrence. Multivariate analysis results further revealed that initial surgery approach and pathological subtype are main factors related to PTC recurrence.
The dissection methods of primary lesions of PTC include (1) hemithyroidectomy with or without isthmectomy, (2) total/near-total thyroidectomy, and (3) extension of surgical scope. In case of severe extrathyroid invasion, such as invasion of the esophagus, trachea, and nerves, extending the scope of surgery is required. The methods of neck dissection are as follows: (1) central compartment node dissection (unilateral or bilateral), (2) selective neck dissection, (3) functional compartmental en-bloc neck dissection, (4) modified neck dissection, and (5) radical neck dissection [
6]. Mazzaferri et al. [
7] found that the recurrence rate after partial thyroidectomy is nearly twice that of total and near-total thyroidectomy. By contrast, Cunningham et al. [
8] revealed that the recurrence rates had no significant difference between hemithyroidectomy and total/near-total thyroidectomy groups. Monacelli et al. [
9] suggested that total thyroidectomy combined with central node dissection must be performed even in the absence of risk factors and without clinically evident nodes. However, some researchers do not advocate prophylactic central neck lymphadenectomy [
10]. Univariate analysis in this research showed that initial surgery approach exerts a great impact on the prognosis. For example, while 47.1 % (16/34) of the recurrent PTC patients received the first type of surgery as initial surgery, only 22.1 % (62/281) of the non-recurrent PTC patients received the first type of surgery. About 52.9 % (18/34) of the recurrent PTC patients received the second and third types of surgery. In comparison, 77.9 % (219/281) of the non-recurrent PTC patients received the second and third types of surgery as the initial surgery. Multivariate analysis revealed that initial surgery approach is the main factor related to PTC recurrence (
P < 0.001); specifically, initial surgery approach demonstrated a negative correlation with PTC recurrence (
β = −0.320, OR = 0.726).
The recurrence rate decreased with increasing surgical scope. Non-standardized surgical approaches with inappropriately small surgical scopes could lead to tumor residue. Moreover, lesions of lymph node metastasis may be missed, thereby increasing the risk of recurrence. Possible reasons behind the inconsistency of results are as follows: (1) Differences among recruited patients. Patients receiving neck dissection showed significant metastases, whereas no cervical lymph node metastasis was discovered before the operation in patients who did not receive neck dissection. (2) Insufficient number of recruited patients. (3) Difference in surgical techniques among surgeons. Considering these factors, blindly extending or narrowing the surgical scope is irrational.
The World Health Organization (WHO) histological classification of tumors has redefined the subtypes of non-conventional PTC [
11]: follicular variant, oncocytic variant, diffuse sclerosing variant, tall cell variant, columnar cell variant, solid variant, PTC with nodular fasciitis-like stroma, clear cell variant, and diffuse follicular variant. PTC patients of different histological subtypes may exhibit diverse clinical and biological behaviors. Subtypes including the tall cell, columnar cell, diffuse sclerosing, and oncocytic variants have higher invasiveness and may promote higher risks of recurrence and metastases [
12‐
14]. The prognosis of patients with the follicular and clear cell variants is similar to that of patients with conventional papillary carcinoma [
15]. Thyroid microcarcinoma is a type of papillary carcinoma that is less than 1 cm in diameter with relatively low invasiveness and good prognosis [
16]. This research classified histological variants according to the WHO histological classification of tumors. Patients with the tall cell, columnar cell, diffuse sclerosing, and oncocytic variants were classified into Group 1; patients with the follicular, clear cell, and conventional PTC variants were classified into Group 2; and patients with papillary microcarcinomas were classified into Group 3. The research conducted by Boone et al. [
17] showed that the recurrence rate of patients with differentiated thyroid carcinoma is lower than that of patients with other types of thyroid carcinoma. Among the differentiated thyroid carcinomas, the recurrence rate of PTC is lower than that of the follicular variant. However, 30 % of the PTC patients continue to suffer from recurrence, metastasis, and even death [
18]. Univariate analysis demonstrated that pathological subtype is obviously correlated with PTC recurrence (
P < 0.01). Multivariate analysis also indicated that pathological subtype is closely related to PTC recurrence (
β = 0.923, OR = 2.517). The recurrence rate of PTC increased as the invasiveness of the tumor increased. Thus, close follow-up must be carried out in patients with the tall cell, columnar cell, diffuse sclerosing, and oncocytic variants. Effective treatment measures must be taken once recurrence is discovered.
Various results are reported in the literature regarding the effect of lymph node metastases on PTC recurrence. Some studies indicate that lymph node metastases do not affect PTC recurrence [
19]. However, some researchers have found that the number of lymph node metastases is associated with postoperative recurrence or re-metastasis. Thus, lymph node metastasis has become an important factor affecting the prognosis and recurrence of thyroid carcinoma [
20]. The results of this research revealed statistically significant differences in lymph node metastases between the recurrent and non-recurrent groups. Patients with lymph node metastases at the time of initial surgery are more likely to suffer recurrence than those without metastases. The correlation of cervical lymph node metastases with recurrence needs to be confirmed through large-sample and long-term studies.
Of the 34 recurrent PTC patients in the group, postoperative recurrence intervals ranged from five months to 18 years, with a median time of 46 months. Recurrence was observed to occur within a short period of time. The majority of PTC patients, for example, showed recurrence within two to five years from surgery. Furthermore, recurrence may also occur more than once. Therefore, PTC patients must have regular reexamination with frequent follow-ups within five years after the first treatment. Ultrasound examination must be performed at least once a year within five years after the first treatment for timely discovery of tumor recurrence.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JZ and PFL conceived and designed the experiments. JZ, XLW and XXZ collected the data. PFL and HFH analyzed the data. PFL and XLW wrote the paper. All authors read and approved the final manuscript.