Journal of Thyroid Disorders & Therapy
Open Access
ISSN: 2167-7948
+44 1300 500008
ISSN: 2167-7948
+44 1300 500008
Research Article - (2016) Volume 5, Issue 1
Purpose The aim of this study is to investigate the predictive value of BRAF V600E mutation for the persistence of papillary thyroid cancer (PTC) after total thyroidectomy and routine central neck dissection. Patients and Methods We collect the clinicopathological data of 288 PTC patients with total thyroidectomy (TT) and routine central neck dissection (CND), and analyzed the relationship between BRAFV600E mutation status and the rate of elevated non-stimulated thyroglobulin (NSTg) value. And we also collect the clinicopathological data of 370 PTC patients who needed radio iodine ablation(RIA) after TT and routine CND, and analyzed the relationship between BRAFV600E mutation status and the rate of elevated stimulated Tg (STg)value before RIA. The clinicopathological data included gender, age at diagnosis, multifocality, bilaterality, tumor size, extrathyroidal invasion, and lymph node status of these patients. All the patents were diagnosis as PTC before operation by the combination with ultrasonograph and FNA (fine needle asperation). Results BRAFV600E mutation is not associated with the elevated rate of elevated Tg value after TT and routine CND. Conclusions BRAF V600E mutation is not an independent predictive factor for the persistence of papillary thyroid cancer (PTC) after TT and routine CND.
<Keywords: Craniomandibular disorders, Temporomandibular disorders
Papillary thyroid cancer (PTC) is a common endocrine malignancy, which accounts for 80% to 85% of all thyroid cancers, and can be classified into several subtype variants, including the common conventional PTC (CPTC), follicular-variant PTC (FVPTC), and a few uncommon variants [1,2]. Although PTC is generally a highly curable disease, the elevated serum Tg (thyroid globin) value is not rare after TT [3]. And the elevated serum Tg value usually indicate the persistence or recurrence of the disease if the patents received TT. Aggressive pathological behaviors of PTC, such as extrathyroidal extension, lymph node metastasis,distant metastasis, are usually the main cause of the elevated serum Tg value.
The association of BRAFV600E mutation with the clinicopathological characteristics of PTC patients and predictive value of this mutation for aggressive behaviors are extensively investigated [4-13]. A number of studies [4-8] demonstrated that BRAFV600E mutation was closely associated with aggressive pathological behaviors of PTC, such as extrathyroidal extension, lymph node metastasis, and high TNM stages. However, whether BRAFV600E mutation will increase the opportunity of disease persistence in the PTC patents after surgery is still unkown.
The aim of this study was to evaluate whether BRAFV600E mutation is an independent predictive factor for the persistence of papillary thyroid cancer (PTC) after TT and routine CND.
Study design
We conducted a retrospective study of PTC patients who underwent total thyroidectomy (TT) and CND in West China Hospital, Sichuan University from January 2013 to December 2014. The Institutional Ethics Committee of the West China Hospital approved this study. The clinicopathological features such as Gender, age at diagnosis, multifocality, bilaterality, extrathyroidal invasion, Tumor size, lymph node metastases (LNM), AJCC stage, TSH(thyroid stimulating hormone), Tg and TGAB (thyroglobulin antibody) value in serum were collected. The stimulated Tg value was tested after the patients stopped to take levo-thyroxin for 3 weeks, and at the same time, the TSH values of all the patients were above 30mIU/L, usually more than 100 mIU/L. The non-stimulated Tg value was tested after the patients had taken levo-thyroxin for at least for 4 weeks after the operation and the TSH values were suppressed lower than 0.5 mIU/L.
We tested the BRAFV600E mutation status of 543 PTC patients who underwent thyroidectomy and routine ipsilateral CND. 255 patients were excluded because of high serum TgAb values or none total thyroidectomy or distant metastasis or lack the data of non-stimulated Tg values before RIA. Distant metastasis was accessed by CT scan of chest and Tg value. If either of them suggests distant metastasis we took whole body scan with 131I to evaluate. At last we got 288 patients and analyzed the relationship between BRAFV600E mutation and the rate of elevated non-stimulated Tg value. These 288 patients defined as group 1 (non-stimulated group).
173 patients of the 543 were excluded because of high serum TgAb concentration, none total thyroidectomy, distant metastasis, or lack of stimulated Tg values, at last we got 370 patients and analysed the association between BRAFV600E mutation and the rate of elevated stimulated Tg value. We defined these 370 patients as group 2 (stimulated group).
The procedure of DNA extraction and BRAFV600E analysis was the same as Li-Bo Yang’ paper [14]. The surgical stratagem of these patents with TT and CND was as follows: TT and routine prophylactic ipsilateral CND was firstly performed, if there was metastasis at pretracheal lymph nodes or prelaryngeal lymph nodes (LN) confirmed by intraoperative frozen-section examination, or obviously enlarged LN in contra lateral central neck area, we performed the bilateral CND. If there was any evidence of metastasis in lateral neck lymph node, such as ultrasonogragh, CT, FNAC (fine needle aspiration cytology), we performed bilateral CND and lateral neck lymph node dissection.
We define non-stimulated Tg value within 1 ng/ml as unelevated, and higher than 1 ng/ml as elevated. And we define stimulated Tg value within 10 ng/ml as unelevated, and higher than 10 ng/ml as elevated.
Statistical analysis was performed with SPSS 16.0 (SPSS, Inc., Chicago, IL). Pearson 2 test and Fisher’s exact test were used to calculate the bivariate analysis.
Independent samples t-tests were used for analysis. The two-sided significance level was set at P<0.05.
The data of group 1 is shown in Table 1. In the group 1 (nonstimulated), bivariate analysis showed that elevated rate of elevated non-stimulated Tg value is only associated with lymph node metastasis.
| Total n ( ) | non-stimulated Tg group | χ2 | P value | ||
|---|---|---|---|---|---|
| Unelevated（239） | Elevated（49） | ||||
| Gender | 0.487 | 0.485 | |||
| male | 70（24.3） | 60（85.7） | 10（14.3） | ||
| Female | 218（75.7） | 179（82.1） | 39（17.9） | ||
| Age at diagnosis | 1.195 | 0.274 | |||
| < 45 | 180（62.5） | 146（81.1） | 34（18.9） | ||
| ≥ 45 | 108（37.5） | 93（86.1） | 15（13.9） | ||
| BRAFV600E | 3.79 | 0.052 | |||
| mutation | 95（33.0） | 73（76.8） | 22（23.2） | ||
| wide type | 193（67.0） | 166（86.0） | 27（14.0） | ||
| Multifocality | 2.411 | 0.12 | |||
| no | 164（56.9） | 141（86.0） | 23（14.0） | ||
| yes | 124（43.1） | 98（79.0） | 26（21.0） | ||
| Bilaterality | 0.634 | 0.426 | |||
| no | 224（77.8） | 188（83.9） | 36（16.1） | ||
| yes | 64（22.2） | 51（79.7） | 13（20.3） | ||
| Extrathyroidal invasion | 0.309 | 0.578 | |||
| no | 196（68.1） | 161（82.1） | 35（17.9） | ||
| yes | 92（31.9） | 78（84.8） | 14（15.2） | ||
| LNM | 6.715 | 0.01 | |||
| yes | 176（61.1） | 138（78.4） | 38（21.6） | ||
| no | 112（38.9） | 101（90.2） | 11（9.8） | ||
| Tumor size (cm) | 0.062 | 0.804 | |||
| ≤ 1 | 175（60.8） | 146（83.4） | 29（16.6） | ||
| > 1 | 113（39.2） | 93（82.3） | 20（17.7） | ||
| AJCC stage | 1.675 | 0.643 | |||
| Ⅰ | 235（81.6） | 197（83.8） | 38（16.2） | ||
| Ⅱ | 3（1.0） | 3（100.0） | 0（0） | ||
| Ⅲ | 35（12.2） | 27（77.1） | 8（22.9） | ||
| Ⅳ | 15（5.2） | 12（80.0） | 3（20.0） | ||
Tabel 1: Tg value and clinicopathological factors in group 1(non stimulated).
There is no significant association of the serum Tg value with gender, age at diagnosis, BRAFV600E mutation, multifocality, bilaterality, extrathyroidal invasion, Tumor size, and AJCC stage in our study. But the relationship between the serum Tg value and LNM were not confirmed by t-test.
The data of group 2 is shown in Tables 2 and 3. In the group 2, bivariate analysis show that higher rate of elevated stimulated Tg is associated with Multifocality, Bilaterality, and LNM. But BRAFV600E mutation is not associated with higher rate of elevated stimulated Tg. Multivariate analysis showed that LNM had significant positive associations with elevated Tg value in group 2.
| Group 2 | χ2 | P value | |||
|---|---|---|---|---|---|
| Total，n（%） | Unelevated（298） | Elevated（72） | |||
| Gender | 1.886 | 0.17 | |||
| male | 90 (24.3) | 68 (75.6) | 22 (24.4) | ||
| female | 280 (75.7) | 230 (82.1) | 50 (17.9) | ||
| age | 2.63 | 0.105 | |||
| ＜ 45 | 226 (61.1) | 176 (77.9) | 50 (22.1) | ||
| ≥ 45 | 144 (38.9) | 122 (84.7) | 22 (15.3) | ||
| BRAFV600E | 0.931 | 0.335 | |||
| mutation | 126 (34.1) | 98 (77.8) | 28 (22.2) | ||
| wide type | 244 (65.9) | 200 (82.0) | 44 (18.0) | ||
| Multifocality | 5.273 | 0.022 | |||
| no | 204 (55.1) | 173 (84.8) | 31 (15.2) | ||
| yes | 166 (44.9) | 125 (75.3) | 41 (24.7) | ||
| Bilaterality | 5.568 | 0.018 | |||
| no | 272 (73.5) | 227 (83.5) | 45 (16.5) | ||
| yes | 98 (26.5) | 71 (72.4) | 27 (27.6) | ||
| Extrathyroidal invasion | 1.064 | 0.302 | |||
| yes | 259 (70.0) | 205 (79.2) | 54 (20.8) | ||
| no | 111 (30.0) | 93 (83.8) | 18 (16.2) | ||
| LNM | 11.069 | 0.001 | |||
| yes | 247 (66.8) | 187 (75.7) | 60 (24.3) | ||
| no | 123 (33.2) | 111 (90.2) | 12 (9.8) | ||
| Tumor size (cm) | 2.771 | 0.096 | |||
| ≤ 1 | 227(61.4) | 189(83.3) | 38(16.7) | ||
| > 1 | 143(38.6) | 109(76.2) | 34(23.8) | ||
| AJCC stage | 1.716 | 0.633 | |||
| Ⅰ | 291 (78.6) | 236 (81.1) | 55 (18.9) | ||
| Ⅱ | 3 (0.8) | 3 (100.0) | 0 (0) | ||
| Ⅲ | 50 (13.5) | 40 (80.0) | 10 (20.0) | ||
| Ⅳ | 26 (7.0) | 19 (73.1) | 7 (26.9) | ||
Tabel 2: TG and clinicopathological factors in group 2 (stimulated).
| 95% confidence interval | ||||
|---|---|---|---|---|
| Features | Odds ratio | Lower bound | upper bound | P value |
| Multifocality（+） | 1.423 | 0.699 | 2.897 | 0.331 |
| Bilaterality（+） | 1.375 | 0.651 | 2.905 | 0.404 |
| LNM（+） | 0.355 | 0.182 | 0.691 | 0.002 |
Tabel 3: Multivariate analysis of the association between clinicopathological features and Tg value in group 2.
In all, the rate of the elevated serum Tg values, no matter TSH is suppressed nor stimulated, is not associated with BRAFV600E mutation after total thyroidectomy and routine CND. Only LNM had significant positive associations with higher rate of elevated Tg value in group 2.
Elevated serum Tg level usually indicated that thyroid or tumor remnants, LNM or distant metastasis, it is usually to be a indicator of persistence of PTC after TT [3].
Some studies reported that the BRAFV600E mutation is related to older age, tumor size, thyroid capsular invasion, extrathyroidal extension, and LNM [15–20]. These features indicated a poor outcome in PTC patients [21–23]. Several studies further defined the relationship between the BRAFV600E mutation and the aggressiveness of thyroid tumor cells. Many studies have investigated the role of the mutation in the decision of the most optimal initial surgical extent, including prophylactic CND for PTC, but the results are controversial [24]. Lee et al. [25] conducted a small series that included only 63 patients with PTC and underscored the prematurity of utilizing BRAF V600E mutation status to determine the surgical management of patients with PTC, specifically whether or not to perform CND. They suggested that prospective, multi-institutional studies that include only patients preoperatively known to have PTC and centers in which routine CND is performed are therefore greatly needed before we can accurately assess whether BRAF V600E mutation status should be incorporated into critical decisions regarding the appropriate operative management of patients with PTC [26].
Papillary thyroid carcinoma (PTC) is the most common histologic type of differentiated thyroid cancer, which is characterized by early lymph node (LN) metastasis (1). Cervical LNM is frequently observed in PTC patients with an average incidence of 60% (2). The most common sites of metastases are the central lymph nodes (CLNs) of the neck (level VI). Therapeutic central compartment neck dissection is well accepted to perform for patients with known LN metastasis diagnosed by physical examination or preoperative ultrasonograph (US) scanning. In china main land, lobotomy/TT with prophylactic ipsilateral CND is a well accepted procedure for PTC if the surgeon can control the complications. TT and routine prophylactic CND for PTC was also reported by other authors (26). If the tumor size is more than 1cm, thyroid capsular invasion, extrathyroidal extension, TT with prophylactic ipsilateral central lymph node dissection is usually performed. In our center, we perform routine CND followed with TT to minimize the opportunity of disease persistence or recurrence, and the rate of permanent recurrent laryngeal nerve palsy or hypoparathyrodism is lower than 0.3%.
In group 2 (TSH stimulated), they all received the RIA (radio iodine ablation), because they had the pathological features of thyroid capsular invasion, extra thyroidal extension, and/or LNM. Interestingly we found that in this group, we do not find that the rate of BRAFV600E mutation was obviously higher than that in the total sample. This may indicate that even though BRAFV600E mutation is associated with thyroid capsular invasion, extra thyroidal extension, and/or LNM in many studies (4-8), the association is not strong.
Our study compares the rate of elevated serum Tg value between the patients with BRAFV600E mutation and wide type after TT with routine CND, and shows no difference between two groups. Although BRAFV600E mutation is usually associated with tumor size more than 1cm, thyroid capsular invasion, extrathyroidal extension and LNM, it seems not to increase the possibility of tumor or LN remnant after TT and routine CND.
In our study, we do not confirmed that the BRAFV600E mutation was an independent predictor for higher rate of elevated serum Tg values after TT and routine CND. This may indicate that TT and routine CND can minimize the disease persistence of the patients even with BRAFV600E mutation and maybe helpful to reduce the recurrence of the disease. If the complication of the surgery can be controlled, TT and routine CND can be considered for the patents at high risk of disease persistence or recurrence.
This work was funded by grants from the National Natural Science Foundation of China (31000601) and Young Investigator Scholar in Sichuan University (2012SCU04A14).