Is the BRAF V600E mutation useful as a predictor of preoperative risk in papillary thyroid cancer? The American Journal of Surgery
Papillary thyroid carcinoma (PTC) is the most common malignancy arising from thyroid follicular cells. Although PTC frequently metastasizes to regional lymph nodes, it generally shows an indolent character and slow growth. However, PTCs showing certain characteristics have poor prognosis and are classified into high-risk groups. There are several classification systems for evaluation of the progression of thyroid carcinoma.
These systems are mainly used for the identification of patients with a poor prognosis to ensure that they receive additional treatment, such as radioiodine ablation and more frequent follow-up monitoring. However, these classification Systems include postoperative data for guidance with regard to the extent of initial surgical resection
Moreover, many patients (80% or more) currently diagnosed with thyroid cancer have small, localized PTC but may receive aggressive treatment because their risk of recurrence and mortality cannot be reliably predicted preoperatively
By contrast, some clinicians in Japan have suggested that patients with a solitary small (1.0 cm) PTC may require observation only, if there is no evidence of lymph node Metastasis or multifocal disease on neck ultrasound.Although the death rate from thyroid cancer has not changed,
The recently discovered activating mutation in the gene for the B type Raf kinase, BRAF, is the most common genetic alteration in thyroid cancer.The most common activating BRAF mutation, a thymidine-to-adenine Transversion at nucleotide 1799, resulting in a valine to Glutamic acid substitution at amino acid 600 (V600E), has Been observed in approximately 29% to 83% of PTCs.The prevalence of this mutation has been found to differ According to PTC subtype.
Although several studies have reported that this mutation is related to poor prognosis and reflects aggressive Clinicopathologic features in patients with PTC, especially in Western countries, other studies have found no statistically significant association between the BRAF V600E mutation and poor prognosis and Aggressive Clinicopathological characteristics, including frequent lymph node metastasis in this disease, especially in eastern countries.
To date, the UICC/AJCC TNM staging system has been the most widely adopted classification systems for evaluation of the prognosis of thyroid carcinoma. Therefore, we evaluated clinicopathologic factors that were suspicious for associationWith poor prognosis based on TNM staging And analyzed the association between the BRAF V600E mutation and these Clinicopathologic factors
Thyroid tumor tissues were sampled from 424 patients with PTC who underwent various thyroidectomy from September 2008 to December 2009 at the Department of Surgery, Seoul St. Mary’s Hospital, Seoul, Korea. We Obtained informative results for 424 patients, and these patients were enrolled in this study. These 424 patients included 79 men and 345 women, and the mean age of patients at surgery was 46.9 ± 12.4 (17 to 76) years.
Total or near total thyroidectomy was performed for 367 patients (86.8%), whereas the remaining patients underwent more limited thyroidectomy, such as subtotal (23 patients), completion (5 patients) thyroidectomy, and lobectomy (29 patients). Central compartment dissection alone was performed For 415 patients (97.9%), and modified radical neck dissection, including central neck dissection, was performed on 9 patients (2.1%).
We investigated lymph node metastasis in 424 patients with PTC who underwent thyroidectomy and neck dissection. Of these patients, lymph node metastasis occurred in 205 (48.3%) patients. (Table 1) Table 2 shows the relationship between lymph node metastasis and clinicopathological features that were suspected to have a prognostic effect to PTC. Lymph node metastasis did not differ significantly between patients with and without the BRAF V600E mutation.
We then performed multivariate analysis. Table3 Shows that age 1 cm, extrathyroidal extension, and galectin 3 expression were independently associated with lymph node metastasis of PTC. We investigated the BRAF V600E mutation in 424 patients with papillary thyroid cancer. Of these patients, 335 (79.0%) Patients showed the BRAF V600E mutation.
Table 4 shows the relationship between the BRAF V600E mutation and Clinicopathologic features, including the Metastasis, Patient Age, Completeness of resection, local Invasion and Tumor Size (MACIS) score, which was identified as a reliable prognostic predicting value.
The incidence of the BRAF V600E mutation was not linked to the MACIS score, age, sex, or cancer size on univariate analysis. Extrathyroidal extension and galectin 3 expression, multifocality, And variant of PTC were associated with the BRAF V600E mutation. Extrathyroidal extension is an independent factor affecting the BRAF V600E mutation on multivariate analysis(Table 5).
The incidence of classic PTC was higher at 84.3% Than the follicular variant of PTC at 7.6%, and, additionally, there was an oncocytic Type and 36 (8.7%) mixed types. The prevalence of the BRAF V600E mutation in the follicular variant of PTC was lower at 62.5%, respectively, than that of classic PTC at 79.7%.
This study shows that the BRAF V600E mutation is not associated with a high-risk MACIS score and lymph node metastasis. However, the BRAF V600E mutation differed Significantly between patients with and Without extrathyroidal extension. Multivariate analysis showed that Extrathyroidal extension is independently associated with the BRAF V600E mutation.
These findings are not consistent with previous reports, particularly in Western areas.However, a recent study in Japan showed that the BRAF V600E mutation did Not show any relationship with prognostic factors, including lymph node metastasis.In addition, other study groups in Korea have reported that age distribution, sex ratio,extrathyroid extension, multifocality, and lymph node metastasis did not differ significantly between patients with and without the BRAF V600E mutation.
In our study population, age< 45 and male sex,size Of cancer ≥1 cm, extrathyroidal extension, galectin 3 expression,and multifocality were associated with lymph node metastasis of PTC.
multivariate analysis showed that extrathyroidal extension is independently associated with the BRAF V600E mutation. The Extrathyroidal extension is one of the risk factors of lymph node metastasis in our study, and the other authors have reported it.The route for metastasis and locoregional invasion preferentially occurs by lymphatic vessels.In our study, the BRAF V600E Mutation is not associated with lymphatic invasion (Table 4).
Therefore, we believe that the BRAF V600E mutation Does not affect lymph node metastasis directly. However, the BRAF V600E mutation may affect lymph node metastasis indirectly because it is Associated with extrathyroidal extension independently.
The BRAF V600E mutation is the most common genetic alteration observed in thyroid cancer and occurs in 36% to 65% of PTCs in Western countries. However, the BRAF V600E mutation was found in 79% of patients in our study. This frequency of the BRAF V600E mutation is higher than that of other studies. The BRAF V600E Mutation of PTC in Korea, a country where iodine intake is very high, is Reported to be highly prevalent (52%–87%) compared with Western countries.This may be Because most PTCs in Korea are the classic type.
Our study cannot show the association between the prognosis of PTC and the presence of the BRAF V600E mutation; however, we found that the BRAF V600E mutation is not associated with a high MACIS score and lymph node metastasis, cancer size, and sex in our study group. A long-term follow-up study is needed to identify the association between the prognosis of PTC and the BRAF V600E mutation.
Although there are only a few published studies of interracial and regional differences between the BRAF V600E mutation and the prognosis of PTC, it appears to be present in the difference between eastern and western countries.
We showed that the BRAF V600E mutation is commonly found in the Korean Population rather than in Western populations; however, it is not related to a high-risk MACIS score and several high-risk clinicopathologic factors, including lymph node metastasis. However, it is Related to a few High risk clinicopathologic factors including multifocality And extrathyroidal extension. Therefore, it is not clear that The BRAF V600E mutation is useful for the prediction of a poor prognosis of PTC.
In addition, although the BRAF V600E Mutation may play some role in the development of local carcinoma, it is not appropriate for determination of the extent of surgical treatment or postoperative treatment and planning of follow-up monitoring in PTC according to the existence of the BRAF V600E mutation.