TITLE:

Is the BRAFV600E

mutation useful as apredictor of preoperative risk in papillary

thyroid cancer?

The American Journal of Surgery

INTRODUCTION:

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 BRAFV600E 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 BRAFV600E

mutation and these Clinicopathologic factors

MATERIALS AND METHODS: PATIENTS

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%).

RESULTSWe 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 BRAFV600E mutation.

We then performed multivariate analysis. Table3 Shows that age

<45, size of cancer >1 cm, extrathyroidal extension, and galectin 3

expression were independently associated with lymph node

metastasis of PTC. We investigated the BRAFV600E mutation in 424

patients with papillary thyroid cancer. Of these patients, 335 (79.0%)

Patients showed the BRAFV600E mutation.

Table 4 shows the relationship between the BRAFV600E 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 BRAFV600E 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 BRAFV600E mutation.

Extrathyroidal extension is an independent factor affecting the

BRAFV600E 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 BRAFV600E

mutation in the follicular variant of PTC was lower at 62.5%,

respectively, than that of classic PTC at 79.7%.

COMMENTS

This study shows that the BRAFV600E mutation is not associated with

a high-risk MACIS score and lymph node metastasis. However, the

BRAFV600E mutation differed Significantly between patients with and

Without extrathyroidal extension. Multivariate analysis showed that

Extrathyroidal extension is independently associated with the

BRAFV600E mutation.

These findings are not consistent with previous reports, particularly in

Western areas.However, a recent study in Japan showed that the BRAFV600E

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 BRAFV600E 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 BRAFV600E 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 BRAFV600E Mutation is not associated

with lymphatic invasion (Table 4).

Therefore, we believe that the BRAFV600Emutation Does not affect

lymph node metastasis directly. However, the BRAFV600E mutation

may affect lymph node metastasis indirectly because it is

Associated with extrathyroidal extension independently.

The BRAFV600E mutation is the most common genetic alteration observed in

thyroid cancer and occurs in 36% to 65% of PTCs in Western countries. However,

the BRAFV600E mutation was found in 79% of patients in our study. This frequency

of the BRAFV600E mutation is higher than that of other studies. The BRAFV600E

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 BRAFV600E mutation; however, we found that the

BRAFV600E 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 BRAFV600E mutation.

Although there are only a few published studies of interracial and

regional differences between the BRAFV600E mutation and the

prognosis of PTC, it appears to be present in the difference between

eastern and western countries.

CONCLUSIONS

We showed that the BRAFV600E 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 BRAFV600E

mutation is useful for the prediction of a poor prognosis of PTC.

In addition, although the BRAFV600E 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 BRAFV600E mutation.