探討BRAF V600E基因突變在低風險性甲狀腺乳突癌之臨床意義

Clinical significance of BRAF V600E mutation in low risk papillary thyroid carcinoma

姜和均(He-Jiun Jiang)

指導教授 ： 許雅玲

共同指導教授 ： 蕭璧容(Pi-Jung Hsiao)

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2018年)

摘要

研究背景

BRAF V600E 基因突變是甲狀腺乳突癌最常見的基因變異，藉由影響MAP kinase/ERK訊號傳遞路徑促使腫瘤生長和擴散，但目前BRAF V600E基因突變與臨床病理特徵、淋巴轉移及預後等關聯性未完全確立，亦缺乏台灣本土報告；且傳統的風險因子雖與疾病復發有關並可影響治療策略，卻未有足夠的證據力指引臨床低風險性甲狀腺乳突癌患者的手術方式。面臨越來越多的小型、低風險性甲狀腺乳突癌患者，本研究希望藉由BRAF V600E與各項臨床因子進行全面性的分析，找尋BRAF V600E的臨床意義，並作為決定低風險性患者治療決策的價值。

研究對象和方法學

本研究為回溯性世代研究，從2016年9月至2018年2月連續性收集共341位甲狀腺乳突癌患者，就臨床病理特徵和BRAF V600E基因突變結果進行相關性分析，當中309位接受過甲狀腺全切除術和放射碘治療，並且完成至少6個月追蹤，其平均無進展生存期為39.7 (±29.0)個月。接著進行BRAF V600E基因突變與傳統風險因子之預後分析，將臨床低風險性(T1、T2)且無臨床異常淋巴結(cN0)的患者共185名，分成BRAF V600E基因突變陽性組和陰性組，進行預防性中央頸部淋巴廓清的預後分析。統計方法學以卡方檢定比較各個名義變項之差異和風險，而二元邏輯迴歸用以比較各項因子對預後的影響力。

結果

本研究341位患者平均年齡為46.4歲(±12.7)，女性佔76.5%，BRAF V600E基因突變陽性佔52.3% (177/341)；帶有BRAF V600E基因突變的患者具有較多的甲狀腺外侵犯、淋巴及微血管侵犯、腫瘤包膜侵犯、病理性中央頸部淋巴轉移及較大的腫瘤；整體來說甲狀腺乳突癌之復發或持續結構性疾病與傳統風險因子相關，包含年齡<45歲、腫瘤>4cm、外側頸部淋巴轉移和遠端轉移，但與BRAF V600E基因突變狀態無直接關聯性；另外一方面，術前中央頸部淋巴轉移的影像篩檢敏感度僅18.9%；至於預防性中央頸部淋巴廓清可明顯改善帶有BRAF V600E基因突變低風險性甲狀腺乳突癌患者之復發率(11.6% vs. 36.8%, p=0.01)和增進早期治療反應(76.8% vs. 52.6%, p=0.015)，但是在未帶有BRAF V600E基因突變的分組，預防性中央頸部淋巴廓清對預後則沒有任何影響。

討論和結論

甲狀腺乳突癌的死亡率雖然很低，但卻容易淋巴轉移，未根除轉移的淋巴結會導致疾病的復發，反覆手術會讓併發症顯著增加，且放射碘治療亦有累積劑量的限制，因此甲狀腺乳突癌初始的治療計畫顯得非常重要；目前美國甲狀腺醫學會提出的甲狀腺癌治療準則，針對臨床低風險性甲狀腺乳突癌患者，並未建議接受較積極的預防性中央頸部淋巴廓清；隨著近年來低風險性腫瘤比例越來越高，有鑑於甲狀腺乳突癌具有相當高比例的淋巴轉移，加上術前影像篩檢敏感度較低，目前缺少明確的生物指標用以指引這些患者的治療策略；但本研究發現到BRAF V600E基因突變與局部侵犯性的特徵有高度相關性，尤其是中央頸部區域的病理性淋巴轉移，且對於臨床低風險性甲狀腺乳突癌患者，具有導引預防性中央頸部淋巴廓清的預測力，因此我們建議納入BRAF V600E基因突變之常規測定，用以輔助臨床低風險性甲狀腺乳突癌患者的治療策略之擬定：也就是針對術前之細針穿刺細胞檢體進行BRAF V600E檢定，若屬陽性患者，雖然是臨床低風險性甲狀腺乳突癌患者，仍建議進行預防性中央頸部淋巴廓清，以免日後之淋巴復發和轉移。

關鍵字

低風險性 ； 甲狀腺乳突癌 ； BRAF,預防性中央頸部淋巴廓清 ； 淋巴轉移

並列摘要

Introduction

BRAF V600E point mutation is the most common genetic event in papillary thyroid carcinoma (PTC) worldwide. Theoretically, it may alter the MAP kinase/ERK signaling pathway to promote cancer cell growth and progression. However, the association between BRAF V600E mutation and clinicopathologic significance of aggressiveness and clinical utilization remained controversial and was not fully documented. As incidence of small and low grade tumor increased recently, it is critical to find an objective marker to guide management strategy for these patients. In this study, we compared BRAF V600E mutation with wild type in pathologic findings, clinical presentation, and interaction with conventional risk factors. Furthermore, we tried to demonstrate clinical utilization in preoperative decision making in low grade papillary thyroid carcinoma.

Materials and Methods

This was a retrospective cohort study to enroll a total of 341 PTC patients consecutively from September 2016 to February 2018. The association between clinicopathological features and BRAF V600E gene mutation status was analyzed. Overall 309 PTC patients after total thyroidectomy and empiric radioiodine therapy with more than 6 months follow-up periods were selected for prognostic analysis of BRAF V600E mutation and conventional risk factors. Furthermore, a total of 185 patients with clinical N0 and low grade status (T1, T2) were divided into positive BRAF V600E mutation and the wild type of BRAF gene to compare disease prognosis with and without prophylactic central neck dissection. The statistical methodologies were compared with each of the nominal variables by Chi-square test. Binary logistic regression was used to compare the impact of various factors on disease prognosis.

Results

Mean age of these 341 patients was 46.4 (±12.7) years with 76.5% female. Frequency of the BRAFV600E mutation was 52.3% (177/341). Patient with BRAF V600E mutation significantly had higher risk of extrathyroid extension, greater risk of harboring lymphovascular invasion and capsule invasion, pathologic N1a status, and bigger main tumor size versus patients with wild type of BRAF gene. In contrast to traditional risk factor such as young age, bigger tumor size, N1b and distant metastasis, patients with BRAF V600E mutation didn’t have greater risk for overall recurrent or persisted structural disease status in analysis. On the other hand, sensitivity of CT or sonography for nodal metastasis screen was only 18.9%. The prophylactic central neck dissection could significantly enhance the treatment response (76.8% vs. 52.6%, p=0.015) and reduce the disease persistence or recurrence (11.6% vs. 36.8%, p=0.01) in low risk PTC population with BRAF V600E mutation.

Discussion and conclusion

The outcome of papillary thyroid carcinoma is good, but prevalence of nodal metastasis is high. It is the major cause of disease recurrence if failure to eradicate metastatic lymph nodes. Repeated surgery and radioiodine ablation therapy are always required but associated with complications. So, the initial surgical planning is very important. According to ATA management guideline, prophylactic central neck dissection was not recommended in clinical low risk patients (T1 and T2 without gross abnormal lymph node (cN1) or extrathyroid involvement). However, the incidence of such low risk PTC cases was increased recent years. The sensitivity of preoperative cervical CT or sonography for central nodal metastasis identification is quite low, especially micrometastasis of lymph nodes. It is critical to find a marker to guide surgical strategy of these patients. Our study pointed out the association between BRAF V600E gene mutation and local invasive behavior, especially pathological central nodal metastasis. BRAF V600E mutation also predicted the better outcome of prophylactic central nodal dissection in low risk PTC patients successfully.
In conclusion, this study proved the clinical significance of BRAF V600E mutation and feasibility to apply this mutation as a surrogate marker for surgical planning, which could determine the treatment strategy in low risk papillary thyroid carcinoma.

並列關鍵字

low risk, papillary thyroid carcinoma ； BRAF ； prophylactic central neck dissection ； nodal metastasis

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