宋牧野 黃健豪 史宏炎 梁錦安 章芷源 吳澤宇
【摘要】目的 探討經(jīng)典型甲狀腺乳頭狀癌( CPTC)跳躍性轉(zhuǎn)移的影響因素,以助外科醫(yī)師在面對中央?yún)^(qū)淋巴結(jié)陰性的N1b期患者時制定正確的治療策略。方法 共納入302例接受雙側(cè)中央?yún)^(qū)淋巴結(jié)清掃+單側(cè)或雙側(cè)改良根治性頸清掃術并被診斷為側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移的CPTC患者。收集其臨床及病理資料,并通過單因素和多因素分析探討它們與跳躍性轉(zhuǎn)移的相關性。結(jié)果 302例CPTC跳躍性轉(zhuǎn)移的發(fā)生率為10.6%,年齡(OR = 5.775,95% CI 2.482 ~ 13.437,P < 0.001)、合并橋本甲狀腺炎(OR = 3.470,95% CI 1.274 ~ 9.452,P = 0.015)和腺外侵犯(OR = 2.397,95% CI 1.060 ~ 5.421,P = 0.036)是CPTC跳躍性轉(zhuǎn)移的獨立影響因素。結(jié)論 CPTC跳躍性轉(zhuǎn)移與年齡、合并橋本甲狀腺炎及甲狀腺腫瘤腺外侵犯相關。
【關鍵詞】經(jīng)典型甲狀腺乳頭狀癌;淋巴轉(zhuǎn)移;危險因素;橋本甲狀腺炎
Risk factors of skip metastasis in conventional papillary thyroid carcinoma Song Muye, Huang Jianhao, Shi Hongyan, Liang Jinan, Zhang Zhiyuan, Wu Zeyu. School of Medicine, South China University of Technology, Guangzhou 510006, China
Corresponding author,Wu Zeyu, E-mail: wu.zeyu@hotmail.com
【Abstract】Objective To identify the risk factors of skip metastasis in conventional papillary thyroid carcinoma (CPTC), aiming to assist the surgeons to determine a correct treatment for N1b-stage CPTC patients with negative central lymph nodes. Method A total of 302 CPTC patients who underwent bilateral central lymph node dissection + unilateral or bilateral modified radical cervical dissection and were diagnosed with lateral cervical lymph node metastasis were recruited in this study. Clinicopathological data were collected. The correlation between clinicopathological data and skip metastasis was investigated by univariate and multivariate analyses. Results The incidence of CPTC skip metastasis was 10.6%. Age (OR = 5.775, 95% CI 2.482 ~ 13.437, P < 0.001), complicated with Hashimotos thyroiditis (OR = 3.470, 95% CI 1.274 ~ 9.452, P = 0.015) and extrathyroidal invasion (OR = 2.397, 95% CI 1.060 ~ 5.421, P = 0.036) were the independent risk factors of CPTC skip metastasis. Conclusion Skip metastasis of CPTC is significantly associated with age, complicated with Hashimotos thyroiditis and extrathyroidal invasion.
【Key words】Conventional papillary thyroid carcinoma; Lymphatic metastasis; Risk factor;
Hashimotos thyroiditis
近年來甲狀腺癌的全球發(fā)病率持續(xù)增加,2020年全球新增甲狀腺癌患者超58萬例,占全年新增腫瘤總量的3%。甲狀腺乳頭狀癌 (PTC) 病例數(shù)的不斷增加是造成這一狀況的主因[1-2]。根據(jù)WHO對甲狀腺腫瘤的新分類,直徑 ≤10 mm的PTC被稱為甲狀腺微小乳頭狀癌 (PTMC) ,而直徑> 10 mm的PTC則被定義為經(jīng)典型甲狀腺乳頭狀癌(CPTC)[3]。研究表明,CPTC的淋巴結(jié)轉(zhuǎn)移率顯著高于 PTMC,這說明CPTC與PTMC可能具有不同的生物學行為,因此有必要單獨研究CPTC的淋巴結(jié)轉(zhuǎn)移特性[4-6]。
目前的研究顯示PTC傾向于通過淋巴管轉(zhuǎn)移,約27% ~ 80%的PTC患者被發(fā)現(xiàn)存在頸部淋巴結(jié)轉(zhuǎn)移,這種轉(zhuǎn)移是腫瘤局部復發(fā)和遠處轉(zhuǎn)移的重要危險因素[7-9]?;诹馨凸芙馄赎P系,中央?yún)^(qū)淋巴結(jié)常被視為最早出現(xiàn)轉(zhuǎn)移的部位,而側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移多為疾病進展后受累[10]。然而,跳躍性轉(zhuǎn)移,即無中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移 (CLNM) 的側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移時有發(fā)生[11]。既往的研究顯示,PTC的跳躍性轉(zhuǎn)移發(fā)生率為6.8% ~ 37.5% ,PTMC的跳躍性轉(zhuǎn)移發(fā)生率為7.5% ~ 25.2%[4, 11-13]。作為淋巴結(jié)轉(zhuǎn)移率較高的CPTC,其跳躍性轉(zhuǎn)移的臨床危險因素尚未能確定,本研究就此問題進行了探討。
對象與方法
一、研究對象
回顧性收集廣東省人民醫(yī)院甲狀腺疝外科病區(qū)2018年6月至2020 年6月收治的接受手術的302例CPTC患者的臨床資料。納入標準:①術前超聲提示出現(xiàn)側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移,并行雙側(cè)甲狀腺全切除+雙側(cè)中央?yún)^(qū)淋巴結(jié)清掃+單側(cè)或雙側(cè)改良根治性頸清掃術(至少包括Ⅱ、Ⅲ和Ⅳ區(qū));②術后石蠟病理診斷為CPTC伴側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移。排除標準:①既往有甲狀腺手術史;②經(jīng)病理證實除PTC外合并其他病理類型的甲狀腺癌;③合并遠處轉(zhuǎn)移,如腦、肺和乳腺等;④臨床資料缺失。本研究獲廣東省人民醫(yī)院醫(yī)學倫理委員會批準。
二、手術范圍
所有患者均接受雙側(cè)甲狀腺全切除+雙側(cè)中央?yún)^(qū)淋巴結(jié)清掃+單側(cè)或雙側(cè)改良根治性頸清掃術(至少包括Ⅱ、Ⅲ和Ⅳ區(qū)), 本科室中央?yún)^(qū)淋巴結(jié)清掃的范圍為上緣至甲狀軟骨,下緣至無名靜脈,外緣至頸動脈鞘,后緣至椎前筋膜。同時,氣管前淋巴結(jié)及喉前淋巴結(jié)也被認為是中央?yún)^(qū)淋巴結(jié)。側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移的清掃范圍為上至二腹肌,下至鎖骨下靜脈,外至斜方肌前沿,后至椎前筋膜。
三、研究方法
以是否存在中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移為標準,將所有患者分為跳躍性轉(zhuǎn)移組(32例)和非跳躍性轉(zhuǎn)移組(270例),比較2組的臨床資料。
四、統(tǒng)計學處理
使用 Microsoft Excel 進行數(shù)據(jù)收集。采用SPSS 25.0進行統(tǒng)計分析。通過χ2檢驗或 Fisher 確切概率法進行單因素分析以探討CPTC臨床與病理特征之間的關系。將單因素分析中P < 0.05的因素納入logistic逐步回歸分析中進行多因素分析。P < 0.05為差異具有統(tǒng)計學意義。
結(jié)果
一、CPTC側(cè)頸淋巴結(jié)轉(zhuǎn)移患者臨床及病理特征
302例中男110例、女192例,年齡(38.2± 13.4)歲,其中32例被診斷為跳躍性轉(zhuǎn)移,302例的臨床及病理特征見表1。
二、CPTC發(fā)生跳躍性轉(zhuǎn)移與臨床及病理特征的單因素分析
單因素分析顯示在CPTC患者中,跳躍性轉(zhuǎn)移的發(fā)生與年齡(P < 0.001)、是否合并橋本甲狀腺炎(P = 0.044)以及腫瘤的腺外侵犯(P = 0.011)相關,見表2。其中年齡因素是根據(jù)美國癌癥聯(lián)合委員會(AJCC)甲狀腺分期系統(tǒng)(第8版)的更新內(nèi)容,采用55歲作為評估的臨界點。
三、CPTC發(fā)生跳躍性轉(zhuǎn)移與臨床及病理特征的logistic逐步回歸分析
將年齡、合并橋本甲狀腺炎和腺外侵犯納入到logistic逐步回歸分析中(設定方法為向前:有條件,α進入 = 0.05, α除去 = 0.10)。結(jié)果顯示三者均為CPTC患者跳躍性轉(zhuǎn)移的獨立影響因素,屬于危險因素,見表3。
討論
傳統(tǒng)的觀點認為甲狀腺腫瘤的淋巴結(jié)轉(zhuǎn)移通常以中央?yún)^(qū)為起點,隨后才逐漸入侵到側(cè)頸區(qū)[4]。因此當患者未被診斷出現(xiàn)中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移時,醫(yī)師往往放松對其他區(qū)域淋巴結(jié)轉(zhuǎn)移的警惕,低估側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移的風險。然而,甲狀腺頸部的淋巴引流是復雜而多樣的,存在跳躍性轉(zhuǎn)移的情況。根據(jù)報道,約6.8% ~ 37.5%的PTC側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移患者存在跳躍性轉(zhuǎn)移,這在臨床診治過程中不可忽視[4, 9-12]。本研究CPTC患者的跳躍性轉(zhuǎn)移發(fā)生率為10.6%。在手術中遺漏了側(cè)頸區(qū)跳躍性轉(zhuǎn)移的淋巴結(jié),則很可能會導致遠處轉(zhuǎn)移和腫瘤復發(fā)等不良后果。盡管目前尚未完全了解CPTC跳躍性轉(zhuǎn)移的意義與后果,但在胃癌、非小細胞肺癌等惡性腫瘤中跳躍性轉(zhuǎn)移對患者的預后有明確負面影響[14-15]。因此,尋找CPTC跳躍性轉(zhuǎn)移的危險因素具有重要的臨床意義。
本研究顯示≥55歲是CPTC跳躍性轉(zhuǎn)移的獨立影響因素。另一方面,我們也發(fā)現(xiàn)合并橋本甲狀腺炎的患者更易發(fā)生跳躍性轉(zhuǎn)移,其同樣是CPTC患者跳躍性轉(zhuǎn)移的獨立影響因素。橋本甲狀腺炎與PTC之間生物學行為的關聯(lián)一直是研究者們感興趣的話題,主流的觀點認為橋本甲狀腺炎淋巴細胞浸潤可能是一種具有拮抗腫瘤侵襲作用的免疫反應,有助于PTC患者獲得較好的預后[16-18]。有研究者初步探討了橋本甲狀腺炎對腫瘤侵襲抑制作用的機制,結(jié)果提示,自身免疫性炎癥反應和循環(huán)抗體會顯著抑制甲狀腺腫瘤的發(fā)展以及PTC患者的淋巴結(jié)轉(zhuǎn)移,同時橋本甲狀腺炎通過增加腫瘤內(nèi)部和周圍CD8+ T淋巴細胞的數(shù)量來影響腫瘤免疫微環(huán)境,從而對抗腫瘤免疫起促進作用[19-20]。
另一項研究顯示,橋本甲狀腺炎對中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移具有一定的保護抑制作用,尤其是在女性中,然而對于侵襲程度較高的側(cè)頸區(qū)淋巴結(jié)轉(zhuǎn)移則缺乏這種保護作用[21]。綜上所述,盡管具體機制尚未清晰,但橋本甲狀腺炎對于甲狀腺癌淋巴結(jié)轉(zhuǎn)移具有一定的拮抗作用,且這種拮抗作用在中央?yún)^(qū)轉(zhuǎn)移中較為明顯,這可能是合并橋本甲狀腺炎的CPTC患者更易出現(xiàn)跳躍性轉(zhuǎn)移的原因之一。
甲狀腺腫瘤的腺外侵犯常被認為是側(cè)頸淋巴結(jié)轉(zhuǎn)移的危險因素,對判斷患者的預后具有重要意義[12]。在本研究中,腺外侵犯也是CPTC跳躍性轉(zhuǎn)移的獨立影響因素,這可能是由于出現(xiàn)腺外侵犯的患者腫瘤侵襲性更強,易造成側(cè)頸轉(zhuǎn)移。然而腺外侵犯的CPTC患者為何中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移較少,則需要進一步的研究來解釋。
本研究旨在確定CPTC跳躍性轉(zhuǎn)移的影響因素,幫助外科醫(yī)師在面對無中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移的 N1b 期患者時制定治療策略。本研究存在一定不足,需要進一步探索如橋本甲狀腺炎對中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移拮抗作用的具體分子機制等。此外,由于各國指南均不推薦預防性側(cè)頸區(qū)淋巴結(jié)切除,因此選擇偏倚不可避免。最后,本研究屬單中心回顧性分析,結(jié)論尚需多中心前瞻性研究進一步驗證。
綜上所述,年齡≥55歲、合并橋本甲狀腺炎和出現(xiàn)甲狀腺腺外侵犯是CPTC出現(xiàn)跳躍性轉(zhuǎn)移的獨立影響因素,對于該類患者,應謹慎評估其側(cè)頸淋巴結(jié)轉(zhuǎn)移的風險,以助發(fā)現(xiàn)更多隱匿的淋巴結(jié)轉(zhuǎn)移,改善患者預后。
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(收稿日期:2021-07-19)
(本文編輯:洪悅民)