李 濤，傅麗蘭，劉子文

(1.北京協(xié)和醫(yī)學(xué)院 臨床醫(yī)學(xué)專(zhuān)業(yè), 北京 100005； 2.中國(guó)醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)院 基本外科, 北京 100730)

研究論文

臨床N0期甲狀腺乳頭狀癌頸部淋巴結(jié)隱匿性轉(zhuǎn)移規(guī)律的分析

李 濤1，傅麗蘭1，劉子文2*

(1.北京協(xié)和醫(yī)學(xué)院 臨床醫(yī)學(xué)專(zhuān)業(yè), 北京 100005； 2.中國(guó)醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)院 基本外科, 北京 100730)

目的探討臨床N0期甲狀腺乳頭狀癌(cN0 PTC)的頸部淋巴結(jié)轉(zhuǎn)移規(guī)律，為cN0 PTC預(yù)防性淋巴結(jié)清掃范圍提供循證醫(yī)學(xué)證據(jù)。方法檢索PubMed、Embase、Cochrane和Medline等數(shù)據(jù)庫(kù)，納入行甲狀腺切除和淋巴結(jié)清掃的cN0 PTC病例。以Stata10.2進(jìn)行分析。結(jié)果共納入6項(xiàng)研究(4 154例cN0 PTC)。中央組淋巴結(jié)轉(zhuǎn)移率57%，側(cè)方淋巴結(jié)轉(zhuǎn)移率40%，各頸部淋巴結(jié)分區(qū)淋巴結(jié)轉(zhuǎn)移率從高到低依次為Ⅵ區(qū)(57%)、Ⅲ區(qū)(42%)、Ⅳ區(qū)(21%)、Ⅱ區(qū)(10%)、Ⅴ區(qū)(6%)、Ⅶ區(qū)(2%)、Ⅰ區(qū)(2%)。結(jié)論預(yù)防性淋巴結(jié)清掃，需同時(shí)清掃Ⅵ區(qū)、Ⅲ區(qū)和Ⅳ區(qū)。

甲狀腺乳頭狀癌；淋巴結(jié)轉(zhuǎn)移

甲狀腺癌的發(fā)病率在近30年均有增加，以乳頭狀癌(papillary thyroid carcinoma, PTC)為著(約80%)[1]。手術(shù)是目前治療PTC的首選，總體預(yù)后良好，但15%～30% PTC術(shù)后出現(xiàn)局部復(fù)發(fā)，以局部淋巴結(jié)轉(zhuǎn)移復(fù)發(fā)為主[2]。臨床N0期(cN0)在術(shù)前常規(guī)檢查未發(fā)現(xiàn)轉(zhuǎn)移淋巴結(jié), 但不少研究表明，cN0 PTC術(shù)后病理淋巴結(jié)轉(zhuǎn)移比例高[3]，存在頸部淋巴結(jié)隱匿性轉(zhuǎn)移者術(shù)后局部復(fù)發(fā)率高[4]。手術(shù)完全切除腫瘤及受累淋巴結(jié)對(duì)降低cN0 PTC的局部復(fù)發(fā)率至關(guān)重要，但cN0 PTC術(shù)前無(wú)法判斷受累淋巴結(jié)，故關(guān)于預(yù)防性淋巴結(jié)切除范圍的確定，目前爭(zhēng)議較大。本研究旨在探討cN0 PTC的頸部淋巴結(jié)轉(zhuǎn)移規(guī)律及各頸部淋巴結(jié)分區(qū)轉(zhuǎn)移比例，為預(yù)防性淋巴結(jié)清掃范圍提供循證醫(yī)學(xué)證據(jù)。

1 材料與方法

1.1 搜索策略

檢索PubMed(1966—2013.9)、Embase(1974—2013.9)、Cochrane(1997—2013.9) 和Medline(1966—2013.9)數(shù)據(jù)庫(kù)，所有數(shù)據(jù)庫(kù)均由兩名研究者獨(dú)立檢索，檢索詞包括“papillary thyroid carcinoma”、“thyroid cancer”、“carcinoma of thyroid”、“thyroid carcinoma”、“N0”、“l(fā)ymph node negative”、“l(fā)ymph-negative”、“l(fā)ymph node metastasis”、“l(fā)ymphatic metastasis”、“l(fā)ymph node dissection”、“neck metastasis”、“cervical metastases”、“neck dissection”和“cervical nodes”。對(duì)檢索出的條目均閱讀其標(biāo)題、關(guān)鍵詞及摘要，選擇符合選取標(biāo)準(zhǔn)的文獻(xiàn)進(jìn)行全文閱讀。原始文獻(xiàn)的選取均由兩名研究者獨(dú)立進(jìn)行，然后匯總，減小研究者主觀判斷偏倚。

1.2 納入標(biāo)準(zhǔn)

1)術(shù)后病理均為PTC。2)術(shù)前分期均為N0期，N0的判斷標(biāo)準(zhǔn)參考Kowalski等提出的頸淋巴結(jié)臨床評(píng)價(jià)標(biāo)準(zhǔn)。3)手術(shù)是初次治療，同時(shí)行中央組及單側(cè)或雙側(cè)淋巴結(jié)清掃。

1.3 排除標(biāo)準(zhǔn)

1)有頸部其他疾病史，如頸部放射史。2)合并其他類(lèi)型腫瘤。3)臨床資料不完整。

1.4 頸淋巴結(jié)分區(qū)標(biāo)準(zhǔn)

根據(jù)1991年美國(guó)耳鼻喉頭頸外科基金會(huì)的頸淋巴結(jié)分區(qū)標(biāo)準(zhǔn)。

1.5 數(shù)據(jù)整理

兩名研究者獨(dú)立閱讀符合選取標(biāo)準(zhǔn)的原始文獻(xiàn)，并提取相應(yīng)數(shù)據(jù)。為提高所整理數(shù)據(jù)的準(zhǔn)確性同時(shí)降低研究者主觀判斷偏倚，對(duì)兩名研究者所提取的數(shù)據(jù)分別進(jìn)行核對(duì)，對(duì)不符合及存在爭(zhēng)議的數(shù)據(jù)，共同討論決定。

1.6 統(tǒng)計(jì)學(xué)分析

使用Stata10.2軟件(Stata Corp College Station，TX，USA)進(jìn)行統(tǒng)計(jì)分析。以Begg’s漏斗圖評(píng)價(jià)發(fā)表偏倚。以Q檢驗(yàn)評(píng)價(jià)入選研究的內(nèi)部異質(zhì)性，并計(jì)算異質(zhì)性指數(shù)I2。依據(jù)異質(zhì)性大小選擇合并模型計(jì)算合并效應(yīng)量。

2 結(jié)果

2.1 入選文獻(xiàn)

共檢索出179條無(wú)重復(fù)條目；閱讀其標(biāo)題、關(guān)鍵詞、摘要后，排除109條不相關(guān)文獻(xiàn)，選取70條相關(guān)文獻(xiàn)；其中有6篇文獻(xiàn)符合本研究的納入及排除標(biāo)準(zhǔn)，其詳細(xì)信,見(jiàn)表1。在這6篇文獻(xiàn)中，有2篇文獻(xiàn)來(lái)自Patron等[5,6]，詳細(xì)比對(duì)后發(fā)現(xiàn)二者數(shù)據(jù)有重復(fù)：2011年發(fā)表的研究只納入側(cè)方淋巴結(jié)清掃完整的病例[6]，故分析頸部各分區(qū)淋巴結(jié)轉(zhuǎn)移情況時(shí)采用；而2012年發(fā)表研究納入所有行側(cè)方清掃的病例[5]，故分析頸部中央組及側(cè)方淋巴結(jié)轉(zhuǎn)移時(shí)采用。

表1 納入的6項(xiàng)研究的基本信息Table 1 Characteristics of the 6 reports

RS.retrospective study; PS.prospective study; TT.total thyroidectomy; LT.limited thyroidectomy; NTT.near total thyroidectomy; PCND.prophylactic central node dissection; ULND.unilateral lymph node dissection; BLND.bilateral node dissection; SLND.selective lateral node dissection.

以各研究的側(cè)方淋巴結(jié)轉(zhuǎn)移率作Begg’s漏斗圖(圖1)，可看出所有研究均落于漏斗內(nèi)，呈倒漏斗形，各研究分布于對(duì)稱(chēng)線兩側(cè)，表明納入的研究無(wú)明顯的發(fā)表偏倚。

Dots represent the 5 relevant studies.The horizontal axis represents the proportion of patients in the particular study presenting with any LLN metastasis.The vertical axis represents the standard error of this proportion of interest圖1 納入文獻(xiàn)的漏斗圖分析Fig 1 Begg’s Funnel Plot assessing publication bias for the studie

2.2 淋巴結(jié)轉(zhuǎn)移情況

納入的全部研究中，其頸部淋巴結(jié)轉(zhuǎn)移情況如表2所示，共包含4 154例cN0 PTC患者，其中193例詳細(xì)提及頸部各分區(qū)淋巴結(jié)轉(zhuǎn)移情況。

分別對(duì)中央?yún)^(qū)淋巴結(jié)、側(cè)方淋巴結(jié)、各頸部分區(qū)淋巴結(jié)轉(zhuǎn)移情況用Stata10.2進(jìn)行分析，其結(jié)果列于圖2。計(jì)算H統(tǒng)計(jì)量，側(cè)方淋巴結(jié)轉(zhuǎn)移H 17.53(15.55，19.76)，中央組H 14.59(12.48，17.07)；Ⅱ、Ⅲ、Ⅳ和Ⅴ區(qū)以I2描述其異質(zhì)性，分別為30.3%、98.9%、95.3%和100%，可以看出除了Ⅱ區(qū)外，余各組異質(zhì)性均較大，故除Ⅱ區(qū)以固定效應(yīng)模型進(jìn)行分析外，其余各組均以隨機(jī)效應(yīng)模型分析。

因Ⅰ區(qū)、Ⅵ區(qū)和Ⅶ區(qū)的數(shù)據(jù)不完整，采用研究5和研究6的數(shù)據(jù)，與分析得到的頸部淋巴結(jié)轉(zhuǎn)移率合并，作cN0 PTC頸部淋巴結(jié)轉(zhuǎn)移情況的條形圖(圖3)?？梢?jiàn)中央組和側(cè)方淋巴結(jié)轉(zhuǎn)移率分別為57%、40%，各頸部淋巴結(jié)分區(qū)淋巴結(jié)轉(zhuǎn)移率從高到低依次為Ⅵ區(qū)、Ⅲ區(qū)、Ⅳ區(qū)、Ⅱ區(qū)、Ⅴ區(qū)、Ⅶ區(qū)、Ⅰ區(qū)。根據(jù)各分區(qū)淋巴結(jié)轉(zhuǎn)移率，可推斷Ⅵ區(qū)為頸部淋巴結(jié)引流第1站，Ⅲ區(qū)和Ⅳ區(qū)為第2站，其余淋巴結(jié)分區(qū)為第3站。

3 討論

目前對(duì)cN0 PTC頸部淋巴結(jié)的轉(zhuǎn)移情況研究尚少，本研究通過(guò)對(duì)截至目前發(fā)表的6項(xiàng)臨床試驗(yàn)結(jié)果進(jìn)行分析，發(fā)現(xiàn)約一半cN0 PTC有頸部淋巴結(jié)轉(zhuǎn)移，中央組淋巴結(jié)轉(zhuǎn)移率最高。各頸部淋巴結(jié)分區(qū)淋巴結(jié)轉(zhuǎn)移率從高到低依次為Ⅵ區(qū)、Ⅲ區(qū)、Ⅳ區(qū)、Ⅱ區(qū)、Ⅴ區(qū)、Ⅶ區(qū)和Ⅰ區(qū)。Ⅲ區(qū)和Ⅵ區(qū)為高風(fēng)險(xiǎn)區(qū)域。

上述發(fā)現(xiàn)對(duì)cN0 PTC預(yù)防性頸部淋巴結(jié)清掃范圍的確定具有重要意義。以中央組淋巴結(jié)為例，多數(shù)研究預(yù)防性切除雙側(cè)中央組淋巴結(jié)[7- 8]，也有研究?jī)H切除同側(cè)中央組淋巴結(jié)[9]。本研究認(rèn)為Ⅵ區(qū)淋巴結(jié)轉(zhuǎn)移率高，為完全切除隱匿性轉(zhuǎn)移的淋巴結(jié)，行預(yù)防性中央淋巴結(jié)切除應(yīng)同時(shí)切除雙側(cè)中央組淋巴結(jié)，這與美國(guó)國(guó)立綜合癌癥網(wǎng)絡(luò)(national comprehensive cancer network, NCCN)發(fā)表的甲狀腺癌指南推薦是一致的。對(duì)于側(cè)方淋巴結(jié)清掃的范圍，文獻(xiàn)報(bào)道有Ⅱ～Ⅳ區(qū)、 Ⅲ～Ⅳ區(qū)和Ⅱ～Ⅴ區(qū)[5- 6,10- 13]，Ⅱ區(qū)和Ⅴ區(qū)存在增加手術(shù)創(chuàng)傷的問(wèn)題，故一般不清掃Ⅱ區(qū)和Ⅴ區(qū)。本研究的結(jié)果與其一致，側(cè)方轉(zhuǎn)移最高為Ⅲ區(qū)和Ⅳ區(qū)，Ⅱ區(qū)和Ⅴ區(qū)轉(zhuǎn)移少。故為減少手術(shù)創(chuàng)傷，行預(yù)防性側(cè)方淋巴結(jié)切除時(shí)應(yīng)清掃Ⅲ區(qū)和Ⅳ區(qū)。綜上所述，針對(duì)cN0 PTC行預(yù)防性淋巴結(jié)清掃，需同時(shí)清掃Ⅵ區(qū)、Ⅲ區(qū)和Ⅳ區(qū)。

表2 入選的6項(xiàng)研究中cN0 PTC頸部淋巴結(jié)情況Table 2 Data for cervical LN metastasis of cN0 PTC extracted from the 6 included studies

NA.not available.

A.lateral LN metastasis; B.central LN metastasis; C.level Ⅱ LN metastasis; D.level Ⅲ LN metastasis; E.level Ⅳ LN metastasis; F.level Ⅴ LN metastasis

圖2各分區(qū)淋巴結(jié)轉(zhuǎn)移的森林圖
Fig2Meta-analysisplotforpatientswithregionalLNmetastasis

The horizontal axis percentages represent the percentage of nodal involvement at the respective levels; The star indicates data from just one single study圖3 cN0期PTC頸部各分區(qū)淋巴結(jié)轉(zhuǎn)移情況Fig 3 Graphical representation of the results of LNs metastasis in cN0 PTC divided into their respective LN levels and group

目前cN0 PTC頸部淋巴結(jié)轉(zhuǎn)移研究尚少，故納入的研究樣本量偏少，多為回顧性研究，各研究之間異質(zhì)性較大，雖以隨機(jī)效應(yīng)模型進(jìn)行分析，但仍存在偏倚。故仍需大樣本、高質(zhì)量的臨床試驗(yàn)來(lái)驗(yàn)證本研究的結(jié)論。

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Analysis of the pattern of occult cervicallymphatic metastasis in N0 papillary thyroid carcinoma

LI Tao1, FU Li-lan1, LIU Zi-wen2*

(1.Clinical Medicine, PUMC, Beijing 100005; 2.Dept. of General Surgery, PUMC Hospital, CAMS & PUMC, Beijing 100730, China)

ObjectiveTo find pattern of lymphatic metastasis in N0 stage (cN0) papillary thyroid carcinoma (PTC) through an analysis of published studies to establish evidence-based guidelines for selecting and delineating clinical target level of prophylactic lymphadenectomy.MethodsThe PubMed, Embase, Cochrane, and Medline databases were searched for relevant articles. The patients included were mainly untreated cN0 PTC cases that underwent thyroidectomy and prophylactic lymphadenectomy. The data were analyzed by Stata 10.2.ResultsA literature search yielded 6 reports. 57% of the cN0 PTC cases presented with central compartment metastasis, and 40% presented with lateral compartment metastasis. The most commonly involved regions include level Ⅵ and level Ⅲ, with lymphatic metastasis rates of 57% and 42%, respectively, followed by level Ⅳ, level Ⅱ, level Ⅴ, level Ⅶ, and level Ⅰ, with metastasis rates of 21%, 10%, 6%, 2%, and 2%, respectively.ConclusionsClearance of level Ⅵ, level Ⅲ and level Ⅳ during prophylactic neck dissection is essential for the complete removal of occult metastatic lymph nodes.

papillary thyroid carcinoma; lymphatic metastasis

2014- 05- 21

2014- 06- 14

*通信作者(correspondingauthor)：lzwpumch@sina.com

1001-6325(2014)08-1071-05

R 653

A