中國醫(yī)師協(xié)會骨科醫(yī)師分會骨腫瘤專業(yè)委員會
郭衛(wèi)1*李建民2*沈靖南3*屠重棋4*
(1.北京大學(xué)人民醫(yī)院骨腫瘤科,北京100044;2.山東大學(xué)齊魯醫(yī)院骨科,濟南250012;3.中山大學(xué)第一附屬醫(yī)院骨科,廣州510080;4.四川大學(xué)華西醫(yī)院骨科,成都610041)
證據(jù)推薦等級方法采用GRADE(Grading of Recommendations Assessment,Development and Evaluation)方法,內(nèi)容見表1。
骨巨細胞瘤(giant cell tumor,GCT)是一種原發(fā)交界性骨腫瘤,1818年由Copper首次描述[1],占所有原發(fā)性骨腫瘤的3%~5%,良性骨腫瘤的15%[2],在東亞人群中更為常見[3]。骨巨細胞瘤好發(fā)于20~40歲[4]。在四肢長骨中,股骨遠端、脛骨近端、橈骨遠端和肱骨近端最為多見,骨盆和脊柱等中軸骨也常受累[3,5,6]。常規(guī)刮除術(shù)后有較高的局部復(fù)發(fā)率[7],肺轉(zhuǎn)移率1%~9%[8,9]。極少數(shù)病例可轉(zhuǎn)化為高度惡性骨肉瘤,預(yù)后差[10,11]。多中心骨巨細胞瘤偶見于個案報道[12]。
初始檢查應(yīng)包括病史、體格檢查、原發(fā)病灶充分的影像學(xué)檢查(X線片、CT和MRI)。CT有助于確定骨皮質(zhì)破壞范圍,而評估腫瘤侵犯周圍軟組織及神經(jīng)血管時首選MRI[13,14]。CT和MR增強掃描還可提供腫瘤的血供信息。骨掃描檢查可用于除外多中心骨巨細胞瘤。PET或PET/CT是一種可選擇的影像學(xué)技術(shù),已應(yīng)用于治療前分期、監(jiān)測腫瘤進展速度和評估輔助治療療效[15-18]。胸部影像學(xué)對確定有無轉(zhuǎn)移性病灶很重要。血清鈣、磷水平和甲狀旁腺激素水平測定可用于甲狀旁腺功能亢進性棕色瘤的鑒別診斷。(1B級)
表1 GRADE推薦等級和證據(jù)分級
活檢是明確診斷的最重要手段,尤其在與甲狀旁腺功能亢進性棕色瘤進行鑒別時。如活檢結(jié)果提示惡變,應(yīng)按照骨肉瘤的治療方案處理。切開活檢和穿刺活檢(粗針或針吸)是骨與軟組織腫瘤診斷的兩種方法[19,20]。切開活檢是最準確的方法,它可以提供較多的標本來進行免疫組織化學(xué)或細胞遺傳學(xué)檢查[21]。但是,切開活檢需要在手術(shù)室進行全身麻醉或區(qū)域麻醉。穿刺活檢可以在局部麻醉下進行,需要或不需要鎮(zhèn)靜。當獲得標本充分的時候,穿刺活檢可作為切開活檢的另一種選擇,其診斷準確率為88%~96%[22-24]。隨著影像學(xué)技術(shù)的發(fā)展,影像學(xué)定位下的穿刺活檢越來越多地在診斷原發(fā)性和繼發(fā)性骨腫瘤中得到應(yīng)用[25]?;顧z應(yīng)該在患者將會接受進一步治療的中心進行?;顧z時,應(yīng)妥善固定病變骨,采取適當?shù)拇胧┓乐共±砉钦鄣陌l(fā)生。活檢的實施對于保肢手術(shù)非常重要,如果活檢不當將會影響患者的預(yù)后[19,20]。如果活檢瘢痕在腫瘤切除時沒有整塊切除,切開活檢和穿刺活檢有可能導(dǎo)致腫瘤局部復(fù)發(fā),這與活檢通道的腫瘤播散有關(guān)。穿刺活檢的腫瘤播散風(fēng)險低[26,27]。然而,穿刺活檢和切開活檢的原則一樣。在計劃活檢路徑時,應(yīng)保證活檢帶在計劃切除的范圍內(nèi),使得手術(shù)時其切除范圍可與原發(fā)性腫瘤一樣,達到同樣的廣泛邊緣切除。(1B級)
無遠處轉(zhuǎn)移患者:若原發(fā)灶可以手術(shù)切除,建議手術(shù)切除。對于原發(fā)灶雖可手術(shù)切除但會導(dǎo)致嚴重并發(fā)癥和功能損失、或中軸骨病變無法切除的患者,建議使用連續(xù)選擇性動脈栓塞聯(lián)合Denosumab(人源RANK配體單克隆抗體),同時還可合并使用干擾素或聚乙二醇-干擾素以及放療。此類患者接受上述治療后,應(yīng)進行定期隨訪監(jiān)測和評估,如病情控制穩(wěn)定或腫瘤縮小明顯,病灶可以切除時應(yīng)選擇手術(shù)治療,切除后進行定期隨訪監(jiān)測。如仍無法切除可繼續(xù)接受上述治療后再進行評估;如病情進展建議在接受上述治療前提下,參加臨床試驗或適時采取根治性手術(shù)。(1B級)
就診時已發(fā)生轉(zhuǎn)移的患者:如原發(fā)灶可切除則按上述方案治療;如果轉(zhuǎn)移灶可切除可考慮手術(shù)切除,并輔以一種有效的輔助治療手段,而后進行隨訪監(jiān)測。如果轉(zhuǎn)移灶無法切除則考慮以下治療方案:Denosumab、干擾素或聚乙二醇-干擾素、放療以及密切觀察轉(zhuǎn)移灶變化。
隨訪內(nèi)容包括體格檢查、手術(shù)部位的影像學(xué)檢查(X線、CT±MRI)以及胸部影像學(xué)檢查(2年內(nèi)每3個月復(fù)查1次、2年后每半年復(fù)查1次)。如出現(xiàn)局部復(fù)發(fā),復(fù)發(fā)灶可切除時建議選擇Denosumab保護下的手術(shù)治療;如二次手術(shù)可能導(dǎo)致嚴重并發(fā)癥和功能損失,或中軸骨病變無法切除時,治療方案參見上述處理原則。(1B級)
對于可切除的骨巨細胞瘤,主要的手術(shù)方式包括廣泛切除和病灶內(nèi)刮除兩種[28-34]。廣泛切除的復(fù)發(fā)率為0~12%,而刮除術(shù)的復(fù)發(fā)率為12%~65%,廣泛切除的復(fù)發(fā)風(fēng)險較低。在部分研究中,病灶內(nèi)手術(shù)以及腫瘤分期是導(dǎo)致局部復(fù)發(fā)的危險因素[35-37]。Blackley等報道了一項包含59例主要診斷為Companacci分級Ⅱ~Ⅲ級腫瘤患者的研究,采用刮除加高速磨鉆及植骨的治療方式,局部復(fù)發(fā)率為12%[36]。Prosser等報道了137例以刮除術(shù)為主要治療方式的患者,其局部復(fù)發(fā)率為19%。其中Ⅰ~Ⅱ級腫瘤的復(fù)發(fā)率僅為7%,而伴有骨外累及的Ⅲ級腫瘤的復(fù)發(fā)率為29%[37]。
病灶內(nèi)刮除術(shù)中常聯(lián)合物理化學(xué)等輔助措施以降低復(fù)發(fā)率。有報道表明對于初治或復(fù)發(fā)的骨巨細胞瘤,此種治療方式可降低局部復(fù)發(fā)[32,38-41]。而另有報道認為輔助治療并未降低局部復(fù)發(fā)率[42-44]。(2B級)
廣泛切除常導(dǎo)致較差的術(shù)后功能以及更高的并發(fā)癥發(fā)生率[32,45-48]。因此,對于Ⅰ~Ⅱ級腫瘤主要采取刮除術(shù)。廣泛切除主要應(yīng)用于Ⅲ級或其他方式無法刮除的腫瘤。(1B級)
對于手術(shù)切緣陽性、不可切除、進展期或復(fù)發(fā)病灶,可采用放療或手術(shù)聯(lián)合放療的方式以改善局部控制率及無病生存率[49-58]。在一項包含58例骨巨細胞瘤患者(45例初治,13例復(fù)發(fā))的回顧性研究中,放療后的5年局部控制率為85%,總體生存率為94%[57]。平均隨訪時間為8年。年齡是影響局部控制率(年輕患者96%,老年患者73%)、總體生存率(年輕患者100%,老年患者87%)以及無病生存率(年輕患者96%,老年患者65%)的唯一因素。其他研究表明腫瘤大于4 cm、復(fù)發(fā)病灶以及放療劑量小于40 Gy是導(dǎo)致局部控制率降低的因素[54,55,59]。
在手術(shù)完整切除難度較大的部位,三維適形調(diào)強放療等技術(shù)可提高骨巨細胞瘤的局部控制率[60,61]。
放療適應(yīng)證:手術(shù)可能導(dǎo)致嚴重并發(fā)癥或功能損失、不可切除、進展期或復(fù)發(fā)病例,并對連續(xù)選擇性動脈栓塞、Denosumab、IFN或PEG IFN治療無效者,考慮行放射治療(50~60 Gy)[50,54,58,60]。在某些研究中發(fā)現(xiàn)放療后腫瘤惡變幾率升高。
Denosumab對不可切除的骨巨細胞瘤有顯著的治療效果[62-64]。在一項Ⅱ期開放試驗中(n=37),Denosumab在不可切除或復(fù)發(fā)的骨巨細胞瘤患者中取得了86%的有效率(巨細胞減少90%或靶病灶影像學(xué)25周無進展)[63]。Chawla等報道了一項開放的Ⅱ期平行對照研究[62],將282例骨巨細胞瘤患者分為3組:組1為不可切除的骨巨細胞瘤患者,組2為切除可導(dǎo)致嚴重并發(fā)癥的患者,組3為既往參與過Denosumab研究的患者。Denosumab治療后可使腫瘤減小并實現(xiàn)外科降級。在中位隨訪時間為13個月的研究中,組1中96%(163/169)的患者無疾病進展。組2的平均隨訪時間為9.2個月,74%(74/100)的患者未接受手術(shù)治療,剩余患者中62%(16/26)接受了低風(fēng)險手術(shù)。
2013年6 月,F(xiàn)DA批準了Denosumab用于治療骨發(fā)育成熟的未成年及成年患者中不可切除或切除后導(dǎo)致嚴重并發(fā)癥和功能損失的骨巨細胞瘤。有學(xué)者提出新輔助治療模式和外科降級的概念[65],但目前尚缺乏高質(zhì)量的隨機對照研究。此外,對于計劃采用手術(shù)治療的患者術(shù)前過度用藥,可能導(dǎo)致大量骨化、纖維增生和骨性分隔,給刮除造成困難,增加復(fù)發(fā)風(fēng)險。有研究認為,術(shù)前3~4次用藥即可達到降低血供、抑制腫瘤的效果,同時不增加骨化和纖維化[66]。
有臨床試驗表明FDG-PET是評估Denosumab早期療效的較敏感的工具。Denosumab用藥期間應(yīng)避免口腔操作,防止發(fā)生下頜骨壞死[67]。
4.4.1 局部病變:對于可切除的腫瘤,根據(jù)病變位置、范圍和殘留骨質(zhì)情況決定采取囊內(nèi)刮除或廣泛切除清除病灶。連續(xù)選擇性動脈栓塞對皮質(zhì)破壞明顯或關(guān)節(jié)受累的肢體巨大骨巨細胞瘤,以及較大的骨盆、脊柱(骶骨)巨細胞瘤是有效的[68-71]。也有研究表明干擾素或長效干擾素治療骨巨細胞瘤是有效的[72,73]。
對于切除可導(dǎo)致嚴重并發(fā)癥或不可切除的中軸骨腫瘤,建議連續(xù)選擇性動脈栓塞、Denosumab、干擾素或長效干擾素作為首選治療方式。放療有導(dǎo)致腫瘤惡變的風(fēng)險,所以當患者無法接受栓塞、Denosumab及干擾素治療時方可采取放療。如病情控制穩(wěn)定或腫瘤縮小明顯,病灶可以切除時應(yīng)選擇手術(shù)治療,切除后進行定期隨訪監(jiān)測,如仍無法切除可繼續(xù)接受上述治療后再進行評估;如病情進展建議在接受上述治療前提下,參加臨床試驗或適時采取根治性手術(shù)。
4.4.2 轉(zhuǎn)移病變:當轉(zhuǎn)移灶可切除時,推薦對原發(fā)灶采取上述治療或?qū)D(zhuǎn)移灶采用病灶切除術(shù)。當轉(zhuǎn)移灶無法切除時,Denosumab、干擾素及長效干擾素、觀察以及放療等均可采用[74-77]。
手術(shù)是肢體骨巨細胞瘤主要治療手段[3]。常用的手術(shù)方式包括:①病灶內(nèi)刮除;②邊緣或廣泛切除[28-31];③若原發(fā)病灶在掌、指(趾)骨,保留骨骼的手術(shù)操作難度大,復(fù)發(fā)率較高,可考慮截指(趾)治療[78]。
病灶刮除術(shù)是最常用的手術(shù)方式,該術(shù)式在清除腫瘤的同時,最大限度地保全了骨關(guān)節(jié)結(jié)構(gòu)和功能,但復(fù)發(fā)率較高,部分文獻報道可達12%~65%。部分研究發(fā)現(xiàn)腫瘤分期是導(dǎo)致局部復(fù)發(fā)的危險因素[14,31,36,44,79]。Prosser等報道了137例以刮除術(shù)為主要治療方式的患者,其局部復(fù)發(fā)率為19%。其中CampanacciⅠ~Ⅱ級腫瘤的復(fù)發(fā)率僅為7%,而伴有骨外累及的CampanacciⅢ級腫瘤的復(fù)發(fā)率為29%[37]。郭衛(wèi)等報道使用病灶刮除治療CampanacciⅠ~Ⅱ級,Enneking靜止期或活躍期的96例四肢骨巨細胞瘤,局部復(fù)發(fā)率為11.9%~13.5%[80]。因此,目前對于Ⅰ~Ⅱ級骨巨細胞瘤建議采取刮除術(shù)。(1B級)
邊緣或廣泛切除可明顯減少骨巨細胞瘤復(fù)發(fā),復(fù)發(fā)率為0~12%,但常導(dǎo)致較差的術(shù)后功能以及更高的并發(fā)癥發(fā)生率[45,47,48]。廣泛切除主要應(yīng)用于Ⅲ級或其他方式無法切除的腫瘤;也適用于腓骨近端、橈骨和尺骨遠端的骨巨細胞瘤以及其他非承重骨的骨巨細胞瘤;另外對于惡性骨巨細胞瘤,廣泛切除也是比較適宜的方法[3]。郭衛(wèi)等報道使用廣泛切除治療CampanacciⅢ級,Enneking侵襲性的32例四肢骨巨細胞瘤,局部復(fù)發(fā)率為6.1%[80]。(1B級)
掌、指(趾)骨的骨巨細胞瘤極少見,但保留骨骼的手術(shù)操作難度大,復(fù)發(fā)率高,建議切除或截指(趾)治療。Yokouchi等報道掌、指(趾)骨的骨巨細胞瘤截指(趾)治療后的病例均無復(fù)發(fā)[81-83]。(1C級)
病灶刮除是骨巨細胞瘤最常用的手術(shù)治療方式,在腫瘤刮除術(shù)同時,常輔以幾種物理或化學(xué)局部處理,來消滅瘤腔壁殘存的瘤細胞,包括:高速磨鉆、苯酚、液氮、氯化鋅、過氧化氫等[39,84,85]。這些措施使病灶邊緣產(chǎn)生近似廣泛刮除的壞死區(qū)域,達到徹底刮除目的[33,35,47,85,86]。(2B級)
單純病灶刮除聯(lián)合植骨術(shù)后復(fù)發(fā)率高達30%~60%[29]。Lizz等總結(jié)不同手術(shù)方法中骨巨細胞瘤復(fù)發(fā)情況的結(jié)果表明,腫瘤刮除同時輔以其他物理或化學(xué)局部處理來消滅殘存的瘤細胞,可明顯降低復(fù)發(fā)率,達到較滿意的治療效果。局部復(fù)發(fā)率10%~25%[86]。Blackley對59例骨巨細胞瘤患者行病灶刮除后用高速磨鉆磨除瘤壁的方法,局部復(fù)發(fā)率僅為12%[36]。Capanna等對138例骨巨細胞瘤進行局部刮除及苯酚處理,局部復(fù)發(fā)率為19%[87]。Malawer等對86例骨巨細胞瘤患者進行局部刮除及液氮處理,局部復(fù)發(fā)率為8%[88]。Zhen等對92例四肢骨巨細胞瘤患者進行病灶內(nèi)刮除及氯化鋅處理,經(jīng)過長達11年的隨訪發(fā)現(xiàn)有13%病例出現(xiàn)局部復(fù)發(fā)[85]。Balke等對42例四肢骨巨細胞瘤患者進行病灶內(nèi)刮除輔助高速磨鉆、過氧化氫滅活、骨水泥填充后局部復(fù)發(fā)率為11%,明顯低于無輔助滅活的病例[39]。
肢體骨巨細胞瘤病灶內(nèi)刮除術(shù)后,瘤腔可使用植骨或骨水泥填充,還可以聯(lián)合接骨板內(nèi)固定重建肢體功能。廣泛切除術(shù)后造成的骨關(guān)節(jié)缺損,應(yīng)進行復(fù)雜的個體化關(guān)節(jié)功能重建[89-91]。(2B級)
病灶刮除滅活后填充物選擇包括自體骨、人工骨、異體骨、骨水泥[92,93]。文獻報道采用高速磨鉆+輔助病灶內(nèi)刮除+異體骨移植的復(fù)發(fā)率為12%[36],高速磨鉆+輔助病灶內(nèi)刮除+骨水泥充填復(fù)發(fā)率為14%,兩者復(fù)發(fā)率較為接近[94]。病灶內(nèi)刮除聯(lián)合骨水泥充填在骨巨細胞瘤的治療方面具有一定優(yōu)勢,因其費用低、術(shù)后恢復(fù)期短,而且X線片上的低密度顯影使腫瘤復(fù)發(fā)病灶極易識別。骨水泥聚合過程由于其本身材料細胞毒性以及聚合時釋放的熱量,可使瘤壁骨質(zhì)深部2~3 mm產(chǎn)生壞死,起到抗腫瘤作用[39,95]。目前,尚無大樣本、前瞻、隨機、對照研究比較不同填充物在局部刮除病灶后對于四肢骨巨細胞瘤的治療效果。單純填充適用于病骨最大破壞橫截面在50%以下或者受累關(guān)節(jié)面的破壞在25%以下的骨缺損。對于病骨最大破壞橫截面達到50%~80%或者受累關(guān)節(jié)面的破壞達到25%~50%時,病理骨折發(fā)生率較高,應(yīng)聯(lián)合應(yīng)用內(nèi)固定[96,97]。
肢體骨巨細胞瘤廣泛切除術(shù)常涉及關(guān)節(jié),術(shù)后患肢功能受限,常用的功能重建方法包括:關(guān)節(jié)融合術(shù)、異體半關(guān)節(jié)或大段異體骨移植術(shù)、人工關(guān)節(jié)置換術(shù)、復(fù)合體置換術(shù)。目前,人工關(guān)節(jié)置換使用最為廣泛[49,98]。
對于局部復(fù)發(fā)的四肢骨巨細胞瘤,仍應(yīng)按照首發(fā)病例相同的原則選擇術(shù)式[41,99],但病灶刮除術(shù)后填充物傾向于骨水泥[41]。對于伴有肺轉(zhuǎn)移的骨巨細胞瘤,在治療原發(fā)病灶同時,如果轉(zhuǎn)移灶可切除,則考慮手術(shù)切除,并聯(lián)合一種有效的輔助治療,之后進行隨訪監(jiān)測[8,9]。對于局部復(fù)發(fā)或轉(zhuǎn)移病例,如果病灶無法切除或切除后有嚴重功能缺失,則可考慮Denosumab、干擾素、放療以及繼續(xù)觀察等處理方式[50,63]。(1B級)
對于局部復(fù)發(fā)的四肢骨巨細胞瘤,若未侵犯關(guān)節(jié)面,骨皮質(zhì)仍然完整,周圍無明顯軟組織腫塊,可以考慮進行病灶刮除、聯(lián)合局部輔助處理、骨水泥填充[38,100],否則應(yīng)進行廣泛切除及重建手術(shù)。Klenke回顧性分析46例局部復(fù)發(fā)細胞瘤病例,發(fā)現(xiàn)對局部復(fù)發(fā)病灶實行病灶內(nèi)刮除后、骨水泥填充的再次復(fù)發(fā)率為14%,而骨材料填充的復(fù)發(fā)率為50%[41]。在全部骨巨細胞瘤患者中,1%~3%會出現(xiàn)肺轉(zhuǎn)移,而在局部復(fù)發(fā)病例中,肺轉(zhuǎn)移比例約6%[75,76,101]。Tubbs對13例肺轉(zhuǎn)移的四肢骨巨細胞瘤患者回顧性分析,發(fā)現(xiàn)對轉(zhuǎn)移灶行手術(shù)切除可獲得長期無瘤生存[101]。
對于局部復(fù)發(fā)或轉(zhuǎn)移病例,如果病灶無法切除、或切除后有嚴重功能缺失,考慮使用Denosumab、干擾素、放療等輔助治療方法[64]。在一項Ⅱ期開放試驗中(n=37),Denosumab在不可切除或復(fù)發(fā)的骨巨細胞瘤患者中有效率為86%(巨細胞減少90%或靶病灶25周無進展)[63]。Kaiser等報道使用干擾素治療骨巨細胞瘤肺轉(zhuǎn)移患者,獲得12個月的無疾病進展時間[73]。Malone等回顧性分析使用局部放療治療13例局部復(fù)發(fā)骨巨細胞瘤患者,5年局部控制率達85%[50]。
影像及臨床表現(xiàn)與骨巨細胞瘤預(yù)后關(guān)系密切,因此骨巨細胞瘤臨床及影像分級是手術(shù)方式選擇的重要依據(jù)[102]。(1B級)
Jaffe將骨巨細胞瘤病理分為三級,但是單純的病理學(xué)分級在臨床上往往無法反映骨巨細胞瘤的生物學(xué)行為。因此,Enneking和Campanacci根據(jù)影像學(xué)及臨床表現(xiàn)提出不同的骨巨細胞瘤分級。Enneking分期是在臨床、X線表現(xiàn)和病理學(xué)三者結(jié)合的基礎(chǔ)上進行的臨床分期。Ⅰ期,無臨床癥狀,X線表現(xiàn)有病灶,病理變化呈良性;Ⅱ期,有臨床癥狀,X線表現(xiàn)明顯,病灶呈膨脹性,但骨皮質(zhì)尚完整未穿破,病理變化呈良性;Ⅲ期,有臨床癥狀,X線表現(xiàn)明顯,病灶呈侵襲性,伴骨皮質(zhì)缺損,形成軟組織腫塊,病灶可伸展至軟骨下,甚至侵犯關(guān)節(jié),病理變化良性、侵襲性或惡性[14]。Campanacci依據(jù)X線表現(xiàn)將骨巨細胞瘤分為三期:Ⅰ期為靜止期,骨巨細胞瘤在X線表現(xiàn)為邊界明顯和完整的局限性骨腫瘤,對周圍骨組織無明顯侵犯;Ⅱ期為活躍期,腫瘤邊界仍清晰,可觀察到其呈膨脹性生長,周圍骨皮質(zhì)變??;Ⅲ期骨巨細胞瘤邊界已難以分辨,病灶呈惡性腫瘤的方式生長,可有骨皮質(zhì)穿破,軟組織受累,甚至發(fā)生病理骨折[29]。
骨巨細胞瘤臨床分級越高,其局部復(fù)發(fā)可能性越大。Prosser回顧性分析137例初發(fā)骨巨細胞瘤病例發(fā)現(xiàn):病灶被刮除后,CampanacciⅠ、Ⅱ期病例局部復(fù)發(fā)率為7%,CampanacciⅢ期病例局部復(fù)發(fā)率為29%[37]。目前建議對于EnnekingⅠ、Ⅱ期或CampanacciⅠ、Ⅱ期的四肢骨巨細胞瘤通??蓪嵭胁≡顑?nèi)刮除手術(shù),對于EnnekingⅢ期或CampanacciⅢ期的四肢骨巨細胞瘤可考慮廣泛切除手術(shù)[102,103]。
楊迪生等報道病骨最大破壞橫截面在50%以下或者受累關(guān)節(jié)面破壞少于25%時,病灶刮除、植骨填充即可;當病骨最大破壞橫截面達到50%~80%或者受累關(guān)節(jié)面破壞達25%~50%時,發(fā)生病理骨折的風(fēng)險加大,應(yīng)聯(lián)合應(yīng)用內(nèi)固定。對于病骨破壞較大、關(guān)節(jié)面破壞超過50%、橈骨和尺骨遠端以及其他非承重骨的骨巨細胞瘤,廣泛切除是比較適宜的方法[96,97]。
骨巨細胞瘤是骨盆及骶骨較常見的原發(fā)性骨腫瘤之一,骶骨、骨盆GCT分別占全身GCT的4%~5%[104-106]、1.5%~6.1%[107-109]。由于存在侵襲性較高、局部解剖復(fù)雜、癥狀隱匿、術(shù)中出血多、復(fù)發(fā)率高等特點,骨盆及骶骨GCT的外科治療仍是一個難題[105,108]。難點主要集中在外科切除邊界的選擇、術(shù)中出血的控制、骶神經(jīng)的保留及輔助治療方法的選擇等方面。
骶骨及骨盆GCT局部復(fù)發(fā)率高,主要的影響因素包括腫瘤分級及外科切除與重建相關(guān)的因素等,多由于其比鄰盆腔大血管、周圍解剖結(jié)構(gòu)復(fù)雜和大量的無法控制的術(shù)中出血[110,111],這些影響手術(shù)視野、術(shù)中瘤腔及邊界的處理。骨盆及骶骨GCT手術(shù)方式多種,對于初發(fā)骶骨GCT外科治療來講,保守的手術(shù)治療(刮除或部分切除)在充分的術(shù)中控制出血情況下,可達到術(shù)后較低的復(fù)發(fā)率及良好的術(shù)后功能[106,112]。
對于首診骶骨骨巨細胞瘤病例,任何Campanacci分級,高位骶椎(S1和S2)均采取刮除術(shù),低位骶椎(S3及以下)均采取廣泛切除或邊緣切除[106,113,114]。
盡管GCT組織學(xué)為良性,但其呈膨脹性溶骨性骨質(zhì)破壞,具有明顯的侵襲性,局部復(fù)發(fā)率高,尤其是位于骶骨的GCT,術(shù)后復(fù)發(fā)率高于四肢GCT[29,106]。囊內(nèi)刮除能夠充分保留神經(jīng)根、保護盆腔臟器和維持骨盆環(huán)的穩(wěn)定,但會增加腫瘤術(shù)后復(fù)發(fā)的風(fēng)險,有研究顯示其復(fù)發(fā)率甚至超過50%[115-118]。就骶骨GCT來說,由于位置深在、瘤體大、術(shù)中出血多,分離瘤體時還要保護骶神經(jīng)根,且多數(shù)腫瘤常侵犯高位骶椎及骶髂關(guān)節(jié),因此廣泛切除難以實施。目前高速磨鉆廣泛用于GCT的外科手術(shù),它可以徹底處理瘤腔,同時還可以通過酒精、灼燒等方式處理殘瘤。Marcove等[106,114]推薦保守的外科治療切除方案,即高位骶椎(S1和S2)首選刮除術(shù),病灶刮除后輔以高速磨鉆磨除,達到近似病灶內(nèi)邊緣切除的效果;低位骶椎(S3及以下)首選廣泛切除或邊緣切除,根據(jù)情況,盡量保留S3神經(jīng)根;對于同時侵犯高位和低位骶骨的病例,S3及以下部分行廣泛切除或邊緣切除,而S2及以上部分采用刮除術(shù)。這種手術(shù)策略得到了較多學(xué)者的認同[113,119-121],它的優(yōu)點在于保持脊柱及骨盆的連續(xù)性,手術(shù)操作較易實現(xiàn)且快速,降低了潛在的出血風(fēng)險和影響患者生命的威脅。同時也確保瘤壁處理徹底,降低了醫(yī)源性神經(jīng)根損害和手術(shù)相關(guān)疾病及并發(fā)癥的發(fā)生。
骶骨GCT復(fù)發(fā)病例可在充分控制術(shù)中出血和De-nosumab的保護下行二次刮除或整塊切除。對于侵及S2以上椎體的GCT,切除后應(yīng)行腰骶髂重建骨盆環(huán)的穩(wěn)定,而S2椎體未受侵犯的病例,行單純整塊切除。
骶骨GCT術(shù)后初次復(fù)發(fā),可根據(jù)腫瘤侵犯情況再次行手術(shù)切除。但復(fù)發(fā)腫瘤邊界范圍往往更大,血供也較豐富,需在充分控制術(shù)中出血的情況下完整切除。術(shù)前評估可能導(dǎo)致嚴重并發(fā)癥時,可考慮行保留神經(jīng)根的切刮術(shù),術(shù)后輔助放療及藥物治療等。腫瘤的完整切除勢必可以減少復(fù)發(fā),但犧牲神經(jīng)功能帶來的相關(guān)并發(fā)癥也不能忽視。對于部分病例,可反復(fù)栓塞骶骨GCT的供瘤血管[68,70,122],從而達到局部控制骶骨GCT的效果,尤其是腫瘤較大的患者。甚至有研究者強調(diào)選擇這種治療手段的優(yōu)勢,即在反復(fù)栓塞供瘤血管的基礎(chǔ)上,選擇其他的治療措施,包括手術(shù)等[70,71,123]。
關(guān)于骶骨切除程度以及是否重建,一直以來都是爭論的焦點[124,125]。以往臨床研究顯示,手術(shù)保留至少1/2 S1的患者術(shù)后并不會出現(xiàn)腰骶髂不穩(wěn)[126,127]。而Gunterberg等[128]研究發(fā)現(xiàn),S1以下切除者,其骨盆環(huán)穩(wěn)定性降低30%,骶骨岬下1 cm以遠切除者降低50%,并認為骶骨次全切除術(shù)后早期患者站立時可完全負重。Huagte等[129]認為,經(jīng)S1神經(jīng)孔下緣水平切除骶骨者能夠承受術(shù)后活動而不發(fā)生骨折,而經(jīng)上緣水平切除者則難以承受。而也有研究發(fā)現(xiàn)[130],經(jīng)S1椎體以下平面切除骶骨時,骨盆環(huán)的穩(wěn)定性受到一定影響,但不是行腰髂局部重建的絕對指征,可根據(jù)患者的年齡、體重、骨質(zhì)條件、經(jīng)濟狀況等綜合考慮,決定是否進行重建。而當切除平面涉及S1椎體(下1/4~1/2 S1平面)切除后,骶髂關(guān)節(jié)應(yīng)力過度集中,整個骨盆穩(wěn)定性大幅下降,極易發(fā)生殘留骶骨骨折或脊椎的下沉,需要進行腰骶髂局部重建以增強骶髂關(guān)節(jié)的穩(wěn)定性。
骶骨骨巨細胞瘤再次復(fù)發(fā)病例,應(yīng)根據(jù)腫瘤侵犯情況及患者需求個性化制定手術(shù)策略,部分患者可能從手術(shù)中受益。
骶骨GCT術(shù)后再次復(fù)發(fā),可根據(jù)腫瘤侵犯情況決定是否再行手術(shù)切除。對于年輕患者,若腫瘤未廣泛浸潤,主要神經(jīng)血管、盆腔臟器等不受累,征求患者及家屬意見后,可考慮再次手術(shù)。當腫瘤完整切除可能導(dǎo)致嚴重并發(fā)癥時,可考慮行保留神經(jīng)根的切刮術(shù),術(shù)后輔助放療及藥物等其他治療方案,可能更適合患者[131]。對廣泛浸潤的難切性腫瘤,進一步的切刮術(shù)勢必可以減瘤,但犧牲神經(jīng)功能帶來的相關(guān)并發(fā)癥也不能忽視,常導(dǎo)致較差的術(shù)后功能以及更高的并發(fā)癥發(fā)生率。因此,對于這部分病例,以及老年再次復(fù)發(fā)患者,可反復(fù)栓塞骶骨供瘤血管,一般在栓塞后3~4個月后疼痛減輕,數(shù)年后腫瘤體積有不同程度的減小。Lin等[68]應(yīng)用選擇性動脈栓塞治療骶骨GCT,認為可單獨應(yīng)用或聯(lián)合其他方法應(yīng)用,作為手術(shù)切除的一種替代治療方法,從而達到局部控制的效果。部分病例也可以通過單純放療控制[106],劑量通常在40~70 Gy,其優(yōu)勢在于避免手術(shù)切除相關(guān)疾病發(fā)生,但也會引起局部皮膚損害及纖維化[54,132-134]、以及與放射相關(guān)的惡變或肉瘤變[135,136]。
對于骨盆GCT病例,任何Campanacci分級,首選初始治療方案為切緣陰性的廣泛切除。
由于骨盆解剖復(fù)雜以及骨巨細胞瘤具侵襲性,目前骨盆GCT尚無標準的治療策略,尤其是累及骨盆Ⅱ區(qū)的GCT。既往的治療方式包括放療[54,137]、囊內(nèi)刮除[105,108,138]和廣泛切除[109,119]等。骨盆GCT未行廣泛切除的局部復(fù)發(fā)率約43%[108,139],Leggon等報道囊內(nèi)刮除的復(fù)發(fā)率約41%,而廣泛切除可確保腫瘤鄰近肌肉附著點切除干凈,短期隨訪未見復(fù)發(fā)的病例[111,117,122,140,141]。
考慮到GCT局部侵襲性生長的特點,首次外科切除對于腫瘤局部控制至關(guān)重要,因為復(fù)發(fā)病例往往達不到完整切除的要求,因此,廣泛切除有助于控制局部復(fù)發(fā)[111,117,121,141]。況且對于骨盆GCT,若腫瘤侵犯髖臼內(nèi)上壁,行囊內(nèi)刮除后并沒有一個可供植骨或是骨水泥填充的腔室[108]。外科切除方式的選擇需平衡患者的局部復(fù)發(fā)率及腫瘤切除手術(shù)相關(guān)疾病發(fā)生率。
骨盆GCT的治療一直是一個挑戰(zhàn),主要的爭議在于控制局部復(fù)發(fā)的切除方式選擇及切除后恢復(fù)髖關(guān)節(jié)功能的重建。盡管廣泛切除后假體重建相關(guān)并發(fā)癥發(fā)生率高,但局部復(fù)發(fā)率低,可征求患者同意后選擇廣泛切除方式。
對于骨盆骨巨細胞瘤復(fù)發(fā)病例,應(yīng)根據(jù)腫瘤侵犯情況及患者需求個性化制定治療策略,部分患者可能從手術(shù)中受益。若復(fù)發(fā)腫瘤未廣泛浸潤,主要神經(jīng)血管、盆腔臟器等不受累,可實現(xiàn)整塊切除情況下,征求患者及家屬同意后,可充分控制術(shù)中出血予再次手術(shù)。當腫瘤廣泛浸潤周圍血管及盆腔臟器時,完整切除已難以實現(xiàn),手術(shù)勢必導(dǎo)致嚴重的術(shù)后并發(fā)癥及較差的肢體功能,結(jié)合放療及藥物等其他治療方案,可能更適合患者[142]。
因此,對于骨盆骨巨細胞瘤復(fù)發(fā)病例,應(yīng)根據(jù)腫瘤侵犯情況及患者需求個性化制定治療策略。
充分有效的控制術(shù)中出血,減少出血的同時,可以清晰顯示腫瘤切緣,降低術(shù)后復(fù)發(fā)率。減少術(shù)中出血的手段有很多,需個性化的選擇。相比低壓麻醉、供瘤血管栓塞及切開臨時阻斷髂血管,應(yīng)用腹主動脈內(nèi)球囊阻斷技術(shù)有一定的優(yōu)勢[106,110,120]。
骶骨GCT術(shù)中出血較大,有研究顯示,出血量最大者甚至超過35000 ml[120]。在沒有充分止血或充分備血的情況下,骶骨GCT行刮除術(shù)很難,因為視野不清以及腫瘤細胞隨出血擴散[106]。通過降低術(shù)中出血,達到顯露充分、降低瘤細胞污染可能、徹底處理瘤壁和減少術(shù)后手術(shù)相關(guān)疾病的發(fā)生率,以保證手術(shù)的安全性和減少局部復(fù)發(fā)。
為控制骶骨及骨盆術(shù)中出血,臨床上曾使用過低壓麻醉,即整個手術(shù)過程中,在保證各生命器官足夠的血液灌注的前提下控制血壓。但因其對麻醉醫(yī)師的綜合素質(zhì)及術(shù)中監(jiān)護要求較高、風(fēng)險極大,且控制效果欠佳而應(yīng)用受限[143,144]。預(yù)先前路結(jié)扎單側(cè)或雙側(cè)髂內(nèi)動脈,甚至經(jīng)腹切開臨時阻斷腹主動脈,因手術(shù)損傷大、術(shù)后并發(fā)癥多而在臨床應(yīng)用較少。經(jīng)股動脈穿刺栓塞雙側(cè)髂內(nèi)動脈及可栓塞的供瘤動脈,大大減少術(shù)中出血,提高手術(shù)安全性,但該方法往往需行多條供血動脈栓塞,才能達到良好的控制出血效果,且費用昂貴、耗時長,并可能增加下肢缺血損傷、局部缺血性疼痛等并發(fā)癥的發(fā)生率,甚至有誤栓發(fā)生的風(fēng)險[70,145,146]。應(yīng)用腹主動脈內(nèi)球囊阻斷技術(shù),通過體外控制血流,其球囊位于腹主動脈的分支腎動脈水平以下,腹主動脈分叉以上,約在第3、4腰椎間隙水平[110,112]。在此腹主動脈供血范圍內(nèi)并沒有對缺血較為敏感的器官,止血效果顯著,術(shù)中出血顯著減少,便于操作,同時理論上又可以無限制延長手術(shù)時間。因此,術(shù)中應(yīng)用腹主動脈內(nèi)球囊阻斷技術(shù)具有一定的優(yōu)勢。
Denosumab是治療骨盆、骶骨骨巨細胞瘤安全、有效的手段[65,66,147],對于體積巨大的腫瘤來說,術(shù)前用藥可以降低手術(shù)難度,減少術(shù)中出血,但我們認為術(shù)前用藥以3~4次為宜,用藥時間不宜超過3周。囊內(nèi)刮除術(shù)后早期用藥(半年)局部復(fù)發(fā)率可降低至15%左右。因此在處理骨盆、骶骨骨巨細胞瘤時,可以適當擴大囊內(nèi)刮除的指征。長時間用藥患者需注意下頜骨壞死和肉瘤變等并發(fā)癥,無法手術(shù)或未達到滿意外科邊界的患者在停藥后存在復(fù)發(fā)風(fēng)險。外科手術(shù)徹底清除腫瘤仍應(yīng)作為骨盆骨巨細胞瘤的基本手段。Denosumab在惡性骨巨細胞瘤(malignancy in giant cell tumor,MGCT)中的療效尚不確定。
由于脊柱骨巨細胞瘤有著較高的復(fù)發(fā)風(fēng)險,大范圍的全脊椎切除術(shù)是首選的手術(shù)方式。
對于那些無法行全脊椎切除手術(shù)的患者,輔以切緣滅活處理和其他藥物治療的病灶刮除或椎體次全切除術(shù)、動脈栓塞和放射治療是經(jīng)典的治療方式。
降低腫瘤局部復(fù)發(fā)風(fēng)險的主要措施是行全脊椎整塊切除術(shù)(en blok切除)[148,149],即使全脊椎切除的局部復(fù)發(fā)率仍較高[108,121,150]。全脊椎整塊切除的手術(shù)難度及風(fēng)險較病灶刮除或分塊切除大大增加,而且有些部位如頸椎的骨巨細胞瘤往往僅能做到瘤內(nèi)刮除或次全切除,其復(fù)發(fā)率可高達40%以上[151]。
術(shù)前根據(jù)影像學(xué)表現(xiàn)按照WBB外科分期系統(tǒng)設(shè)計手術(shù)方案[151-153]。當腫瘤主體位于椎體內(nèi)且至少一側(cè)椎弓根未受到侵犯時(4~8區(qū)或5~9區(qū)),可采取一期后路全脊椎切除術(shù)(Tomita方法[154])或前后路聯(lián)合全脊椎切除術(shù)(Boriani方法[152]),可大幅降低脊椎腫瘤切除后的局部復(fù)發(fā)率。當腫瘤呈偏心性生長而累及一側(cè)椎弓根或(和)橫突時(3~5區(qū)或8~10區(qū)),為了獲得良好手術(shù)邊界,應(yīng)進行病椎的矢狀切除。對于單純后方附件結(jié)構(gòu)的病變(3~10區(qū)),可行單純后弓切除。在可能的情況下行椎體切除時盡量避免分塊切除。
首次選擇較為徹底的手術(shù)方式是降低脊柱骨巨細胞瘤局部復(fù)發(fā)的關(guān)鍵[150,155,156],病灶內(nèi)手術(shù)以及腫瘤分期是局部復(fù)發(fā)的危險因素[123]。研究發(fā)現(xiàn)全脊椎切除并長期應(yīng)用雙膦酸鹽可顯著降低脊柱骨巨細胞瘤的復(fù)發(fā)率[148,157,158],年齡<40歲患者預(yù)后更好[157]。對于行病灶刮除術(shù)的患者,局部應(yīng)用乙醇、苯酚或過氧化氫處理后填充骨水泥可一定程度上降低局部復(fù)發(fā)率[2,39,159]。
局部復(fù)發(fā)的病例仍可采用前后路聯(lián)合全脊椎切除術(shù)。但脊柱骨巨細胞瘤手術(shù)后復(fù)發(fā)再次手術(shù)治愈的可能性大大減小。
Teixeira的回顧性分析指出腫瘤大小和Ⅲ級腫瘤是局部復(fù)發(fā)的高風(fēng)險因素[160]。有研究發(fā)現(xiàn)骨巨細胞瘤的初次手術(shù)后的短期復(fù)發(fā)率為9%,局部復(fù)發(fā)后再次手術(shù)后的復(fù)發(fā)率為16%[161]。郭衛(wèi)等研究發(fā)現(xiàn)二次手術(shù)后的復(fù)發(fā)率達57.1%[155]。Fidler報告了9例胸腰椎的骨巨細胞瘤,均采用前、后聯(lián)合入路全脊椎切除術(shù),術(shù)后只有l(wèi)例二次手術(shù)的患者局部復(fù)發(fā)[150]。
由于脊柱骨巨細胞瘤血供較為豐富,在行全脊椎切除術(shù)前應(yīng)盡量行節(jié)段動脈栓塞,以減少術(shù)中出血并能改善預(yù)后。
脊柱骨巨細胞瘤的節(jié)段動脈栓塞是一項重要的輔助治療措施,術(shù)前動脈栓塞能最大限度地減少富血管性腫瘤切除術(shù)中的出血量[121,155,162]。對于無法耐受全脊椎切除術(shù)或術(shù)后可能導(dǎo)致嚴重神經(jīng)功能障礙的患者可應(yīng)用節(jié)段動脈栓塞及病灶刮除術(shù)[121]。
在行椎體的全切或次全切除術(shù)后應(yīng)當行脊柱的功能重建,常見的功能重建材料有自體骨、同種異體骨、骨水泥、鈦網(wǎng)、前路鈦板和后路椎弓根螺釘,可根據(jù)手術(shù)方式的不同選擇重建材料組合使用。
由于手術(shù)方式的多樣性,針對脊柱骨巨細胞瘤切除術(shù)后的重建材料選擇多為病例報道[121,163,164],尚無對照研究,治療中多為參照其他脊柱腫瘤切除術(shù)后的力學(xué)性能需求進行脊柱的穩(wěn)定性重建。
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