甲状腺肿瘤射频消融治疗后再手术临床分析.pdf

现代肿瘤医学2 0 2 3年10 月第31卷第19 期头颈神经肿瘤【Head and Neck Oncology and Neuro-oncology】甲状腺肿瘤射频消融治疗后再手术临床分析MODERN ONCOLOGY,Oct.2023,VOL.31,No.193583张?轶,李思雨”,丁亚磊,付利军,李建华,邱新光1郑州大学第一附属医院甲状腺外科;体检科,河南郑州450 0 0 0【摘要】目的：分析总结甲状腺肿瘤射频消融（radiofrequencyablation,RFA）术后再手术患者临床资料，探讨减少再手术方法和注意事项。方法：回顾性分析2 0 19 年0 4月至2 0 2 2 年10 月我院收治的17 例甲状腺肿瘤射频术后再手术患者临床资料。结果：17 例患者共有2 6 个结节再RFA治疗后接受手术,其中良性12例均为甲状腺良性结节（benign thyroid nodule,BTN）（BT N组），恶性5例均为甲状腺乳头状癌（papillarythyroid cancer,PTC）（PT C组）。BTN组均因结节再生长接受手术治疗，术前最大径较 RFA前明显增大,2例术后病理提示滤泡癌,1例滤泡性肿瘤,1例合并PTC。PT C 组结节最大径同术前无差异,5例恶性结节有3例未完全灭活,2 例合并中央区淋巴结转移。术后2 例（No.10,16）发生暂时甲状旁腺功能减低,无其他并发症。结论：RFA治疗甲状腺肿瘤时应严格把握适应证；良性肿瘤RFA术后再生长应警惕滤泡性肿瘤;PTC射频术后存在原发灶未灭活和中央区淋巴结转移的风险。【关键词】射频消融；甲状腺肿瘤；甲状腺乳头状癌；再手术Modern Oncology 2023,31(19):3583-3587【中图分类号】R736.1【文章编号】16 7 2-49 9 2-(2 0 2 3)19-358 3-0 5Surgery affer ultrasound-guided radiofrequency ablation for thyroid tumors:A retrospec-tive studyZHANG Yi,LI Siyu,DING Yalei,FU Lijun,LI Jianhua,QIU XinguangDepartment of Thyroid Surgery;Department of Physical Examination,the First Affliated Hospital of Zhengzhou University,HenanZhengzhou 450000,China.Abstract Objective:To analyze the causes and clinical characteristics of surgery after radiofrequency ablation(RFA)for thyroid tumors,exploring methods and precautions for reducing reoperation.Methods:Clinical data of 17patients with 26 thyroid nodule from Apr.2019 to Oct.2022 in our hospital were retrospectively collected and ana-lyzed.Results:A total of 17 patients with 26 nodules were treated with surgery after RFA,including 12 benign thyroidnodules(BTN group)and 5 papillary thyroid cancer(PTC group).In BTN group,all patients received surgery due tothe regrowth of nodules.The preoperative maximum diameter was significantly larger than that before RFA.Accordingto postoperative pathology,there were 2 follicular carcinoma,1 follicular tumor,and 1 PTC.The maximum diameter ofthe nodules in PTC group had no difference from that before operation.For 3 of 5 PTC,the tumors were not completelyinactivated,and 2 of 5cases had central lymph node metastasis.Two cases(No.10,16)developed temporary hypopar-athyroidism after surgery.There are no other complications besides this.Conclusion:The indications of RFA in thetreatment of thyroid tumors should be strictly controlled.Follicular tumors should be cared when benign tumor regrowthafter RFA.RFA for PTC primary lesions may be incomplete and leave residual lymph node metastasis.Key words radiofrequency ablation,thyroid tumors,papillary thyroid carcinoma,reoperation射频消融（radiofrequencyablation，R FA）为常见的热消融治疗方法，已广泛应用于甲状腺、肝脏、肺、肾脏等良恶性肿【收稿日期】2022 10-20【修回日期】2023 05-31【基金项目】河南省科技攻关项目（编号：2 32 10 2 310 16 0）【作者简介】张轶（19 9 0 一），男，河南辉县人,主治医师,在读博士，主要从事甲状腺肿瘤临床研究。E-mail：8 9 59 0 9 533 【通信作者】邱新光（19 6 3一），男，河南人，主任医师，主要从事甲状腺肿瘤临床研究。E-mail:【文献标识码】AD0I:10.3969/j.issn.1672-4992.2023.19.009瘤的治疗。射频消融术具有微创、不影响美观、创伤小、并发症少等优点，应用越来越多，范围也越来越广。意大利发布的甲状腺结节射频消融的意见声明（2 0 15年）1和韩国发布的韩国射频消融指南（2 0 17 年）2 1 都推荐将热消融用于治疗甲状腺良性结节和复发性甲状腺癌。多篇报道肯定了射频消融治疗甲状腺良性结节（benignthyroid nodule,BTN)3-4和复发癌的效果5-6 。现阶段将热消融应用于甲状腺乳头状癌（papillarythyroidcancer,PTC）原发灶的治疗是目前的研究热点之_7-8 。对11项符合条件的研究进行荟萃分析，包括7 15例甲状腺微小癌（papillary:3584thyroidmicrocarcinoma,PTMC），研究表明热消融后PTMC的完全消失率和复发率分别为57.6%和0.4%。平均体积减少7 3.5mm，减少了98.1%。尽管这些报告已经证实射频消融后疾病的发生率很低，但还缺乏关于长期疗效的随机对照研究。研究表明，由于适应证把握不严格和操作不规范,RFA后出现PTC原发病灶再生长和淋巴结转移，增加了患者费用和疾病进展的风险。在这项回顾性研究中,记录了17例射频消融术后再次手术的病例,并对术后病理和再手术原因进行了分析，探讨减少再手术方法和注意要点。1资料与方法1.1一般资料回顾性分析我院2 0 19年0 4月至2 0 2 2 年10 月收治的17例射频消融术后再手术患者资料。纳入标准：(1)RFA术后再手术；（2)RFA术前行细针/粗针穿刺活检（fine-needleaspiration/core needle biopsy,FNA/CNB）诊断明确;（3)RFA前及再手术前未接受其他治疗。排除标准：（1)RFA医师治疗经验不足10 0 例；（2）射频术前未行穿刺病理学检查；(3)远处转移或者肿瘤复发行RFA姑息治疗患者。本研究统计了临床、放射学、手术和病理数据，包括年龄、性别、FNA结果、RFA位置、结节大小、RFA和手术的间隔时间、射频消融前和手术前的超声检查、手术范围和术后病理结果。该研究获得我院科研和临床试验伦理委员会的批准(No.2022-KY-0844-001)。PatientsIntervalGendernumber(years)monthsposition1Female2Female3Female4Female5Female6Female7Female8Female9Male10Female11Female12Male13Female14Female15Female16Female17Female注：L:左;R：右;LNM:淋巴结转移。Note:L:Left,R:Right,LNM:Lymph node metastasis.张轶,等甲状腺肿瘤射频消融治疗后再手术临床分析1.2手术方式根据术前彩超、穿刺病理及术中快速冰冻结果，同患者沟通后签署手术同意书，确定手术方式。3例行单侧腺叶+峡部切除,5例行双侧甲状腺切除,3例行单侧腺叶+峡部切除+患侧中央区淋巴结清扫，6 例行双侧甲状腺切除+双侧中央区淋巴结清扫。均未行侧区淋巴结清扫。1.3 统计学分析采用SPSS21.0软件，符合正态分布计量资料组间比较采用t检验，以均数标准差比较；定性资料组间比较采用卡方检验。P0.05为差异有统计学意义。2结果2.1一般资料17例患者，其中男性2 例,女性15例,平均年龄(37.2 912.84）岁（2 1 58 岁），手术间隔时间为（2 0.6 7 2 0.7 0）个月（1 6 2 个月），根据术前穿刺结果分为甲状腺乳头状癌组（PT C,n=5)和甲状腺良性结节组（BTN,n=12）,所有患者临床资料见表1。PTC组2 例行单侧甲状腺+峡部切除+中央区清扫,3例行甲状腺全切除+双侧中央区淋巴结清扫。BTN组2 例行单侧甲状腺+峡部切除,6 例行甲状腺全切除，1例行单侧腺叶+峡部切除+患侧中央区淋巴结清扫,3例行甲状腺全切除+双侧中央区淋巴结清扫。两组在手术间隔时间上(P=0.006)差异有统计学意义（见表2)。表1患者临床资料Tab.1Characteristics and clinical features of patientsAgeAblation25325632958151328252623281927442160266397554851154641124762Size(beforeFNAablation,mm)LPTCRPTCLPTCRBTNLPTCLPTCRPTCLPTCLBTNRBTNLBTNRBTNLBTNLBTNLBTNRBTNLBTNRBTNLBTNRBTNLBTNRBTNLBTNRBTNLBTNLBTNSize(afterablation,mm)6.3 5.4 4.313 6.5 7.58.7 6.5 7.431 18 196.5 5.5 442 28 2212.5 9.5 8.515.5 12.5 124.55.5 48.5 8.5 7.55.5 5 4.687613 14.5 9.516 15 106.5 5.6 4.79 8 833 31 2461 49 3616 27 2655543428 21 1640 34 2727 2418.538352718 16.5 1532 301931 27 26.551.5 37 2142 31 2854 3930109.58.514.5 14.5 1213.5 12 11.520 13.5 843 33 2839 30248.5 7 5.515.5 13 10.527 25 1526 23 1838 32 1952 36 2218 14 1729 21 1445 39 2561 40 367 6.5 5.58.5 8 816 14 12.518 17.5 10.535 25 1640 33 21TI-RADS4b33334b55333334a34a333333334a3PathologyPTCPTCBTNBTNBTNBTNBTNPTCFTCFTCBTNBTNBTNBTNBTNBTNBTNBTNPTCBTNBTNBTNBTNBTNBTNFTTLNM7/90/71/60/40/60/40/90/270/9现代肿瘤医学2 0 2 3年10 月第31卷第19期表2 患者一般临床资料和特征Tab.2 The baseline characteristics and clinical features of patientsCharacteristicsGenderMaleFemaleAge(years,xs)RFA sideLeftRightBilateralInterval months(x s)Number of nodulesBTNMalignant noduleOperative procedureLobectomyTotal thyroidectomy2.2再手术指征PTC组再手术原因包括结节再生长（No.2,3）,中央区淋巴结转移（No.1,3），彩超分级4b（No.1,4,5），穿刺提示PTC(No.1,5）。BT N组12 例均因结节再生长接受手术,1例(No.14)术后一月出现压迫症状,1例(No.10)合并甲状腺功能亢进，1例(No.9)第一次RFA术后7 月因结节再生长再次行RFA手术，术后结节再生长接受手术治疗（见表3）。2.3术前彩超情况术前彩超PTC组有3例4b级,另外2 例为3级;BTN组3例为4a级,其余均为3级。结合术后病理 PTC组准确率为6 3%（5/8），BTN组准确率为6 7%（12/18）。同RFA前AMODERN ONCOLOGY,Oct.2023,VOL.31,No.19彩超相比,PTC组最大径无显著差异（P=0.066）,BT N组有显著差异(P0.001)。PT C 组2 例术前彩超提示中央区淋PTC(n=5)BTN(n=12)0251038.20 15.3536.92 12.392501364.40 3.1326.08 21.952186033293585.巴结转移与术后病理一致。表3再手术因素和术后彩超病理情况分析Tab.3The characteristics of reoperation indication,ultrasound and pa-thologyVariableReoperation indicationNoduleregrowthLNMTI-RADS above 4bFNA:PTCTI-RADS(Before surgery)34aMaximum diameter(mm,x s)Before RFABefore surgeryPostoperative pathologyPTCFTCBTN2.4术后病理结果PTC组术后病理提示3个结节仍为PTC（见图1A），另外5个结节为炎症,消融后改变未见PTC组织残留,2 例发生中央区淋巴结转移。BTN组12 例中有2 例为滤泡癌（f o l l i c u l a r t h y r o i d c a r c i n o m a,FT C）（见图1B），1例为滤泡性肿瘤（follicularthyroid tumor,FTT）恶性潜能未定，均无淋巴结转移，一例术后病理为PTC,最大直径为3mm,其余均为结节性甲状腺肿和消融术后改变。PatientNo.2PTC(n=5)2(No.2,3)2(No.1,3)3(No.1,4,5)2(No.1,5)238.25 3.4317.88 12.26302BTN(n=12)120009325.94 12.1736.39 16.90129MPatientNo.6B图1术前超声和术后病理A,B分别为病例2 和6 的彩超及病理(HE200)。Fig.1 Preoperative ultrasoundand postoperative pathology(A,B)Ultrasoundand pathology(HE 200)of 2 patients(numbers 2 and 6).2.5术后并发症情况所有病例术中无喉返神经损伤（见图2），无声音嘶哑、饮水呛咳,无术后出血。2 例患者发生暂时性甲状旁腺功能减低,甲状旁腺功能术后较术前明显减低（P=0.019）,术前(42.0823.91)pg/mL,术后(2 8.5513.6 7)pg/mL。术后随访6 个月均无复发和肿瘤进展。3586图2 喉返神经（箭头标记处)和病理标本（甲状腺滤泡癌）Fig.2 Recurrent laryngeal nerve(arrow marking)and pathological speci-mens(follicular thyroid carcinoma)3讨论热消融技术在实体肿瘤中应用越来越多，适应证也越来越广泛10-13。2 0 0 1年RFA首次被报道应用于治疗甲状腺复发癌以来,其应用于甲状腺良性结节和PTC的治疗也相继报道14.6.4-17 。甲状腺良性结节和分化型甲状腺瘤因其生长缓慢、恶性程度低，治疗方案也由单一的手术治疗过度到措施多样化、治疗个体化。2 0 15年美国甲状腺协会成人甲状腺结节与分化型甲状腺癌诊治指南提出积极监测应用于低风险PTC 患者18 。但积极监测患者中仍有很大比例因焦虑而放弃密切随访并接受手术19。良性结节较大的患者多因压迫症状、影响美观或持续生长等情况而接受手术治疗。RFA因其具有微创、美观、有效、并发症低、局部麻醉等优势2 0-2 1,为有良性结节、对美容要求高、有全麻手术禁忌或高风险患者提供了新的可选方案。其在良性甲状腺结节的治疗中,无论是囊性还是实性结节中均取得较好效果,研究表明其结节缩小率可达6 5%8 0%3-4。此外有数据显示RFA在治疗PTMC的安全性和有效性同样可靠,其肿瘤消失率为6 0%7 5%，复发率仅为0.1%1%，并发症发生率仅为 2%3%2 2 。尽管RFA已被广泛应用于甲状腺肿瘤的治疗中,并得到了很大程度的认可,但仍有一些争议和不确定性。在良性肿瘤中,基于彩超和穿刺的最终诊断存在误诊的可能,从本研究结果可以看到,复发患者中有2 例甲状腺滤泡癌和1例滤泡性肿瘤。滤泡癌和滤泡性肿瘤术前诊断较为困难,单依靠彩超和 FNA 很难识别,B-rafr60基因阴性可能会误导临床医师的判断。粗针穿刺、血清学检验和增强彩超等方法有助于鉴别诊断。此外,如RFA术后结节出现较快的增大,应考虑滤泡性肿瘤和滤泡癌的可能性。术前穿刺是非常必要的，对于体积过大或过小的结节，也会出现穿刺未见恶性细胞而术后病理为恶性的假阴性。有些学者主张术前进行2次穿刺，以减少假阴性的发生，但这会增加患者的经济负担和住院时间。此外,12 例再手术患者RFA术前均为实性结节,部分病例术后病理提示细胞生长活跃。因此,对于体积较大和快速生长的实性结节,RFA术后更应警惕复发和再生长风险。RFA应用于PTC的主要争议包括肿瘤是否完全灭活，甲状腺癌多灶性导致的遗漏和彩超未发现的中央区淋巴结转移。从本研究来看,2 例4个结节完全灭活，术后病理未见恶性肿瘤组织,3例共3个结节存在肿瘤组织未完全灭活。肿瘤组织完全灭活技术上是可行的，但部分结节特别是距离张轶,等甲状腺肿瘤射频消融治疗后再手术临床分析周围重要组织如喉返神经、气管、食管相邻时，可能会发生肿瘤组织未完全灭活的情况。术后常规性血流信号和造影增强彩超检查可以减少区域灭活不完全的情况。甲状腺恶性肿瘤的多灶性和彩超未能发现的淋巴结转移同样会导致RFA治疗的失败。研究显示,甲状腺恶性肿瘤多灶性和彩超提示cN。而预防性中央区清扫术后提示转移的病例为2 0%35%23-26，本研究有2 例术后病理提示中央区淋巴结转移，如何避免上述情况的发生仍需继续探索。现阶段除了彩超技术的进步，深度学习构建的预测模型AUC可达0.6 30.9027-28,随着进一步深人研究,将来可以达到更高水平。该研究再手术前彩超TI-RADS分级均由2 名经验丰富的彩超医师共同判断,同术后病理对比来看,指南的 TI-RADS分级应用于射频术后结节的评估效果并不理想。由于RFA术后结节超声表现边界不规则、回声不均匀等，为术后彩超判断带来很大困难，应结合病史、消融前及消融后复查彩超情况进行综合判断，如结节出现快速生长应警惕恶性的可能，必要时行CNB排除滤泡性肿瘤及滤泡癌。RFA术后再手术,术中可见不同程度的粘连和水肿，并不会给手术带来太大的困难，但仍有可能延误患者病情，增加患者经济负担。因此，需要对此进行深入研究以减少其发生。综上所述，本研究回顾性分析了射频消融术后再手术的情况，为射频消融临床应用提供参考。在积极开展射频消融手术时，仍需要严格把握适应证，并正确认识射频消融所存在的潜在风险。不能盲目扩大手术适应证，夸大治疗效果，在进行射频消融时需要术前细致评估、术中规范操作、术后客观评价，减少术后再手术风险。RFA应用于原发性甲状腺乳头状癌患者时更应谨慎。1 GARBEROGLIO R,ALIBERTI C,APPETECCHIA M,et al.Radio-frequency ablation for thyroid nodules:which indications?The firstItalian opinion statement J.Journal of Ultrasound,2015,18(4):423430.2KIM JH,BAEK JH,LIM HK,et al.2017 thyroid radiofrequency ab-lation guideline:Korean society of thyroid radiology J.KoreanJournal of Radiology,2018,19(4):632-655.3LEE GM,YOU JY,KIM HY,et al.Successful radiofrequency abla-tion strategies for benign thyroid nodules J.Endocrine,2019,64(2):316 321.4HUBER TC,PARK AW.Radiofrequency ablation of benign thyroidnodules J.Seminars in Interventional Radiology,2021,38(3):377-381.5MAURI G,CENNARO N,LEE MK,et al.Laser and radiofrequencyablations for benign and malignant thyroid tumors J.InternationalJournal of Hyperthermia,2019,36(2):13-20.6TUFANO RP,PACE-ASCIAK P,RUSSELL JO,et al.Update ofradiofrequency ablation for treating benign and malignant thyroidnodules.The future is now J.Frontiers in Endocrinology,2021,12:689 698.7 CHO SJ,BAEK SM,LIM HK,et al.Long-term follow-up resultsof ultrasound-guided radiofrequency ablation for low-risk papil-lary thyroid microcarcinoma:more than 5-year follow-up for 84tumorsJ.Thyroid,2020,30(12):1745-1751.8CAO XJ,YU MA,ZHU YL,et al.Ultrasound-guided thermal ab-lation for papllary thyroid microcarcinoma:a multicenter retrospec-tive study J.International Journal of Hyperthermia,2021,38(1):【参考文献】现代肿瘤医学2 0 2 3年10 月第31卷第19期916-922.9CHOI Y,JUNG SL.Efficacy and safety of thermal ablation tech-niques for the treatment of primary papillary thyroid microcarci-noma:a systematic review and meta-analysis J.Thyroid,2020,30(5):720 731.10 KOBE A,TSELIKAS L,DESCHAMPS F,et al.Thermal ablationcombined with selective transarterial embolization of centrally lo-cated renal cell carcinomas measuring 3 cm or larger J.Cardio-vascular and Interventional Radiology,2022,45(3):380-381.11 SUN H,XU W,YANG H.Anatomical thermal ablation:A valuabletreatment method for hepatocellular carcinoma smaller than 5 cmJ.Hepatology Research,2022,52(10):893.12 ZHANG X,NI T,ZHANG W.Ultrasonography-guided thermalablation for cervical lymph node metastasis of recurrent papillarythyroid carcinoma:is it superior to surgical resection J.Fron-tiers in Endocrinology,2022,13:907195.13 ZHAO X,HAN LJ,ZHANG M,et al.Clinical study on combinedthermal and cold ablation under bronchoscope in the treatment ofobstructive atelectasis caused by non-small cell lung carcinoma(NSCLC)JJ.Modern Oncology,2021,29(10):1706-1710.14 YE X,FAN W,WANG Z,et al.Clinical practice guidelines on im-age-guided thermal ablation of primary and metastatic lungtumors J.Journal of Cancer Research and Therapeutics,2022,18(5):1213 1230.15GARRIDO PAREJA F,PEREZ NARANJO P,REDONDO OLME-DILLA MD,et al.Radiofrequency ablation for thyroid and parathy-roid disease J.Radiologia,2022,64(4):383-392.16HA EJ,BAEK JH,CHE Y,et al.Radiofrequency ablation of be-nign thyroid nodules:recommendations from the asian conferenceon tumor ablation task force-secondary publication J.Journalof Medical Ultrasound,2021,29(2):77-83.17MUHAMMAD H,SANTHANAM P,RUSSELL JO.Radiofrequencyablation and thyroid nodules:updated systematic review J.En-docrine,2021,72(3):619 632.18 HAUCEN BR,ALEXANDER EK,BIBLE KC,et al.2015 Ameri-can Thyroid Association management guidelines for adult patientswith thyroid nodules and differentiated thyroid cancer:The Ameri-can Thyroid Association guidelines task force on thyroid nodulesMODERN ONCOLOGY,Oct.2023,VOL.31,No.1919SUGITANI I,ITO Y,TAKEUCHI D,et al.Indications and strategyfor active surveillance of adult low-risk papillary thyroid micro-carcinoma:consensus statements from the Japan association of en-docrine surgery task force on management for papillary thyroid mi-crocarcinoma J.Thyroid,2021,31(2):183-192.20YAN L,ZHANG M,SONG Q,et al.Ultrasound-guided radiofre-quency ablation versus thyroid lobectomy for low-risk papillarythyroid microcarcinoma:a propensity-matched cohort study of884 patients J.Thyroid,2021,31(11):1662-1672.21 ZHANG M,TUFANO RP,RUSSELL JO,et al.Ultrasound-guided radiofrequency ablation versus surgery for low-risk papil-lary thyroid microcarcinoma:results of over 5 years follow-upJ.Thyroid,2020,30(3):408-417.22MIN Y,WANG X,CHEN H,et al.Thermal ablation for papillarythyroid microcarcinoma:how far we have come J.Cancer Man-agement and Research,2020,12:13369-13379.23CHEN J,HUANG N,JI Q,et al.Multifocal papillary thyroid canc-er in children and adolescents:12-year experience in a singlecenter J.Gland Surgery,2019,8(5):507-515.24 RAMIA DE CAP M.Multifocal papillary thyroid carcinoma J.American Journal of Clinical Pathology,2021,155(6):913.25 MANSOUR J,SAGIV D,ALON E,et al.Prognostic value of lymphnode ratio in metastatic papillary thyroid carcinoma J.The Jour-nal of Laryngology and Otology,2018,132(1):8-13.26YU ST,CE JN,SUN BH,et al.Lymph node yield in the initialcentral neck dissection(CND)associated with the risk of recur-rence in papillary thyroid cancer:A reoperative CND cohort studyJ.Oral Oncology,2021,123:105567.27MASUDA T,NAKAURA T,FUNAMA Y,et al.Machine learningto identify lymph node metastasis from thyroid cancer in patientsundergoing contrast-enhanced CT studies J.Radiography,2021,27(3):920-926.28YU J,DENG Y,LIU T,et al.Lymph node metastasis prediction ofpapillary thyroid carcinoma based on transfer learning radiomicsJ.Nature Communications,2020,11(1):4807.3587.and dfferentiated thyroid cancer J.Thyroid,2016,26(1):1-133.（编校：巩森森）关于统计学符号规范化书写的要求根据国家标准CB3358-93统计学术语的有关规定，作者在书写统计学符号时应注意以下要求：样本的算术平均数用英文小写x，不用大写X也不用Mean或M;标准差用英文小写s，不用SD；标准误用英文小写s不用SEt检验用英文小写t;F检验用英文大写F;卡方检验用希文小写；相关系数用英文小写r;自由度用希文小v;样本数用英文小写n;概率用英文大写P;以上符号x、s、S、t、FV、r Vn、P均为斜体。现代肿瘤医学编辑部