第二大組外科胸腺瘤肌無力巡診

1、Thymoma and myasthenia gravis杜宇 古兆琦指導(dǎo)老師：梁乃新2016-4-11Anatomy Blood supplyArteries:Internal thoracic arteries; inferior thyroid and pericardiophrenic arteries.Veins:Left brachiocephalic vein (innominate vein), and the thyroid veins.Nerves zSympathetic nerve and parasympathetic nerve fibers, sympatheti

2、c nerve fibers from the thoracic ganglion and other small ganglion neurons;zAdrenergic nerve fibers - thymus cortex.zCholinergic nerve fibers - parenchymal cells of the medulla and the cortex and medulla.Roggero E, Besedovsky H, O, del Rey A, The Role of the Sympathetic Nervous System in the Thymus

3、in Health and Disease. Neuroimmunomodulation 2011;18:339-349Histology Epidemiology of thymomaz Rare, 0.17/100,000 in europe1, 0.15/100,000 in US2z 0.3-0.4/100,000 in Asia3z 90% of thymic tumors are thymomaz 20-25% of all mediastinal tumorsz 50% of anterior mediastinal massesz 20-50 yrsz No sexual pr

4、edilection exists.1 Rare thoracic cancers, including peritoneum mesothelioma.Siesling S, van der Zwan JM, Izarzugaza I, Jaal J, Treasure T, Foschi R, Ricardi U, Groen H, Tavilla A, Ardanaz E; RARECARE Working Group.Eur J Cancer. 2012 May;48(7):949-60. doi: 10.1016/j.ejca.2012.02.047. Epub 2012 Mar 9

5、.2 Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Engels EA, Pfeiffer RM. Int J Cancer. 2003 Jul 1;105(4):546-51.3 Chen KN, Fang WT. Thymic Tumors Preface. Zhongguo Fei Ai Za Zhi, 2014, 17(2):73-74. 陳克能, 方文濤. 胸腺腫瘤專題前言. 中國肺癌雜志,

6、 2014, 17(2): 73-74. doi: 10.3779/j.issn.1009-3419.2014.02.02.Pathology 71% associated with myasthenia gravisMasaokas staging Follow-up study of thymomas with special reference to their clinical stages.Masaoka A, Monden Y, Nakahara K, Tanioka T.Cancer. 1981 Dec 1;48(11):2485-92Modified Masaokas stag

7、ing Stage I: Grossly and microscopically encapsulated. Stage II: The thymoma invades beyond the and into the nearby fatty tissue or to the pleura. Sometimes divided into:Stage IIa: Microscopic transcapsular invasionStage IIb: Macroscopic capsular invasionStage III: Macroscopic invasion of neighborin

8、g organs, including the pericardium, the lungs, or the main blood vessels leading into or exiting from the heart.Stage IVA: Pleural or pericardial dissemination. The thymoma has spread widely throughout the pleura and/or pericardium.Stage IVB: Hematogenous or lymphatic dissemination. The thymoma has

9、 spread to distant organs.Clinical presentationszThoracic manifestations Common symptoms: chest pain, shortness of breath, cough. When disseminated: severe pain, phrenic nerve palsy, superior vena cava syndrome. Clinical presentations5-15%, Spindle cell morphology 5%, Spindle cell morphology 25-40%,

10、Type B217-28% of patients with T present with a second synchronous or metachronous primary malignancy.Diagnosis z Clinical manifestationsz Imaging zChest filmzCTzMRIzPET-CTzOctreotide scanningz Biospy zFine needle aspiration (sens. 60%)zAnterior mediastinotomy (Chamberlain procedure) zVideo-assisted

11、 thoracic surgery (VATS) zTotal thymectomyDifferantial diagnosisOf common anterior mediastinal massesFat Water Calcified massSignificant contrast enhancementBenign Terotoma;Thymolipoma Pericardial cyst; Thymic cyst; AbscessThyroid goitorAneurysmMalignant Thyroid cancer; Thymic carcimona and carcinoi

12、ds;Lymphoma;Germ cell tumors;Parathyroid adenoma Management b Determination of resectability should be made by a board-certified thoracic surgeon, with primary focus on thoracic oncology.Management d R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residual tumor.Management

13、LOCALLY ADVANCED, ADVANCED,OR RECURRENT DISEASETargeted therapyClass Agent Clinical trial phaseEGFR inhinibitorGefitinib IIErlotinib+bevacizubamIICetuximab IIKIT inhibitorImatinib IISrc inhibitorSaracatinib IIIGF-IR inhibitorCixutumumab IIAngiogenesis inhibitorBevacizumab IISunitinib II ongoingSUO14

14、813I ongoingAflibercept I ongoing with docetaxelMotesanib IHDAC inhibitorBelinostat IICDK/TRKA inhibitorMilciclib maleateII ongoing靶向治療Cancer Treat Rev. 2014 May;40(4):495-506. doi: 10.1016/j.ctrv.2013.11.003. Epub 2013 Nov 26. Thymic neoplasms: an update on the use of chemotherapy and new targeted

15、therapies. A literature review.Berardi R, De Lisa M et al.Survival Thymoma and thymic carcinomas. Scorsetti M, Leo F, Trama A, DAngelillo R, Serpico D, Macerelli M, Zucali P, Gatta G, Garassino MC. Crit Rev Oncol Hematol. 2016 Mar;99:332-50. doi: 10.1016/j.critrevonc.2016.01.012. Epub 2016 Jan 19. M

16、yasthenia gravis(MG) and thymomazUp to of patients with thymoma have symptoms consistent with MG1.zThe majority of AChR antibody positive MG have thymic abnormalities: hyperplasia 60-70% and thymoma 10-12%2.zMG rare in thymic carcinoma2.Epidemiology 1 Prognostic factors for cure, recurrence and long

17、-term survival after surgical resection of thymoma. Safieddine N, Liu G, Cuningham K, Ming T, Hwang D, Brade A, Bezjak A, Fischer S, Xu W, Azad S, Cypel M, Darling G, Yasufuku K, Pierre A, de Perrot M, Waddell T, Keshavjee S J Thorac Oncol. 2014 Jul;9(7):1018-22.2 Myasthenia gravis.Drachman DB N Eng

18、l J Med. 1994;330(25):1797.MG and thymomaz MG and AChR, MuSK, seronegative myastheniaz Thymic epithelial cells prime helper T cells, which then attack the AChR on myoid cells and create infiltrating germinal centers in the hyperplastic thymus where deposition of complement is found. Antibodies in th

19、e germinal centers diversify to recognize intact muscle AChR. z Overexpression of cathepsin V has been noted in the thymic tissue of patients with myasthenia and thymoma.z Autoantibodies directed against titin or the ryanodine receptor. Presence of antititin antibodies is predictive of a thymic epit

20、helial tumor (sens. 69-80 % and spec. 90-100%) in MG patients.z Patients who have late onset MG without thymoma may also have titin or ryanodine receptor antibodies, which may be associated with worse prognosis.z Familial MG is associated with certain HLA types.Etiology 眼、肢體、球晨輕暮重重癥肌無力復(fù)習(xí)z臨床表現(xiàn)z重癥肌無力危

21、象z診斷zOsserman分型z治療肌無力危象膽堿能危象反拗危象疲勞試驗(yàn)（）新斯的明試驗(yàn)（）肌電圖特點(diǎn)：波幅遞減單纖維肌電圖：顫抖增寬乙酰膽堿受體抗體滴度的檢測I型眼肌型；IIA型輕度全身型，四肢肌群常伴眼肌受累，無假性球麻痹的表現(xiàn)；IIB型中度全身型，有球麻痹表現(xiàn)；III急性進(jìn)展型，發(fā)病急，累計(jì)球部、四肢，伴危象；IV型晚發(fā)全身肌無力型，常合并胸腺瘤；V型較早伴有明顯肌萎縮表現(xiàn)者。膽堿酯酶抑制劑糖皮質(zhì)激素免疫抑制劑血漿置換IVIG手術(shù)MG and thymectomyz Indications: MG with thymic tumors, thymic hyperplasia and di

22、fficult to treat with drugs;z Contraindications: patients18 without thymoma/thymic hyperplasia, and MG not severe;z 70% remission, some persist or advance;z If complete excision not possible or disease relapsed after surgery, apply radiation.病例：黃飛，M，27Y，北京IT男近一月逐漸出現(xiàn)咀嚼力弱、眼皮沉重，加重一周z近一月咀嚼力弱，偶有吞咽費(fèi)力、無飲水嗆

23、咳。z并逐漸出現(xiàn)雙眼皮沉重，晨輕暮重。z無明顯雙瞼下垂、 斜視、復(fù)視。抬臂、上樓可z近2周病情加重?，F(xiàn)病史z既往史：2013年曾行肛周膿腫切除術(shù)，否認(rèn)甲亢， 無外傷、輸血、食物藥物過敏史。z個人史：長期大量吸煙史，10包年z家族史：無殊z 一般情況：神清、語利，對答切題，高級智能正常。顱神經(jīng)：z 未查z 粗測視力、視野正常。z 雙側(cè)眼裂等大，雙側(cè)瞳孔等大等圓，d=3mm，直接、間接對光反射靈敏，雙眼活動充分， 未引出眼震，無復(fù)視。z 角膜反射存在，面部針刺覺、觸覺正常存在，咀嚼有力對稱，張口下頜無偏斜，未引出下頜反射。z 額紋對稱，閉目有力，雙側(cè)鼻唇溝對稱，鼓腮有力，示齒口角不偏。z 未查。z

24、 構(gòu)音尚可，懸雍垂居中，雙側(cè)軟腭抬舉可，雙側(cè)咽反射存在。z 雙側(cè)轉(zhuǎn)頸有力、聳肩有力。z 伸舌居中，未見舌肌萎縮、有纖顫。體格檢查運(yùn)動系統(tǒng)：z 肌容積：雙側(cè)對稱未見明顯異常。z 肌力：四肢肌力正常。疲勞試驗(yàn)（-）。z 肌張力：肌張力正常。z 共濟(jì)運(yùn)動：雙側(cè)指鼻、輪替、跟膝脛試驗(yàn)（-）；Romberg征（-）。z 步態(tài)及姿勢：行走左上肢伴隨動作減少，行走直線可，后拉試驗(yàn)（+）。z 反射：四肢腱反射對稱，腹壁反射對稱可引出。雙側(cè)髕陣攣（-），雙側(cè)踝陣攣（-）。z 病理反射：雙側(cè)掌頜反射（-）、雙側(cè)Hoffmann征（-）。雙側(cè)Babinski征、Chaddock征、Oppenheim征(-),Gor

25、don征（-）。感覺系統(tǒng)：四肢淺感覺、音叉振動覺、關(guān)節(jié)位置覺、復(fù)合覺（-）。腦膜刺激征：頸軟，克氏征（-），布氏征（-）。植物神經(jīng)系統(tǒng)：皮膚未見干燥脫屑，劃痕征正常，皮溫不低。體格檢查用力眨眼30次后眼裂明顯變小兩臂持續(xù)平舉后出現(xiàn)上臂下垂，休息后恢復(fù)蹲起10-20次后不能繼續(xù)zAchRab z肌電圖（右面神經(jīng)）（右面神經(jīng)）z胸部胸部CT平掃平掃z胸部胸部CT增強(qiáng)增強(qiáng)z甲功（甲功（-）輔助檢查患者間AChR-Ab滴度與疾病嚴(yán)重程度的相關(guān)性較差?？贵w低滴度或甚至抗體陰性的患者可能比抗體高滴度患者的臨床病情嚴(yán)重得多。然而，對于個體患者，通過成功的免疫治療其抗體滴度往往會下降，并且滴度與臨床改善一致。

26、MuSK-Ab見于38%-50%的AChR-Ab陰性的全身型重癥肌無力患者。MuSK是一種受體酪氨酸激酶，在發(fā)育過程中介導(dǎo)聚集蛋白依賴性AChR的集聚和神經(jīng)肌肉接頭的形成。RNS：將記錄電極置于肌肉終板區(qū)域，并刺激支配該肌肉的運(yùn)動神經(jīng)。以2Hz或3Hz低頻電刺激神經(jīng)6-10次，肌肉處的電極可記錄電刺激神經(jīng)后的復(fù)合肌肉動作電位(compound muscle action potential, CMAP)波幅。包括靜息時CAMP讀數(shù)，接著是運(yùn)動試驗(yàn)?；顒雍驝AMP降幅比靜息時大，稱為運(yùn)動后或活動后耗竭。這種運(yùn)動試驗(yàn)可將RNS的敏感性提高5%-10%。通常選擇面神經(jīng)支配的眼輪匝肌、腋神經(jīng)支配的三角

27、肌、尺神經(jīng)支配的小指展肌及副神經(jīng)支配的斜方肌等。特點(diǎn)特點(diǎn)胸廓胸膜肺門（淋巴結(jié)）支氣管心臟縱膈腫物？囊實(shí)性？內(nèi)部分隔?大小邊界血管包繞擠壓心包侵犯增強(qiáng)？z 非侵襲性 邊緣清晰光滑 脂肪間隙規(guī)整z 侵襲性 索條進(jìn)入脂肪間隙 侵入/包埋鄰近結(jié)構(gòu)超 3/4周 與肺組織界面不規(guī)整 胸膜/心包結(jié)節(jié) 穿過橫膈入腹腔Anatomy CT增強(qiáng)CTz男，52歲，發(fā)熱乏力，雙側(cè)腋下淋巴結(jié)腫大女，50歲，體檢發(fā)現(xiàn)左前縱隔腫物女，女，76歲，無明顯頸胸部不適歲，無明顯頸胸部不適zAchRab 1.275（0.625），MuSK. Ab 0.046 （ 0.258） AchE.Ab 0.189（0.352），Titin.

28、 Ab 0.181（0.472），RyR.Ab 0.171（0.382）z肌電圖：RNS可見低頻刺激波幅遞減現(xiàn)象（右面（右面神經(jīng)）神經(jīng)）z胸部胸部CT平掃平掃z胸部胸部CT增強(qiáng)增強(qiáng)z甲功（甲功（-）輔助檢查z重癥肌無力 胸腺瘤可能性大診斷zLambert-Eaton綜合征z慢性炎性肌病z眼肌型營養(yǎng)不良z進(jìn)行性球麻痹z肉毒桿菌中毒鑒別診斷多見于小細(xì)胞未分化型肺癌或其他腫瘤。本病自身免疫的靶器官為突觸前膜的鈣離子通道，使乙酰膽堿的釋放減少，導(dǎo)致肌無力。其臨床表現(xiàn)也是骨骼肌無力，但受累肌群分布與有所不同。該病常侵犯四肢近端肌肉，腦神經(jīng)支配肌肉少受累在主動運(yùn)動后肌力可有暫時性增加，持續(xù)運(yùn)動后肌無力加重。肌電圖重復(fù)頻率刺激時可出現(xiàn)波幅“高頻遞增、低頻遞減”的現(xiàn)象。血清乙酰膽堿受體抗體水平不高，多數(shù)對新斯的明缺乏反應(yīng)。懷疑此病時，應(yīng)全面查找原發(fā)腫瘤包括慢性多發(fā)性肌炎，皮肌炎及包涵體肌炎肌肉壓痛血清激酶（CK，LDH）增高肌電圖提示肌源性損傷，重復(fù)點(diǎn)刺激陰性血清AchR滴度不高抗膽堿酯酶藥物治療無效病情長達(dá)數(shù)年，數(shù)十年癥狀無波動，進(jìn)展緩慢抗膽堿酯酶藥物治療無效延髓支配肌肉無力及萎縮，舌肌明顯萎縮伴纖顫