膀胱尿路上皮癌惡性程度分級和浸潤程度分期的進展.

1、膀胱癌最新WHO分級法、UICC-TNM分期法介紹,濟寧市第一人民醫(yī)院泌尿外科馬鳴,介紹,近年來，WHO和國際抗癌協(xié)會（UICC）分別對膀胱癌的組織學分級、TNM分期法進行了一些重要的改動和修訂歐洲泌尿外科醫(yī)師協(xié)會也適時推出了膀胱癌的新版指南2006-Guidelines on TaT1 ( Non-muscle invasive )bladder cancer。在我國，中華醫(yī)學會泌尿外科學分會腫瘤學組正在著手制定膀胱癌診斷治療指

2、南。,主要分期（Stage)和分級（Grade)標準,Grade Bergkvist分級法1965改良Bergkvist法[7]（1987） 世界衛(wèi)生組織(WHO)WHO 1973WHO/ISUP 1998 Consensus WHO 1999WHO 2004,Stage國際癌控制中心UICC ( Union International Contre le Cancer，1998，2002) 的TNM分期法為標準 [3

3、，4]美國Jewett-Strong-Marshall分期法 （AJCC）,膀胱尿路上皮癌的組織學分級,被覆尿路的上皮統(tǒng)稱為尿路上皮(urothelium) 。傳統(tǒng)上將尿路上皮稱為移行上皮[14] , 目前在文獻上和習慣上這兩個名詞常常交替使用。,膀胱癌的組織學分級,膀胱腫瘤的惡性程度以級（grade）來表示。關于膀胱癌的分級，國際上有不少版本，綜合于（表1）。,Grading system,歷史發(fā)展和演變,WHO 1973 Cl

4、assification 1973年WHO提出，方法簡單，便于分類，主要是根據(jù)腫瘤細胞核間變的程度，將膀胱尿路上皮癌分為3級，分化良好、中度分化和分化不良，用grade 1、2、 3或grade Ⅰ、Ⅱ、Ⅲ分別表示。目前仍然廣泛使用（WHO1999相同）。,歷史發(fā)展和演變,1998年，世界衛(wèi)生組織（WHO）和國際泌尿病理協(xié)會（ISUP）提出了非浸潤性膀胱癌的新分類。以后，2004年WHO正式出版了這一新的分類方法（表1）。本新分類法

5、應用特殊的細胞學和結(jié)構(gòu)學標準，對膀胱癌的各個級別有詳盡的描述?？梢栽诰W(wǎng)頁www.pathology.jhu.edu/bladder查到各級膀胱的說明例證。這個分級法把尿路上皮腫瘤分為低度惡性潛能（PUNLMP）、低級和高級尿路上皮癌。,Urothelial Papilloma Urothelial papilloma is defined as discrete papillary growth with a central fibr

6、ovascular cores lined by urothelium of normal thickness and cytology. There is no need for counting the number of cell layers. 散在的乳頭狀腫瘤，其中央有中心纖維血管核心，排列著正常厚度，正常細胞的尿路上皮。不需計數(shù)細胞的層次。,Papillary Urothelial Neoplasm of Low Mali

7、gnant Potential Papillary urothelial neoplasm of low malignant potential is a papillary urothelial lesion with an orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear

8、 atypia irrespective of the number of cell layers. The urothelium in papillary urothelial neoplasms of low malignant potential is much thicker than in papillomas and/or the nuclei are significantly enlarged and somewhat

9、hyperchromatic. Mitotic figures are infrequent in papillary urothelial neoplasms of low malignant potential, and usually confined to the basal layer.低度惡性潛能的尿路上皮癌指乳頭狀尿路上皮損害，乳頭狀腫瘤細胞排列有序，結(jié)構(gòu)輕度異常，細胞核輕度間變，可不考慮細胞層次的數(shù)目。低度惡性潛能的尿

10、路上皮癌比乳頭狀瘤細胞層次明顯多，和/或細胞核輕微增大，染色質(zhì)增多，有絲分裂相偶見，通常限于基底層。,Low-grade Papillary Urothelial Carcinoma Low-grade papillary urothelial carcinomas are characterized by an overall orderly appearance but with easily recognizable varia

11、tion of architectural and or cytologic features even at scanning magnification. Variation of polarity and nuclear size, shape, and chromatin texture comprise the minimal but definitive cytologic atypia. Mitotic figures a

12、re infrequent and usually seen in the lower half, but may be seen at any level of the urothelium. It is important to recognize that there may be a spectrum of cytologic and architectural abnormalities within a single les

13、ion, such that the entire lesion should be examined, with the highest grade of abnormality noted.低級乳頭狀尿路上皮癌 整體排列整齊。高倍視野下細胞特征和結(jié)構(gòu)有明顯的變異，極向和細胞核大小、形狀、染色質(zhì)的變化雖然不是很明顯，但又肯定的細胞的病變。有絲分裂相少見。,High-grade Papillary Urothelial Carci

14、noma High-grade papillary urothelial carcinomas are characterized by a predominantly or totally disorderly appearance at low magnification. The disorder results from both architectural and cytologic abnormalities. Archi

15、tecturally, cells appear irregularly clustered and the epithelium is disorganized. Cytologically, there is a spectrum of pleomorphism ranging from moderate to marked. The nuclear chromatin tends to be clumped and nucleol

16、i may be prominent. Mitotic figures, including atypical forms, are frequently seen at all levels of the urothelium. There is an option in the diagnosis of high-grade papillary urothelial carcinoma to comment on whether t

17、here is marked nuclear anaplasia. 高級乳頭狀尿路上皮癌 在低倍顯微鏡下有明顯的，或完全的排列紊亂。細胞學和結(jié)構(gòu)有明顯的異常。結(jié)構(gòu)上，細胞不規(guī)則成簇狀，上皮排列紊亂。細胞學，中度到嚴重的多型性，核染色質(zhì)成堆，核仁明顯。有絲分裂相，在各層尿路上皮中可見。,總之，1998/2004 WHO 分類法有3個主要改變。不再使用分級系統(tǒng)（沒有G）；提出PUNLAMP(低度惡性潛能)的概念； 認為所有非浸潤性‘

18、High grade’癌與浸潤性一樣有同樣的特征（遺傳性上的不穩(wěn)定）。鑒于目前這兩種分類法仍在廣泛使用，EAU推薦目前WHO 1973,2004 兩個版本可以同時使用；直到證明2004年更加合理。,膀胱癌的分期,膀胱腫瘤的分期指腫瘤的浸潤深度及轉(zhuǎn)移情況，是判斷膀胱腫瘤預后的最有價值的參數(shù)。目前有兩種主要分期方法。一種是美國的Jewett-Strong-Marshall分期法和美國癌癥聯(lián)合會分期法，另一種為國際抗癌協(xié)會(The I

19、nternational Union Against Cancer，UICC)的TNM分期法。,膀胱癌的分期,這兩種國際上流行的分類或分期系統(tǒng)已經(jīng)歷經(jīng)半個世紀的發(fā)展和演變，雖日趨完善，仍還有不少爭議和不盡人意之處，有待于進一步的完善。目前普遍采用國際抗癌協(xié)會的2002年第6版TNM分期法（表2）。,膀胱癌的TNM分期,根據(jù)膀胱鏡檢查、影像學所見、經(jīng)尿道電切及組織病理學檢查，可以把膀胱癌分為淺表性膀胱癌（Tis, Ta, T1)和浸潤性

20、膀胱癌(T2以上)兩大組。淺表性膀胱癌指局限于黏膜層的乳頭狀腫瘤（Ta）或已經(jīng)侵入固有膜的T1期膀胱癌。,膀胱癌的TNM分期,局限于黏膜層的扁平狀原位癌，雖然也屬于淺表性膀胱癌，但與低級別Ta和T1期膀胱癌明顯不同；原位癌分化差，屬于高度惡性的腫瘤。它可能是浸潤性膀胱癌的前身，如果不治療，比絕大多數(shù)淺表性膀胱癌病變進展的幾率要高得多[22] 。因此，應該將原位癌與淺表性膀胱癌加以區(qū)別。,表2 膀胱癌 2002 TNM 分期,膀胱

21、癌的TNM分期-N分期,N ( 淋巴結(jié))NX 區(qū)域淋巴結(jié)無法評估N0 無區(qū)域淋巴結(jié)轉(zhuǎn)移N1 單個淋巴結(jié)轉(zhuǎn)移，最大徑小于或等于2 cmN2 單個淋巴結(jié)轉(zhuǎn)移，最大徑大于2 cm 但小于 5 cm ，或多個淋巴結(jié)轉(zhuǎn)移，最大徑小于5 cmN3 淋巴結(jié)轉(zhuǎn)移，最大徑超過 5 cm,膀胱癌的TNM分期-M分期,M 遠處轉(zhuǎn)移MX 遠處轉(zhuǎn)移無法評估M0 無遠處轉(zhuǎn)移M1 遠處轉(zhuǎn)移,膀胱癌的TNM分期注意事項,T分期 TUR

22、 和雙合診：TUR時, 要切到深肌層或膀胱周圍脂肪組織，以識別膀胱癌的浸潤深度。在男性，必須取前列腺尿道部活檢；女性，膀胱頸部要取活檢。此外，在經(jīng)尿道膀胱癌電切前后，做雙合診識別有無可捫及的腫塊，或了解腫瘤是否與骨盆壁固定。,膀胱癌的TNM分期,影像學：影像學檢查的目的是識別局部腫瘤的范圍，了解淋巴結(jié)和其他器官轉(zhuǎn)移情況。如果考慮膀胱癌為浸潤性癌，應該進行影像學檢查。1）靜脈法腎盂造影（IVP）：發(fā)現(xiàn)腎積水提示預后不良[25] 。,膀胱

23、癌的TNM分期,2) CT: CT檢查不能準確地區(qū)分限于器官和膀胱外擴散的膀胱癌，CT發(fā)現(xiàn)和膀胱切除標本的符合率為65-80% [26,27]。 3) 核磁共振 (MRI) MRI的診斷價值與CT相似，MRI不能識別膀胱周圍脂肪的微小轉(zhuǎn)移病變，分期誤差約為30% [28，29] 。,膀胱癌的TNM分期,2. N分期 CT和 MRI對淋巴結(jié)為轉(zhuǎn)移的漏診率高達70% [27，30,31]。三維MRI 可能比較靈敏，但現(xiàn)有經(jīng)驗有限

24、。正電子發(fā)射斷層攝影術（Positron emission tomography ，PET)， 腹腔鏡淋巴結(jié)切除的價值有待進一步探討。目前，淋巴結(jié)切除活檢是惟一能夠排除淋巴結(jié)轉(zhuǎn)移的方法。,膀胱癌的TNM分期,M分期 在制定治療方案之前，必須確定是否存在遠處轉(zhuǎn)移。所有病人必須行胸部X線檢查，如果懷疑骨骼受累應行骨掃描檢查，如果骨掃描發(fā)現(xiàn)可疑病變，可以做MRI可以確定骨轉(zhuǎn)移病變[32] 。B超可以發(fā)現(xiàn)肝臟的轉(zhuǎn)移。,淺表性膀胱癌-高危

25、/低危的概念,淺表性膀胱癌在初期治療后（TUR或膀胱部分切除）的主要問題是腫瘤的復發(fā)和進展。絕大多數(shù)淺表性膀胱癌發(fā)展為浸潤性膀胱癌的幾率不高，但高分級T1G3膀胱的復發(fā)進展率高達50% [34，35] 。一些臨床和病理參數(shù)可以預測膀胱癌復發(fā)和進展的危險[36～38] 。 這些因素被稱為淺表性膀胱癌的預后因素。,淺表性膀胱癌-高危/低危的概念,與膀胱癌復發(fā)相關的因素，按照重要性排列如下：1.初診時腫瘤的數(shù)目。2.以前的復發(fā)率，3個

26、月復發(fā)率。3.腫瘤的大小，腫瘤愈大，復發(fā)的危險就愈高4.腫瘤的間變程度。,淺表性膀胱癌-高危/低危的概念,膀胱癌的間變程度和T分類是最重要的判斷疾病進展的參數(shù)。膀胱頸部腫瘤比其他部位腫瘤預后差[39] 。按照預后因素，可以把淺表性膀胱癌分為低危、高危和中度危險3組。1.低危腫瘤：單個腫瘤、Ta,G1 直徑小于3cm。2.高危腫瘤：T1,G3,多灶性或頻繁復發(fā)，TIS3. 中度危險：所有其他腫瘤、Ta-T1, G1-G2,多

27、灶性，直徑大于3厘米。,參考文獻,1. Mostofi FK, Sorbin LH, Torloni H. Histologic typing of urinary bladder tumours. International classification of tumours, No 10. WHO, Geneva, 1973. 2. World Health Organization. Histologic typing of u

28、rinary bladder tumours. International classification of tumours, No 10. Second edition，Geneva, 1999.3. UICC International Union Against Cancer. In: TNM Classification of Malignant Tumours 4th ed. (Hermanck P, Sobin LH e

29、ds). Springer-Verlag, Philadelphia, Berlin, 1998, pp 135～137.4. Sobin DH and Witteking Ch (eds).TNM Classification of Malignant Tumours. 6th edn. Wiley-Liss: New York, 2002.,參考文獻,5. Fleshner NE, Herr HW, Stewart AK, Mur

30、phy GP, Mettlin C, Menck HR. The National Cancer Data Base report on bladder carcinoma. Cancer, 1996, 78(7):1505-15136.顧方六.尿路上皮腫瘤的診斷和治療.見：吳階平主編.吳階平泌尿外科學,濟南：山東科學技術出版社，2004，959-9807. Kantor AF, Hartge P, Hoover RN, Fraum

31、eni JF Jr. Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder. Cancer Res 1988; 48(13):3853-5.8. Lynch CF, Cohen MB. Urinary system. Cancer, 1995, 75(Suppl):316-329.,參考文獻,9. Ben

32、nett JK, Wheatly JK, Walton KN. 10-year experience with adenocarcinoma of the bladder. J Urol 1984, 131:262-263.10. Nielsen K, Nielsen KK. Adenocarcinoma in exstrophy of the bladder--the last case in Scandinavia? A case

33、 report and review of the literature. J Urol, 1983, 130:1180-1182.,參考文獻,11. Costello AJ, Tiptaft RC, England HR, et al: Squamous cell carcinoma of the bladder. Urology 1984; 23:234. 12. Kantor AF, Hartge P, Hoover RN, e

34、t al: Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder. Cancer Res 1988; 48:3853-385513. El-Bolkainy MN, Chu EW,(eds)： Detection of bladder cancer associated with schistosomi

35、asis. The National Cancer Institute, Cairo University. AL-Ahram Press, Cairo, 1981 14. Melicow MM. Histological study of vesical urothelium intervening between gross tumours in total cystectomy. J Urol 1952; 68: 261-279

36、,參考文獻,15. Bergkvist A, Ljungqvist A, Moberger G. Classification of bladder tumours based on the cellular pattern. Preliminary report of a clinical-pathological study of 300 cases with a minimum follow-up of eight years.

37、Acta Chir Scand, 1965, 130(4):371-378. 16. Malmstrom PU, Busch C, Norlen BJ. Recurrence, progression and survival in bladder cancer. A retrospective analysis of 232 patients with greater than or equal to 5-year follow-u

38、p. Scand J Urol Nephrol, 1987, 21(3):185-195.17. Epstein JI, Amin MB, Reuter VR et al. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cel

39、l) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol, 1998, 22:1435-1448.18. Jewett HJ, Strong GH: Infiltrating carcinoma of the bladder: Relation of depth of penetration of the

40、bladder wall to incidence of local extension and metastases. J Urol, 1946, 55:366-372,參考文獻,19. Marshall VF (1952). The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neopla

41、sms. J Urol, 1952, 68: 714-72320. AJCC (1983) American Joint Committee on Cancer. Manual for staging of cancer, 2nd edn. Lippincott, Philadelphia: 1983,參考文獻,21. AJCC. Cancer Staging Manual. Fifth Ed. Lippincott-Raven,

42、 Philadelphia. New York: 1997 22. Lamm DL. Cancer in situ. Urol Clin North Am, 1992, 19:499-50823. Fossa SD, Ous S, Berner A. Clinical significance of the ‘palpable mass’ in patients with muscle-infiltrating bladder ca

43、ncer undergoing cystectomy after pre-operative radiotherapy. Br J Urol, 1991, 67: 54-6024. Wijkstrom H, Norming U, Lagerkvist M, Nilsson B, Naslund I, Wiklund P. Evaluation of clinical staging before cystectomy in trans

44、itional cell bladder carcinoma: a long-term follow-up of 276 consecutive patients. Br J Urol, 1998, 81: 686-691.,參考文獻,25. Haleblian GE, Skinner EC, Dickinson MG, Lieskovsky G, Boyd SD, Skinner DG. Hydronephrosis as a pro

45、gnostic indicator in bladder cancer patients. J Urol, 1998, 160: 2011-2014.26. Herr HW. Routine CT scan in cystectomy patients: does it change management? Urology 1996; 47: 324-325.27. Paik ML, Scolieri MJ, Brown SL, S

46、pirnak JP, Resnick MI. Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol 2000; 163: 1693-1696.,參考文獻,28. Barentsz JO, Engelbrecht MR, Witjes JA, de la Rosette JJ,

47、van der Graaf MV. MR imaging of the male pelvis. Eur Radiol, 1999, 9: 1722-1736.29. Kim B, Semelka RC, Ascher SM, Chalpin DB, Carroll PR, Hricak H. Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-w

48、eighted MR imaging, dynamic gadolinium-enhanced imaging, and late gadolinium-enhanced imaging. Radiology, 1994, 193: 239-245.30. Tavares NJ, Demas BE, Hricak H. MR imaging of bladder neoplasms: correlation with patholog

49、ic staging. Urol Radiol, 1990, 12: 27-33.,參考文獻,31. Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJ. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted m

50、agnetization-prepared-rapid gradient-echo sequence. AJR Am J Roentgenol 1996; 167:1503-1507.32. Davey P, Merrick MV, Duncan W, Redpath AT. Bladder cancer: the value of routine bone scintigraphy. Clin Radiol, 1985, 36:

51、77-79. 33. Pawinsky A, Sylvester R, Kurth KH, et al. A combined analysis of the European Organization for Research and Treatment of Cancer and the Medical Research Council randomized clinical trials for the prophylactic

52、 treatment of stage Ta, T1 bladder cancer .J Urol, 1996, 156:1934-194134.Cookson MS, Herr Hw, Zhang ZF, Soloway S, et al. The treated nature history of high risk superficial bladder cancer: 15 years outcome. J Urol, 199

53、7, 158:62-67,參考文獻,35.Herr HW. Tumour progression and survival in patients with T1G3 bladder tumours :15 years outcome.Br J Urol,1997,80:162-76536.Parmar MKB, Freedman LS, Hargreave TB, Tolley DA. Prognostic factors for

54、recurrence and follow-up policies in the treatment of superficial bladder cancer: report from the British Medical Research Council subgroup on Superficial bladder cancer. J Urol, 1989,142:284-28837.Witjes JA, Kiemenig L

55、a LM, Oostergof Gon, Debruyne FML. Prognostic factors in superficial bladder tumours. Eur Urol, 1992,21:89-9738.Kurth KH, Ten Kate FJW, Sylvester R. Prognostic factor in superficial bladder tumours. Problems in Urology,