膀胱尿路上皮癌惡性程度分級(jí)和浸潤(rùn)程度分期的進(jìn)展

1、介紹,近年來(lái)，WHO和國(guó)際抗癌協(xié)會(huì)（UICC）分別對(duì)膀胱癌的組織學(xué)分級(jí)、TNM分期法進(jìn)行了一些重要的改動(dòng)和修訂歐洲泌尿外科醫(yī)師協(xié)會(huì)也適時(shí)推出了膀胱癌的新版指南2006-Guidelines on TaT1 ( Non-muscle invasive )bladder cancer。在我國(guó)，中華醫(yī)學(xué)會(huì)泌尿外科學(xué)分會(huì)腫瘤學(xué)組正在著手制定膀胱癌診斷治療指南。,主要分期（Stage)和分級(jí)（Grade)標(biāo)準(zhǔn),Grade Bergkvist

2、分級(jí)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(guó)際癌控制中心UICC ( Union International Contre le Cancer，1998，2002) 的TNM分期法為標(biāo)準(zhǔn) [3，4]美國(guó)Jewett-Strong-Marshall分期法 （AJCC）,膀胱尿路

3、上皮癌的組織學(xué)分級(jí),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(xiàn)上和習(xí)慣上這兩個(gè)名詞常常交替使用。,膀胱癌的組織學(xué)分級(jí),膀胱腫瘤的惡性程度以級(jí)（grade）來(lái)表示。關(guān)于膀胱癌的分級(jí)，國(guó)際上有不少版本，綜合于（表1）。,Grading system,歷史發(fā)展和演變,WHO 1973 Classification 1973年WHO提出，方法簡(jiǎn)單，便于分類，主要是根據(jù)腫瘤細(xì)

4、胞核間變的程度，將膀胱尿路上皮癌分為3級(jí)，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(guó)際泌尿病理協(xié)會(huì)（ISUP）提出了非浸潤(rùn)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）。本新分類法應(yīng)用特殊的細(xì)胞學(xué)和結(jié)構(gòu)學(xué)標(biāo)準(zhǔn)，對(duì)膀胱癌的各個(gè)級(jí)別有詳盡的描述?？梢栽诰W(wǎng)頁(yè)www.pat

5、hology.jhu.edu/bladder查到各級(jí)膀胱的說(shuō)明例證。這個(gè)分級(jí)法把尿路上皮腫瘤分為低度惡性潛能（PUNLMP）、低級(jí)和高級(jí)尿路上皮癌。,Urothelial Papilloma Urothelial papilloma is defined as discrete papillary growth with a central fibrovascular cores lined by urothelium of norm

6、al 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(xì)胞的尿路上皮。不需計(jì)數(shù)細(xì)胞的層次。,Papillary Urothelial Neoplasm of Low Malignant Potential Papillary urothelial neopl

7、asm of low malignant potential is a papillary urothelial lesion with an orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear atypia irrespective of the number of cell

8、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 hyperchromatic. Mitotic figures are infrequ

9、ent 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(xì)胞排列有序，結(jié)構(gòu)輕度異常，細(xì)胞核輕度間變，可不考慮細(xì)胞層次的數(shù)目。低度惡性潛能的尿路上皮癌比乳頭狀瘤細(xì)胞層次明顯多，和/或細(xì)胞核輕微增大，染色質(zhì)增多，有絲分裂相偶見，通

10、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 variation of architectural and or cytologic feat

11、ures even at scanning magnification. Variation of polarity and nuclear size, shape, and chromatin texture comprise the minimal but definitive cytologic atypia. Mitotic figures are infrequent and usually seen in the lower

12、 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 lesion, such that the entire lesion should be

13、examined, with the highest grade of abnormality noted.低級(jí)乳頭狀尿路上皮癌 整體排列整齊。高倍視野下細(xì)胞特征和結(jié)構(gòu)有明顯的變異，極向和細(xì)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(xì)胞的病變。有絲分裂相少見。,High-grade Papillary Urothelial Carcinoma High-grade papillary urothelial carci

14、nomas are characterized by a predominantly or totally disorderly appearance at low magnification. The disorder results from both architectural and cytologic abnormalities. Architecturally, cells appear irregularly cluste

15、red 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 nucleoli may be prominent. Mitotic figures, includ

16、ing 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 there is marked nuclear anaplasia. 高級(jí)乳頭狀尿路上

17、皮癌 在低倍顯微鏡下有明顯的，或完全的排列紊亂。細(xì)胞學(xué)和結(jié)構(gòu)有明顯的異常。結(jié)構(gòu)上，細(xì)胞不規(guī)則成簇狀，上皮排列紊亂。細(xì)胞學(xué)，中度到嚴(yán)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(gè)主要改變。不再使用分級(jí)系統(tǒng)（沒有G）；提出PUNLAMP(低度惡性潛能)的概念； 認(rèn)為所有非浸潤(rùn)性‘High grade’癌與浸潤(rùn)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

18、分類法仍在廣泛使用，EAU推薦目前WHO 1973,2004 兩個(gè)版本可以同時(shí)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(rùn)深度及轉(zhuǎn)移情況，是判斷膀胱腫瘤預(yù)后的最有價(jià)值的參數(shù)。目前有兩種主要分期方法。一種是美國(guó)的Jewett-Strong-Marshall分期法和美國(guó)癌癥聯(lián)合會(huì)分期法，另一種為國(guó)際抗癌協(xié)會(huì)(The International Union Against Cancer，UICC)的TNM

19、分期法。,膀胱癌的分期,這兩種國(guó)際上流行的分類或分期系統(tǒng)已經(jīng)歷經(jīng)半個(gè)世紀(jì)的發(fā)展和演變，雖日趨完善，仍還有不少爭(zhēng)議和不盡人意之處，有待于進(jìn)一步的完善。目前普遍采用國(guó)際抗癌協(xié)會(huì)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(xué)所見、經(jīng)尿道電切及組織病理學(xué)檢查，可以把膀胱癌分為淺表性膀胱癌（Tis, Ta, T1)和浸潤(rùn)性膀胱癌(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

20、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(jí)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(rùn)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(jìn)展的幾率要高得多[22] 。因此，應(yīng)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,膀胱癌的TNM分期-N分期,N ( 淋巴結(jié))NX 區(qū)域淋巴結(jié)無(wú)法評(píng)估N0 無(wú)區(qū)域淋

21、巴結(jié)轉(zhuǎn)移N1 單個(gè)淋巴結(jié)轉(zhuǎn)移，最大徑小于或等于2 cmN2 單個(gè)淋巴結(jié)轉(zhuǎn)移，最大徑大于2 cm 但小于 5 cm ，或多個(gè)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(guò) 5 cm,膀胱癌的TNM分期-M分期,M 遠(yuǎn)處轉(zhuǎn)移MX 遠(yuǎn)處轉(zhuǎn)移無(wú)法評(píng)估M0 無(wú)遠(yuǎn)處轉(zhuǎn)移M1 遠(yuǎn)處轉(zhuǎn)移,膀胱癌的TNM分期注意事項(xiàng),T分期 TUR 和雙合診：TUR時(shí), 要切到深肌層或膀胱周圍脂肪組織，以識(shí)別膀胱癌的浸潤(rùn)深度。在男性

22、，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(shí)別有無(wú)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(xué)：影像學(xué)檢查的目的是識(shí)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(rùn)性癌，應(yīng)該進(jìn)行影像學(xué)檢查。1）靜脈法腎盂造影（IVP）：發(fā)現(xiàn)腎積水提示預(yù)后不良[25] 。,膀胱癌的TNM分期,2) CT: CT檢查不能準(zhǔn)確地區(qū)分限于器官和膀胱外擴(kuò)散的膀胱癌，

23、CT發(fā)現(xiàn)和膀胱切除標(biāo)本的符合率為65-80% [26,27]。 3) 核磁共振 (MRI) MRI的診斷價(jià)值與CT相似，MRI不能識(shí)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(duì)淋巴結(jié)為轉(zhuǎn)移的漏診率高達(dá)70% [27，30,31]。三維MRI 可能比較靈敏，但現(xiàn)有經(jīng)驗(yàn)有限。正電子發(fā)射斷層攝影術(shù)（Positron emission tomography ，P

24、ET)， 腹腔鏡淋巴結(jié)切除的價(jià)值有待進(jìn)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(yuǎn)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(yīng)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/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(wèn)題是腫瘤的復(fù)發(fā)和

25、進(jìn)展。絕大多數(shù)淺表性膀胱癌發(fā)展為浸潤(rùn)性膀胱癌的幾率不高，但高分級(jí)T1G3膀胱的復(fù)發(fā)進(jìn)展率高達(dá)50% [34，35] 。一些臨床和病理參數(shù)可以預(yù)測(cè)膀胱癌復(fù)發(fā)和進(jìn)展的危險(xiǎn)[36～38] 。 這些因素被稱為淺表性膀胱癌的預(yù)后因素。,淺表性膀胱癌-高危/低危的概念,與膀胱癌復(fù)發(fā)相關(guān)的因素，按照重要性排列如下：1.初診時(shí)腫瘤的數(shù)目。2.以前的復(fù)發(fā)率，3個(gè)月復(fù)發(fā)率。3.腫瘤的大小，腫瘤愈大，復(fù)發(fā)的危險(xiǎn)就愈高4.腫瘤的間變程度。,淺表性膀

26、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(jìn)展的參數(shù)。膀胱頸部腫瘤比其他部位腫瘤預(yù)后差[39] 。按照預(yù)后因素，可以把淺表性膀胱癌分為低危、高危和中度危險(xiǎn)3組。1.低危腫瘤：?jiǎn)蝹€(gè)腫瘤、Ta,G1 直徑小于3cm。2.高危腫瘤：T1,G3,多灶性或頻繁復(fù)發(fā)，TIS3. 中度危險(xiǎn)：所有其他腫瘤、Ta-T1, G1-G2,多灶性，直徑大于3厘米。,參考文獻(xiàn),1. Mostofi FK, Sorbin LH,

27、Torloni H. Histologic typing of urinary bladder tumours. International classification of tumours, No 10. WHO, Geneva, 1973. 2. World Health Organization. Histologic typing of urinary bladder tumours. International class

28、ification 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 eds). Springer-Verlag, Philadelphia, Berlin,

29、 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(xiàn),5. Fleshner NE, Herr HW, Stewart AK, Murphy GP, Mettlin C, Menck HR. The National C

30、ancer 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(xué),濟(jì)南：山東科學(xué)技術(shù)出版社，2004，959-9807. Kantor AF, Hartge P, Hoover RN, Fraumeni JF Jr. Epidemiological characteristics

31、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(xiàn),9. Bennett JK, Wheatly JK, Walton KN. 10-year exp

32、erience 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 report and review of the literature. J Uro

33、l, 1983, 130:1180-1182.,參考文獻(xiàn),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, et al: Epidemiological characteristics of s

34、quamous 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 schistosomiasis. The National Cancer Institute, Cairo

35、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: 261-279,參考文獻(xiàn),15. Bergkvist A, Ljungqvist A, Moberg

36、er 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. Acta Chir Scand, 1965, 130(4):371-378. 16.

37、 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-up. Scand J Urol Nephrol, 1987, 21(3):185-19

38、5.17. Epstein JI, Amin MB, Reuter VR et al. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladde

39、r 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 bladder wall to incidence of local extensio

40、n and metastases. J Urol, 1946, 55:366-372,參考文獻(xiàn),19. Marshall VF (1952). The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J Urol, 1952, 68: 714-72320. AJCC (19

41、83) American Joint Committee on Cancer. Manual for staging of cancer, 2nd edn. Lippincott, Philadelphia: 1983,參考文獻(xiàn),21. AJCC. Cancer Staging Manual. Fifth Ed. Lippincott-Raven, Philadelphia. New York: 1997 22. Lamm DL.

42、 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 cancer undergoing cystectomy after pre-operat

43、ive 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 transitional cell bladder carcinoma: a long-term

44、 follow-up of 276 consecutive patients. Br J Urol, 1998, 81: 686-691.,參考文獻(xiàn),25. Haleblian GE, Skinner EC, Dickinson MG, Lieskovsky G, Boyd SD, Skinner DG. Hydronephrosis as a prognostic indicator in bladder cancer patient

45、s. 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, Spirnak JP, Resnick MI. Limitations of compu