1、膀胱癌最新WHO分级法、UICC-TNM分期法介绍,济宁市第一人民医院泌尿外科马鸣,介绍,近年来，WHO和国际抗癌协会（UICC）分别对膀胱癌的组织学分级、TNM分期法进行了一些重要的改动和修订欧洲泌尿外科医师协会也适时推出了膀胱癌的新版指南2006-Guidelines on TaT1 ( Non-muscle invasive )bladder cancer。在我国，中华医学会泌尿外科学分会肿瘤学组正在着手制定膀胱癌诊断治疗指南。,主要分期（Stage)和分级（Grade)标准,Grade Bergkvist分级法1965改良Bergkvist法7（1987） 世界卫生组织(WHO)WHO
2、 1973WHO/ISUP 1998 Consensus WHO 1999WHO 2004,Stage国际癌控制中心UICC ( Union International Contre le Cancer，1998，2002) 的TNM分期法为标准 3，4美国Jewett-Strong-Marshall分期法 （AJCC）,膀胱尿路上皮癌的组织学分级,被覆尿路的上皮统称为尿路上皮(urothelium) 。传统上将尿路上皮称为移行上皮14 , 目前在文献上和习惯上这两个名词常常交替使用。,膀胱癌的组织学分级,膀胱肿瘤的恶性程度以级（grade）来表示。关于膀胱癌的分级，国际上有不少版本，综合于（
3、表1）。,Grading system,历史发展和演变,WHO 1973 Classification 1973年WHO提出，方法简单，便于分类，主要是根据肿瘤细胞核间变的程度，将膀胱尿路上皮癌分为3级，分化良好、中度分化和分化不良，用grade 1、2、 3或grade 、分别表示。目前仍然广泛使用（WHO1999相同）。,历史发展和演变,1998年，世界卫生组织（WHO）和国际泌尿病理协会（ISUP）提出了非浸润性膀胱癌的新分类。以后，2004年WHO正式出版了这一新的分类方法（表1）。本新分类法应用特殊的细胞学和结构学标准，对膀胱癌的各个级别有详尽的描述。可以在网页www.patholo
4、gy.jhu.edu/bladder查到各级膀胱的说明例证。这个分级法把尿路上皮肿瘤分为低度恶性潜能（PUNLMP）、低级和高级尿路上皮癌。,Urothelial Papilloma Urothelial papilloma is defined as discrete papillary growth with a central fibrovascular cores lined by urothelium of normal thickness and cytology. There is no need for counting the number of cell layers. 散
5、在的乳头状肿瘤，其中央有中心纤维血管核心，排列着正常厚度，正常细胞的尿路上皮。不需计数细胞的层次。,Papillary Urothelial Neoplasm of Low Malignant 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 minim
6、al nuclear 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 hyperchromatic. Mitotic figures are infrequent in papillary urothelial
7、 neoplasms of low malignant potential, and usually confined to the basal layer.低度恶性潜能的尿路上皮癌指乳头状尿路上皮损害，乳头状肿瘤细胞排列有序，结构轻度异常，细胞核轻度间变，可不考虑细胞层次的数目。低度恶性潜能的尿路上皮癌比乳头状瘤细胞层次明显多，和/或细胞核轻微增大，染色质增多，有丝分裂相偶见，通常限于基底层。,Low-grade Papillary Urothelial Carcinoma Low-grade papillary urothelial carcinomas are characterized
8、 by an overall orderly appearance but with easily recognizable variation 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 are infrequen
9、t 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 lesion, such that the entire lesion should be examined, with the highest grade of abnormality n
10、oted.低级乳头状尿路上皮癌 整体排列整齐。高倍视野下细胞特征和结构有明显的变异，极向和细胞核大小、形状、染色质的变化虽然不是很明显，但又肯定的细胞的病变。有丝分裂相少见。,High-grade Papillary Urothelial Carcinoma High-grade papillary urothelial carcinomas are characterized by a predominantly or totally disorderly appearance at low magnification. The disorder results from both arch
11、itectural and cytologic abnormalities. Architecturally, 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 nucleoli may be prominent. Mitotic figures,
12、 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 there is marked nuclear anaplasia. 高级乳头状尿路上皮癌 在低倍显微镜下有明显的，或完全的排列紊乱。细胞学和结构有明显的异常。结构上，细胞不规则成簇状，上皮排列紊乱。细胞学，中度到严重的多型性，核染色
13、质成堆，核仁明显。有丝分裂相，在各层尿路上皮中可见。,总之，1998/2004 WHO 分类法有3个主要改变。不再使用分级系统（没有G）；提出PUNLAMP(低度恶性潜能)的概念； 认为所有非浸润性High grade癌与浸润性一样有同样的特征（遗传性上的不稳定）。鉴于目前这两种分类法仍在广泛使用，EAU推荐目前WHO 1973,2004 两个版本可以同时使用；直到证明2004年更加合理。,膀胱癌的分期,膀胱肿瘤的分期指肿瘤的浸润深度及转移情况，是判断膀胱肿瘤预后的最有价值的参数。目前有两种主要分期方法。一种是美国的Jewett-Strong-Marshall分期法和美国癌症联合会分期法，另一
14、种为国际抗癌协会(The International Union Against Cancer，UICC)的TNM分期法。,膀胱癌的分期,这两种国际上流行的分类或分期系统已经历经半个世纪的发展和演变，虽日趋完善，仍还有不少争议和不尽人意之处，有待于进一步的完善。目前普遍采用国际抗癌协会的2002年第6版TNM分期法（表2）。,膀胱癌的TNM分期,根据膀胱镜检查、影像学所见、经尿道电切及组织病理学检查，可以把膀胱癌分为浅表性膀胱癌（Tis, Ta, T1)和浸润性膀胱癌(T2以上)两大组。浅表性膀胱癌指局限于黏膜层的乳头状肿瘤（Ta）或已经侵入固有膜的T1期膀胱癌。,膀胱癌的TNM分期,局限于黏
15、膜层的扁平状原位癌，虽然也属于浅表性膀胱癌，但与低级别Ta和T1期膀胱癌明显不同；原位癌分化差，属于高度恶性的肿瘤。它可能是浸润性膀胱癌的前身，如果不治疗，比绝大多数浅表性膀胱癌病变进展的几率要高得多22 。因此，应该将原位癌与浅表性膀胱癌加以区别。,表2 膀胱癌 2002 TNM 分期,膀胱癌的TNM分期-N分期,N ( 淋巴结)NX 区域淋巴结无法评估N0 无区域淋巴结转移N1 单个淋巴结转移，最大径小于或等于2 cmN2 单个淋巴结转移，最大径大于2 cm 但小于 5 cm ，或多个淋巴结转移，最大径小于5 cmN3 淋巴结转移，最大径超过 5 cm,膀胱癌的TNM分期-M分期,M 远处
16、转移MX 远处转移无法评估M0 无远处转移M1 远处转移,膀胱癌的TNM分期注意事项,T分期 TUR 和双合诊：TUR时, 要切到深肌层或膀胱周围脂肪组织，以识别膀胱癌的浸润深度。在男性，必须取前列腺尿道部活检；女性，膀胱颈部要取活检。此外，在经尿道膀胱癌电切前后，做双合诊识别有无可扪及的肿块，或了解肿瘤是否与骨盆壁固定。,膀胱癌的TNM分期,影像学：影像学检查的目的是识别局部肿瘤的范围，了解淋巴结和其他器官转移情况。如果考虑膀胱癌为浸润性癌，应该进行影像学检查。1）静脉法肾盂造影（IVP）：发现肾积水提示预后不良25 。,膀胱癌的TNM分期,2) CT: CT检查不能准确地区分限于器官和膀胱
17、外扩散的膀胱癌，CT发现和膀胱切除标本的符合率为65-80% 26,27。 3) 核磁共振 (MRI) MRI的诊断价值与CT相似，MRI不能识别膀胱周围脂肪的微小转移病变，分期误差约为30% 28，29 。,膀胱癌的TNM分期,2. N分期 CT和 MRI对淋巴结为转移的漏诊率高达70% 27，30,31。三维MRI 可能比较灵敏，但现有经验有限。正电子发射断层摄影术（Positron emission tomography ，PET)， 腹腔镜淋巴结切除的价值有待进一步探讨。目前，淋巴结切除活检是惟一能够排除淋巴结转移的方法。,膀胱癌的TNM分期,M分期 在制定治疗方案之前，必须确定是否存
18、在远处转移。所有病人必须行胸部X线检查，如果怀疑骨骼受累应行骨扫描检查，如果骨扫描发现可疑病变，可以做MRI可以确定骨转移病变32 。B超可以发现肝脏的转移。,浅表性膀胱癌-高危/低危的概念,浅表性膀胱癌在初期治疗后（TUR或膀胱部分切除）的主要问题是肿瘤的复发和进展。绝大多数浅表性膀胱癌发展为浸润性膀胱癌的几率不高，但高分级T1G3膀胱的复发进展率高达50% 34，35 。一些临床和病理参数可以预测膀胱癌复发和进展的危险3638 。 这些因素被称为浅表性膀胱癌的预后因素。,浅表性膀胱癌-高危/低危的概念,与膀胱癌复发相关的因素，按照重要性排列如下：1.初诊时肿瘤的数目。2.以前的复发率，3个
19、月复发率。3.肿瘤的大小，肿瘤愈大，复发的危险就愈高4.肿瘤的间变程度。,浅表性膀胱癌-高危/低危的概念,膀胱癌的间变程度和T分类是最重要的判断疾病进展的参数。膀胱颈部肿瘤比其他部位肿瘤预后差39 。按照预后因素，可以把浅表性膀胱癌分为低危、高危和中度危险3组。1.低危肿瘤：单个肿瘤、Ta,G1 直径小于3cm。2.高危肿瘤：T1,G3,多灶性或频繁复发，TIS3. 中度危险：所有其他肿瘤、Ta-T1, G1-G2,多灶性，直径大于3厘米。,参考文献,1. Mostofi FK, Sorbin LH, Torloni H. Histologic typing of urinary bladde
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