上海市徐汇区枫林街道社区卫生服务中心膀胱原位癌推荐专家

简介:

徐汇区枫林街道社区卫生服务中心，前身为宛平医院，自1951年7月1日创建以来，一直致力于为枫林地区居民提供全方位的医疗服务。作为一家拥有悠久历史和丰富经验的医疗机构，徐汇区枫林街道社区卫生服务中心现更名为宛平医院，秉承“六位一体”的服务理念，为社区居民提供医疗、预防、保健、康复、健康教育、计划生育技术指导等服务。在宛平医院，泌尿外科是重点科室之一，其中膀胱原位癌是泌尿系统中最常见的肿瘤。膀胱原位癌多数为移行上皮细胞癌，主要发生在膀胱侧壁及后壁，其次是三角区和顶部，甚至可能为多中心发生。膀胱肿瘤还可能伴有肾盂、输尿管、尿道肿瘤。在全球范围内，膀胱肿瘤的发病率在男性泌尿生殖器肿瘤中仅次于前列腺癌，位居第二；而在我国，膀胱肿瘤的发病率则位居首位。男性发病率为女性的3～4倍，患者年龄主要集中在50～70岁之间。宛平医院泌尿外科拥有一支专业、高效的医疗团队，科室医生数量众多，其中包括{{query}}位资深专家。在这些专家的带领下，科室在膀胱原位癌等泌尿系统疾病的治疗方面积累了丰富的临床经验，为患者提供了优质、高效的医疗服务。如果您或您的家人不幸患有相关疾病，欢迎来宛平医院泌尿外科就诊，我们将竭诚为您服务。膀胱原位癌是泌尿系统中最常见的肿瘤。多数为移行上皮细胞癌。在膀胱侧壁及后壁最多,其次为三角区和顶部,其发生可为多中心。膀胱肿瘤可先后或同时伴有肾盂、输尿管、尿道肿瘤。在国外,膀胱肿瘤的发病率在男性泌尿生殖器肿瘤中仅次于前列腺癌,居第2位；在国内则占首位。男性发病率为女性的3～4倍,年龄以50～70岁为多。本病组织类型上皮性肿瘤占95%,其中超过90%系移行上皮细胞癌。，①长期接触芳香族类的工种,如染料、皮革、橡胶、油漆工等,可出现较高的膀胱肿瘤发生率。②吸烟也是一种增加膀胱肿瘤发生率的原因。③体内色氨酸的代谢异常。④膀胱黏膜局部长期遭受刺激。⑤近年来某些药物也可诱发膀胱癌。⑥寄生虫病如发生在膀胱内,亦可诱发膀胱癌。，膀胱，1.手术治疗（1）尿道切除（TURBt）或电灼,对于表浅的膀胱肿瘤可采用经尿道切除或电灼。（2）膀胱部分切除术。（3）分次切除,多发的肿瘤可分次切除。（4）激光疗法。 2.非手术治疗（1）膀胱内注射BCG。（2）口服BCG。（3）膀胱内灌注丝裂霉素。（4）膀胱内灌注阿霉素。，膀胱结石,膀胱结核，少吃辛辣刺激性的食物,要多饮水，1.尿常规检查2.B型超声波检查3.膀胱镜检查4.膀胱造影5.静脉肾盂造影6.CT检查，。

true 韩威威主治医师

一级医院上海市徐汇区枫林街道社区卫生服务中心

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糖尿病、高血压、冠心病、骨质疏松、骨关节炎、脑梗死后遗症，内外妇儿等社区常见病多发病。您身边的家庭医生，为您的家庭健康保驾护航。

接诊医生：

2024-10-31 17:29:31

科普文章

晚期尿路上皮癌用药CP来了，欧盟认定

24年8月27日，有两个单抗上了欧盟热搜，那就是批准恩诺单抗（enfortumab vedotin，一种抗体药物偶联物 [ADC]）与帕博利珠单抗（pembrolizumab，一种 PD-1 抑制剂）被欧盟委员会批准了，可联合用于不可切除或转移性尿路上皮癌成人患者的一线治疗。

这项批准是基于 Ⅲ期KEYNOTE-A39的结果：与含铂化疗相比，恩诺单抗与帕博利珠单抗联合使用时，中位总生存期（OS）几乎能达到翻倍的效果，并且无进展生存期（PFS）显著延长。这个试验新高度给癌症治疗带来更多选择，研究人员顺便还发了个“新英格兰”，具体怎么做到的？来通过这篇文章快速揭秘。

KEYNOTE-A39研究发现新赛道？

在治疗局部晚期或转移性尿路上皮癌的赛道上，论起改善总体生存率这个指标，没有治疗手段敢叫板铂类药的化疗。研究者选出恩诺单抗和帕博利珠单抗这个CP，想观察二者在这个赛道上是否有奇效。用更为官宣的说法，该研究将比较这两个药与通常用于治疗该癌症的其他药物（标准治疗）的效果，而参与这个研究的患者的癌症已经发生了转移，已从他们的泌尿系统扩散到身体其他部分。

3张图带你看懂主要结果

研究的主要结果是无进展生存期（PFS）和总生成率（OS）这两个指标，联合治疗组纳入442个患者，化疗组纳入444个患者，我们直接跳过过程看结果，可以发现：

这种联合治疗的中位总生存期（OS）为31.5个月（95% CI: 25.4-未达到），而含铂化疗为16.1个月（95% CI: 13.9-18.3），死亡风险降低了53%（风险比[HR]=0.47；95%置信区间[CI]: 0.38-0.58；P<0.00001）。
联合治疗的中位无进展生存期（PFS）为12.5个月（95% CI: 10.4-16.6），而化疗为6.3个月（95% CI: 6.2-6.5），癌症进展或死亡的风险降低了55%（HR=0.45；95% CI: 0.38-0.54；P<0.00001）。

很多人在关注疗效的同时，也关注联合药物方案的安全性，一组安全数据出炉：在联合用药组，中位治疗周期数为12（范围1至46），而在化疗组为6（范围1至6）。在联合用药组，55.9%的患者发生了3级或更高级别的治疗相关不良事件，在化疗组这一比例为69.5%。

这里的3级或更高级别的不良事件，指的是如斑丘疹、高血糖、中性粒细胞减少、周围感觉神经病变、腹泻和贫血等。

临床试验方法

看到这么好的试验结果，你一定好奇这项开放标签、随机化、对照试验的方法，答案确实平平无奇的一般方法。赛道选的好，运动员选的好，研究者直接躺平：

实验组 A（Arm A）

干预/治疗: 恩诺单抗 + 帕博利珠单抗
- 药物: 恩诺单抗
  - 给药方式：每3周周期的第1天和第8天通过静脉注射(IV infusion)给药
- 药物: 帕博利珠单抗
  - 给药方式：每3周周期的第1天通过静脉注射给药

对照组 B（Arm B）

干预/治疗: 吉西他滨 + 顺铂或卡铂
- 药物: 顺铂
  - 给药方式：每3周周期的第1天通过静脉注射给药
- 药物: 卡铂
  - 给药方式：根据当地指南剂量，并在每3周周期的第1天通过静脉注射给药
- 药物: 吉西他滨
  - 给药方式：每3周周期的第1天和第8天通过静脉注射给药

实验组 C（Arm C，不招募）

干预/治疗: 恩诺单抗 + 帕博利珠单抗 + 顺铂或卡铂
- 药物: 恩诺单抗
  - 给药方式：每3周周期的第1天和第8天通过静脉注射给药
- 药物: 帕博利珠单抗
  - 给药方式：每3周周期的第1天通过静脉注射给药
- 药物: 顺铂
  - 给药方式：每3周周期的第1天通过静脉注射给药
- 药物: 卡铂
  - 给药方式：根据当地指南剂量，并在每3周周期的第1天通过静脉注射给药

再看恩诺单抗+帕博利珠单抗这对CP

恩诺单抗

适应证：

与帕博利珠单抗联合使用，适用于治疗成人局部晚期或转移性尿路上皮癌（mUC）患者。

PADCEV作为单药治疗，适用于治疗成人局部晚期或mUC患者，这些患者：

之前已经接受过程序性死亡受体-1（PD-1）或程序性死亡配体-1（PD-L1）抑制剂和含铂化疗，或者
不适合接受含顺铂的化疗，并且之前已经接受过一种或多种其他治疗方案。
注意事项：警告：严重的皮肤反应
恩诺单抗可引发严重的皮肤不良反应，包括史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN），这些反应主要发生在治疗的第一个周期，但也可能发生在之后。
密切监测患者是否出现皮肤反应。
怀疑SJS或TEN或严重皮肤反应时，立即暂停恩诺单抗使用，并考虑转诊进行专业护理。
在确诊SJS或TEN的患者中，或在出现4级或复发的3级皮肤反应的患者中，永久停止使用恩诺单抗。

帕博利珠单抗

适应证：

适应证较多，包括黑色素瘤、非小细胞肺癌（NSCLC）、头颈鳞状细胞癌（HNSCC）、经典霍奇金淋巴瘤（cHL）、原发性纵隔大B细胞淋巴瘤（PMBCL）、尿路上皮癌、高微卫星不稳定性或错配修复缺陷癌症（MSI-H/dMMR）、高微卫星不稳定性或错配修复缺陷结直肠癌（MSI-H/dMMR CRC）、胃癌、食管癌、宫颈癌、肝细胞癌（HCC）、胆道癌（BTC）、默克尔细胞癌（MCC）、肾细胞癌（RCC）、子宫内膜癌。

注意事项：

免疫介导的肺炎：可发生于3.4%的患者，可能需要使用皮质类固醇治疗。
免疫介导的结肠炎：可发生于1.7%的患者，可能伴有巨细胞病毒（CMV）感染。
肝毒性和免疫介导的肝炎：可发生于0.7%的患者，可能需要皮质类固醇治疗。
免疫介导的内分泌疾病：
- 肾上腺功能不全：可发生于0.8%的患者。
- 垂体炎：可发生于0.6%的患者。
- 甲状腺疾病：甲状腺炎、甲状腺功能亢进和甲状腺功能减退。
1型糖尿病：可发生于0.2%的患者，需要长期胰岛素治疗。
免疫介导的肾炎：可发生于0.3%的患者，可能需要皮质类固醇治疗。
免疫介导的皮肤病：如皮疹或湿疹，可发生于1.4%的患者。
其他免疫介导的不良反应：包括心肌炎、脑膜炎、血管炎、多发性神经炎、眼部炎症等。

其他获批：

其实早在这次获批前，美国药监局早已识得“英雄”，在2023年12月美国食品药品监督管理局（FDA）就实锤了恩诺单抗与帕博利珠单抗这对CP，可用于治疗成人局部晚期或转移性尿路上皮癌。

此外，欧盟对恩诺单抗似乎也是情有独钟，早在2022年4月就批准恩诺单抗作为单药治疗，用于治疗之前接受过含铂化疗和程序性死亡受体-1（PD-1）或程序性死亡配体-1（PD-L1）抑制剂的成人局部晚期或转移性尿路上皮癌患者。

关于尿路上皮癌

尿路上皮癌，也称为膀胱癌，起始于尿路上皮细胞，这些细胞覆盖在尿道、膀胱、输尿管、肾盂以及一些其他器官的内层。尿路上皮癌也可能出现在肾盂、输尿管和尿道。如果癌症无法通过手术进行治疗，就被称为不可切除。如果癌症已经扩散到周围的器官或肌肉，就被称为局部晚期疾病。如果癌症已经扩散到身体其他部位，就被称为转移性疾病。持续的治疗和监测使得膀胱癌成为患者一生中最昂贵的癌症类型之一，与其他恶性肿瘤相比，已被证明是成本最高的癌症。

关于安斯泰来制药

安斯泰来制药集团是一家制药企业，业务遍及全球70多个国家和地区。目前，其正在推进“焦点领域的研究策略”，旨在通过聚焦生理机制和治疗手段，确定持续研发新药的机会，解决尚未被满足的医疗需求。

与此同时，其正在将目光投向处方药以外的业务领域，将其专业技能和知识与不同领域外部合作伙伴的尖端技术相结合，打造RX+医疗解决方案。

参考文献：

European Commission Approves Astellas' PADCEV(enfortumab vedotin) in Combination with KEYTRUDA(pembrolizumab) for First-Line Treatment of Advanced Urothelial Cancer
Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. doi: 10.1056/NEJMoa2312117. PMID: 38446675.
Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302)
PADCEV EJFV- enfortumab vedotin injection, powder, lyophilized, for solution
KEYTRUDA- pembrolizumab injection, powder, lyophilized, for solution

得了膀胱癌不想切除膀胱怎么办？

治"泌"病，解"男"题 — 您身边的泌尿生殖专家

膀胱癌治疗的金标准是根治性膀胱切除术。但是，根治性手术仍存在以下几个主要问题：

①任何其他的人体组织器官都无法替代人体原有膀胱的功能。

②根治性膀胱切除属于大手术，技术较复杂，术后并发症较多，并非所有患者都能够耐受。

③根治性膀胱切除术后绝大部分患者性功能受到影响。

④无论各种改道方式都会伴有生活质量的降低，人格尊严也会受到影响。

如何解决这些问题？

北大泌尿男科朱鹤医生开展"钬激光"技术多年，已服务众多膀胱肿瘤患者，与传统膀胱肿瘤电切手术相比，钬激光膀胱肿瘤整块切除术具有以下优势：

1、安全性高

与经尿道膀胱肿瘤电切术相比，钬激光对人体组织的穿透深度很浅，故对周围组织热损伤小，组织穿透深度小于0.4mm，其余热损伤深度可达0.5～1.0mm，组织的凝固与坏死局限于3～4mm。不产生电切时的闭孔神经反射，可避免膀胱穿孔等损伤，安全性高。

膀胱肿瘤整块切除示意图

2、基底切除彻底

钬激光可以整块切除肿瘤，解剖层次清晰，基底切除彻底，减少肿瘤残留，避免了常规电切手术2-6周后二次电切的痛苦。

3、避免癌细胞的扩散

在剜除肿瘤前可封闭肿瘤蒂部周围的淋巴管、血管，剜除时不压迫肿瘤从而减少或避免癌细胞的扩散，避免癌细胞种植和转移。

4、出血少、创伤小

与传统电切手术相比，钬激光膀胱肿瘤剜除具有出血少、创伤小，视野清晰的优点。

膀胱肿瘤传统电切示意图

5、止血更为确切

特别适合年老体弱、有凝血机制障碍、安装心脏起搏器的患者也可耐受该手术，可以不停抗凝药进行手术。

各位病友可结合当地医疗机构设备情况，病人身体情况以及经济情况，选择最佳的医疗服务。

我的团队可协助您在当地完成手术治疗。

年近80岁的女性尿频是膀胱原位癌引起的

一位住在罗东的年近八十岁的老妇人，最近经常出现尿频问题，以为年纪大了，膀胱无力，并未注意。直到孩子照顾时发现带到医院，进一步去诊治发现她的尿频是膀胱原位癌引起的。幸运的是，药物治疗后，现在痊愈了。

尿频是老年人的常见症状。

这位78岁的老妇人尿频来看医生，尿频是老人常见的症状，特别是女性，不怎么看医生，但这位老妇人尿频症状严重，原来被其他医院认为是膀胱过动症。

细胞学检测+膀胱镜检测确诊。

但是，这位老妇人吃药治疗后，症状没有改善，效果不好，所以她又来了我们医院。首先检查尿液，发现没有感染，细胞学检查和膀胱镜检查，证明她患膀胱原位癌，以免疫疗法在膀胱内注入药物治疗后痊愈。

膀胱原位癌容易被误诊。

在这里我们要进一步说明，膀胱原位癌不易发现，容易误诊的主要是这种癌症在膀胱壁上生长，没有突起物，只有红炎的变化，必须切片进行细胞学检查。此外，膀胱原位癌与其他癌症相比，恶性度高，复发率高。因此，如果人们有频繁的尿液症状，不要忽视它。要尽快到医院进行确诊，如果药物治疗无效，应进一步检查和确认。

膀胱癌的日常护理措施。

健康的生活方式有助于远离疾病，正常的休息时间，合理的营养饮食计划，养成良好的生活习惯，平时多注意运动以及保持心情愉悦，避免更多的疾病发生，对酸性体质者，更应该及时调整。

平时，少吃脂肪、油腻和熏烤食物，加上必要的身体锻炼可以保持我们身体的弱碱性。倡导以清淡、营养、新鲜蔬菜为主要摄取，保证良好心情，严禁烟酒。在日常生活中，多喝水是预防疾病发生的最有效的方法，最好每天保持在2000ml左右的范围内。

膀胱癌的护理措施。

术后的食疗。

许多初期患者接受手术治疗，术后患者病情一定缓和，但免疫力下降。因此，手术后进行必要的食疗有助于促进疾病的恢复，恢复身体的抵抗力。

食疗坚固的方法：常用的薏米、红豆煮粥可以长期服用，不仅可以恢复体质，还可以预防复发现象的发生。也可以选择用水炖银耳的食疗方法，每天一次，也有很好的效果。

膀胱癌切除膀胱后怎么排尿

膀胱电切的恢复时间主要和膀胱病变有一定的关系的，对于良性的病变，例如膀胱息肉，恢复时间大约在 3 到 5 天左右，对于恶性的病变，例如膀胱癌，恢复时间大约在 7 到 10 天。

膀胱电切主要是用于膀胱浅表层的肿瘤，息肉，癌变的电切，通过膀胱镜经尿道进入膀胱内，一般来说良性的病变，术后并发症少，在及时应用药物预防感染，出血后就可以出院。

膀胱癌患者进行电切后，需要观察手术后有无出血，感染等问题，进行病理学检查，确定肿瘤的分型，并且需要根据相关的结果进行膀胱的灌洗治疗，注入化疗药物，需要延长治疗的时间的。

膀胱电切后注意尽量的多饮水，多排尿，可以有效的预防感染，活动的过程中注意不要牵拉到尿管。

膀胱电切手术后需要定期的进行膀胱镜的复查。

膀胱癌要切除膀胱吗？

膀胱癌是否需要切除膀胱主要是根据肿瘤的大小，发生的部位，有无远处的转移以及患者身体情况。

对于早期的膀胱癌的患者，肿瘤并没有侵犯到肌层，只在浅表层，可以通过经尿道的电切手术，烧灼肿瘤的位置，并不需要进行膀胱的切除的，此类手术伤口小，治愈率高，但是术后需要定期的进行膀胱的灌洗治疗，应用化疗药物，消除癌细胞。

对于频繁到肌层的膀胱癌，需要进行膀胱的全切手术，此类膀胱癌恶性程度高，容易发生转移，早期进行膀胱全切后可以有效的避免转移，延长存活时间，主要是通过腹腔镜切除，并且需要进行尿道的改道。

对于发生多处转移的老年患者，例如盆腔，骨，肺等转移，进行膀胱切除效果并不佳，建议通过姑息治疗，辅助放化疗，免疫疗法。

膀胱癌手术以后如何护理？

膀胱癌手术在泌尿外科算是一个很大的手术，因为膀胱癌手术以后的并发症很多，所以说术后护理很重要。

一、密切观察呼吸、心跳、体温，观察尿液的颜色、性质，记录 24 小时的尿量。

二、早期床上活动，取半卧位，防止下肢静脉血栓。

三、禁食直到肛门有放屁，先进食米汤，鸽子汤等流质，半流质（面条、稀饭）逐渐过渡到普食，另多饮水。勿进食使尿液味道过重的食物，另要清淡饮食，不要吃辛辣刺激性的食物。

四、心理护理很重要，家属应积极关注病人的心理变化，予以安慰支持正能量。

五、有部分患者术后在腹壁有收集尿液的造口、让患者平静接受造瘘袋带来身体外形的改变，并能自我管理造瘘袋，学会造口袋的更换。平时要观察造口形状、颜色、高度、大小，手术后造口（有些是输尿管壁组成，有些是肠管壁组成）是水肿而鲜红色的，如果发生灰暗、暗紫色时，可能血液供应受阻碍，需立刻告知医生和护士。造口袋与皮肤粘贴紧密，防止外渗形成皮炎或恶臭，一般 5 天左右更换一次。

六、密切观察造口袋内引流尿液或者尿道排出尿液的颜色，量，性状，一般尿色由血性逐渐变清澈，且伴有黏膜分泌物。

七、如有畏寒及发热，腰痛，脓尿，可能有尿路感染情况。应积极就医。如尿量减少，可能进食及补液不够，或发生造口狭窄，输尿管狭窄或尿瘘等并发症。

表浅膀胱癌如何治疗？

膀胱癌是泌尿系常见的肿瘤之一，严重影响人类的健康。其中表浅膀胱癌是最常见的类型。

表浅膀胱癌又称非肌层浸润性膀胱癌，肿瘤主要侵犯膀胱粘膜和黏膜固有层，临床上对于确诊的表浅膀胱肿瘤主要行经尿道膀胱肿瘤切除或者经尿道激光切除手术治疗，术后配合膀胱灌注化疗药物治疗可以减少和预防膀胱肿瘤的复发率，常用的化疗药物包括丝裂霉素、吡柔比星、羟基喜树碱。

表浅膀胱肿瘤复发率高，行经尿道膀胱肿瘤切除手术后，除了定期规律药物灌注化疗外，按照要求定期复查膀胱镜也是非常重要的。通过膀胱镜检查可以及时发现复发的肿瘤，对于复发的肿瘤，仍需要手术治疗，术后仍需要定期灌注治疗。

膀胱癌做了手术能活多久？

膀胱癌多数因无痛肉眼血尿被发现。

膀胱癌一般分为浅表性膀胱癌和浸润性膀胱癌，但多数是浅表性的。尽管医学科学发展到今天，膀胱癌的治疗效果有了很大的提高，但能治愈的手段唯有手术切除或其它外科方法将肿瘤消灭。外科手段能不能治愈膀胱癌呢？主要看以下几个方面。

1. 如何知道膀胱癌是早期还是晚期？膀胱癌的分期（早晚程度）。

主要看肿瘤的浸润深度和转移情况，浸润深度是肿瘤临床（T）和病理（P ）分期的依据。根据癌浸润膀肌壁的深度（乳头状瘤除外），多采用 TNM 分期标准分为：

Tis 原位癌
Ta 无浸润的乳头状癌
T1 浸润粘膜固有层
T2 ：浸润肌层，又分为 T2a 浸润浅肌层（肌层内 1 / 2 ) , T2b 浸润深肌层（肌层外 1 / 2 )
T3 浸润膀胱周围脂肪组织，又分为 T3a 显微镜下发现肿瘤侵犯膀胱周围组织；T3b 肉眼可见肿瘤侵犯膀胱周围组织；T 4；浸润前列腺、子宫、阴道及盆壁等邻近器官。临床上习惯将 Tis 、Ta、和 T 1，期肿瘤称为表浅膀胱癌一般属于早期肿瘤。

多数膀胱癌刚发生时都局限在膀胱最里层的粘膜内，恶性程度不高，为早期疾病。随着疾病严重程度逐步增加，癌细胞会逐步往外层侵犯（膀胱粘膜下层-肌层-浆膜层），最后侵犯周围邻近器官，有一些则转移扩散至远处器官（肝、肺、骨等部位）。一旦侵犯周围器官或转移，疾病就属于晚期，无法治愈。

淋巴转移是最主要的转移途径，主要转移到盆腔淋巴结，如闭孔、骼内、外及骼总淋巴结群。浸润浅肌层者约 50 ％淋巴管内有癌细胞，浸润深肌层者几乎全部淋巴管内有癌细胞，浸润至膀胱周围者，多数已有远处淋巴结转移。血行转移多在晚期，主要转移至肝、肺、骨和皮肤等处。肿瘤细胞分化不良者容易发生浸润和转移。

2. 如何反映膀胱癌的恶性程度？

主要看分化程度，1973 年，世界卫生组织（WHO ）根据膀胱肿瘤细胞的形态、结构特征和细胞间排列位置将其分为乳头状瘤；尿路上皮癌 1 级，分化良好，恶性程度较低；尿路上皮癌 11 级，中度分化，恶性程度中等；尿路上皮癌 111 级，分化不良，恶性程度较高。为了更好地反映肿瘤的危险倾向，2004 年，WHO 将膀胱等尿路上皮肿瘤分为乳头状瘤、乳头状低度恶性倾向的尿路上皮肿瘤、低级别乳头状尿路上皮癌（恶性程度较低）和高级别乳头状尿路上皮癌（恶性程度较高）。

3.肿瘤大小

肿瘤体积与复发有关。≤3cm 的肿瘤比＞3cm 肿瘤的复发率要低。

4.肿瘤形态

肿瘤形态比肿瘤体积更重要。乳头状肿瘤比实体（无蒂或结节状）肿瘤的预后更好。

5.肿瘤数目

多发的膀胱肿瘤治疗效果不佳。多发意味着膀胱存在广泛的异常，以后发生复发的风险相对较高。

6.肿瘤复发的时间

Tis 原位癌五年复发可能性 50%-90%；Ta，低级别五年复发可能性 50%；Ta，高级别五年复发可能性 60%；T1 低级别五年复发可能性 50%；T1 低级别五年复发可能性 50%-70%。

7.是否有原位癌

膀胱原位癌（Tis）：这些“扁平”的肿瘤局限于膀胱的粘膜内，具有多病灶、高分级、高侵袭性以及潜在致命的特点。肿瘤可呈红色毛茸状或颗粒状区域，有时膀胱镜下无法发现但在膀胱粘膜随机活检中可检出。如果患者存在弥漫性 Tis 同时伴有刺激症状，那么进展为侵袭性疾病的可能性高达 80%；对于局限性 Tis，没有刺激症状的患者，其进展可能性小于 10%。

8.非肌层浸润性膀胱癌危险度分型？

低危 NMIBC ：原发、单发、TaGl (低级别尿路上皮癌)、直径<3cm，没有 CIS 。

中危 NMIBC：所有不包含在低危和高危分类中的 NMIBC

高危 NMIBC 以下任何一项: ① T1 期肿瘤② G3(或高级别尿路上皮癌)③ CIS ④同时满足:多发、复发和直径>3cm 的 TaGIG2(或低级别尿路上皮癌)

低危患者 1 年复发率 15%，5 年 30%；中危组患者 1 年复发率 38%，5 年 62%；高危组患者 1 年复发率达 61%，5 年 78%。

9．膀胱癌自然病程

大部分膀胱癌患者确诊时处于分化良好或中等分化的非肌层浸润性膀胱癌，其中约 10%的患者最终发展为肌层浸润性膀胱癌或转移性膀胱癌。膀胱癌的大小、数目、分期与分级与其进展密切相关，尤其是分期与分级，低分期低分级肿瘤发生疾病进展的风险低于高分期高分级肿瘤。总体上说，T1 期膀胱癌发生肌肉浸润的风险要远高于 Ta 期。研究发现： G1 级膀胱癌出现进展的风险（6%）仅为 G3 级膀胱癌（30%）的 1/5。一组长达 20 年的随访资料发现，G3 级膀胱癌出现疾病进展风险更高，TaG1 膀胱癌为 14%，而 T1G3 则高达 45%，但是其复发的风险却相同，约为 50%。

各期膀胱癌患者 5 年生存率分别为 Ta-T1 期 91.9％、T2 期 84.3％、T3 期 43.9％、T4 期 10.2％。各分级膀胱癌患者 5 年生存率分别为 G1 级 91.4％、G2 级 82.7％、G3 级 62.6％。

晚期膀胱癌病人即使是外科治疗联合其它治疗，例如干扰素、白介素、分子靶向药物，以及免疫治疗，也只有少数人能长期生存，中位生存时间约 14 个月，而能够获得无肿瘤进展生存的患者约 15%；大部分病人会在 5 年内因肿瘤进展而失去生命。

不管膀胱癌到了那一期，积极争取外科手术治疗都有治愈的希望，只是越早期治愈的希望越大，越晚治愈的机会越小。

病例31-2023：一名79岁男性，身体不自主运动，一过性反应迟钝

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Carrie Chui (Neurology): A 79-year-old man was admitted to this hospital because of involuntary movements on the left side and transient unresponsiveness.

The patient had been in his usual state of health until 9 months before admission, when involuntary movements of the left shoulder and left side of the face developed. The movements were described by the patient as twitching, were not associated with a change in the level of consciousness, and resolved after 1 to 2 minutes. During the next 6 months, the patient had similar episodes approximately once per month, but the episodes increased in duration, lasting 5 to 6 minutes.

Three months before admission, the episodes of involuntary movements increased in frequency, and the patient was evaluated by his primary care physician. The physical examination was normal. Results of kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 129 mmol per liter (reference range, 135 to 145). There was a history of inappropriate antidiuretic hormone secretion, and the sodium level was similar to levels obtained during the past 4 years. Magnetic resonance imaging (MRI) of the head (Figure 1A), performed before and after the administration of intravenous contrast material, revealed a focus of enhancement in the right middle frontal gyrus that was thought to be a small vascular anomaly. Electroencephalography (EEG), performed with the patient in awake and drowsy states, revealed rare, brief, focal slowing in the left temporal lobe during drowsiness; no epileptiform abnormalities were present.

Figure 1

MRI of the Head and CT Angiogram of the Head and Neck.

Two months before admission, the patient was evaluated in the epilepsy clinic affiliated with this hospital. He reported that the episodes of involuntary movements had increased in both frequency and duration, occurring once or twice per day and lasting approximately 10 minutes. Episodes began with tingling and numbness in the left leg that prompted the patient to voluntarily stomp the left foot to relieve the uncomfortable sensation. Then, the patient had involuntary movements that he described as an uncontrollable invisible force moving the left leg and arm, with hyperextension of the arm backward and pronation of the wrist. There was associated numbness in the distal portions of the left third, fourth, and fifth fingers and involuntary movement of the left cheek. No prodromal symptoms occurred. The patient had awareness during the episodes, and after the episodes, he felt fatigued but had a normal level of consciousness, without confusion. The examination in the epilepsy clinic was normal. A diagnosis of seizure disorder was considered, and treatment with levetiracetam was started.

Three weeks before admission, the patient was again evaluated in the epilepsy clinic. He reported that the episodes of involuntary movements still occurred on a daily basis but had decreased in duration and involved only the left leg, without abnormal movements of the arm or face. Dizziness, headache, and weakness had developed and were attributed to the use of levetiracetam. The patient’s family had recorded a video of one of the episodes of involuntary movements. After reviewing the video, the patient’s neurologist thought that the episodes were less likely to be caused by seizures and more consistent with choreoathetoid movements. Cross-tapering of medications — with the simultaneous administration of levetiracetam in decreasing doses and clobazam in increasing doses — was initiated, and the patient was referred to the movement disorders clinic affiliated with this hospital.

On the morning of admission, an episode of involuntary movements of the left leg and left shoulder occurred and persisted for 1 hour. Several hours after the symptoms abated, the patient’s wife found the patient to be unresponsive; he was sitting in a chair. Emergency medical services were called, and when they arrived, the patient was responsive. The fingerstick blood glucose level was 180 mg per deciliter (10.0 mmol per liter) and the blood pressure 110/80 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the patient reported dysuria and increased urinary frequency. The patient’s daughter noted that he had been more anxious during the past 3 years and occasionally had trouble with memory. Other medical history included Barrett’s esophagus, benign prostatic hypertrophy, chronic hepatitis B virus infection, eczema, gastroesophageal reflux disease, hypertension, nonischemic cardiomyopathy, and osteoporosis. There was no history of head trauma or extended loss of consciousness. Medications included aspirin, atorvastatin, doxazosin, finasteride, omeprazole, metoprolol, sacubitril, and valsartan. There were no known drug allergies. The patient was a lifelong nonsmoker and drank alcohol rarely; he did not use illicit drugs. His mother had had gastric cancer, and his sister had had esophageal cancer; there was no family history of seizures.

On examination, the temporal temperature was 36.8°C, the blood pressure 152/97 mm Hg, the pulse 65 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 96% while the patient was breathing ambient air. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 21.7. The blood pressure decreased to 130/63 mm Hg with standing. The patient was alert and interactive. The lower jaw was held to the left, but the nasolabial folds and smile were symmetric with activation. There were nonrhythmic, nonstereotyped, writhing movements of the left arm. Tone was normal, and strength was assessed as 5 out of 5 in the arms and legs. Results of liver-function and kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 125 mmol per liter. The lactate level was 2.1 mmol per liter (19 mg per deciliter; reference range, 0.5 to 2.0 mmol per liter [5 to 18 mg per deciliter]). The urinalysis was normal. Intravenous fluids were administered. Imaging studies were obtained.

Dr. Rajiv Gupta: Computed tomographic (CT) angiography of the head and neck (Figure 1B) revealed extensively calcified plaque with severe stenosis of the distal right common carotid artery (CCA), extending into the proximal right internal carotid artery (ICA), as well as stenosis of the right and left paraclinoid ICAs and the left vertebral artery at its origin. There was no vascular abnormality on the CT angiogram that corresponded to the abnormality in the right middle frontal gyrus seen on the previous MRI.

Dr. Chui: The patient was admitted to the hospital. On the second hospital day, the sodium level had increased to 130 mmol per liter, and the lactate level was normal. Additional imaging studies were obtained.

Dr. Gupta: MRI of the head showed no evidence of acute infarction. The focus of enhancement in the right frontal lobe that had been noted previously was not seen on the current MRI.

Dr. Chui: Blood levels of thyrotropin, cobalamin, and glycated hemoglobin and results of coagulation tests were normal. Screening tests for Lyme disease, tuberculosis, and syphilis were negative, as were tests for antibodies to cardiolipin and β₂-glycoprotein. A test for antinuclear antibodies was positive, at a titer of 1:160 in a homogeneous pattern. During a physical therapy session, the patient had abnormal movements of the left leg, left arm, and left side of the face. The abnormal movements diminished when the patient used distraction techniques, such as thigh tapping, finger snapping, and walking while holding a glass of water.

The transient unresponsiveness that led to the patient’s admission was attributed to a combination of sedation from clobazam and hypovolemia. Treatment with clobazam was stopped, and hydration was encouraged. A diagnosis of functional neurologic disorder was considered; outpatient physical therapy with continued use of distraction techniques was recommended. The patient was discharged home on the third hospital day.

Episodes of involuntary movements continued to occur on a daily basis at home. Two weeks after discharge, when the patient was doing exercises while sitting in a chair and having a conversation with his wife, he suddenly stopped talking. She found him slumped in the chair with his eyes closed, no longer exercising. When she asked him questions, he repeatedly said “yes.” Emergency medical services were called, and when they arrived, the patient was alert, diaphoretic, and nonverbal. He had a facial droop on the left side and a right gaze preference. The fingerstick blood glucose level was 130 mg per deciliter (7.2 mmol per liter) and the blood pressure 120/60 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the temporal temperature was 36.6°C, the blood pressure 143/63 mm Hg, the pulse 66 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 98% while the patient was breathing ambient air. He was alert and interactive. There was a facial droop on the left side. There was no effort against gravity in the left arm. The patient was able to lift the left leg off the bed for 1 to 2 seconds. He had a right gaze deviation that could not be overcome and mild dysarthria. The remainder of the examination was normal. A diagnosis of stroke was considered, and emergency CT angiography was performed.

Dr. Gupta: CT angiography showed no evidence of acute territorial infarction and no changes in cerebrovascular disease.

Dr. Chui: On repeat physical examination performed after CT angiography, the gaze deviation and dysarthria had resolved, and strength was normal. Mild facial paralysis was present.

A diagnosis was made.

Differential Diagnosis

Dr. Albert Y. Hung: This 79-year-old man initially presented with involuntary movements of the left shoulder and face without associated loss of consciousness. Diagnosis of an unusual movement disorder, especially one that is present episodically, can be challenging. Videos brought in by the patient can be very useful.¹ Most movement disorders result from abnormal functioning of extrapyramidal circuits involving the basal ganglia, rather than a specific neuroanatomical lesion, and the first step toward diagnosis is to identify the type of abnormal movements.²

Four salient aspects of this patient’s involuntary movements can help in characterizing the movement disorder before generating a differential diagnosis. First, the movements were paroxysmal, lasting for short periods of time with resolution between episodes. Second, the movements were nonstereotyped, appearing randomly and variably. Third, the movements were restricted to the left side of his body throughout the course, localizing the disease process to the right cerebral hemisphere. Finally, the symptoms were progressive, increasing in both duration and frequency.

Movement Disorders

This patient had abnormal involuntary movements, symptoms indicative of a hyperkinetic movement disorder. Tremor, the most common hyperkinetic disorder, is unlikely because the patient did not have rhythmic movements. Dystonia is also unlikely, because he did not have sustained muscle contractions that were causing twisting or abnormal postures of the legs, arms, head, neck, or face. Although the patient initially described the movements as twitching, his later descriptions are not suggestive of myoclonus or tics, which manifest as sudden, rapid, recurrent movements.

This patient’s neurologist described the involuntary movements as “choreoathetoid” after reviewing a video of an episode. Chorea, athetosis, and ballism make up a spectrum of involuntary movements that often occur in combination. Chorea refers to involuntary movements that are “dancelike” — irregular, random, unintended, and flowing from one body part to another. When these movements are slow and writhing (with a lower amplitude) and involve the distal limbs, the term athetosis is used. The presence of both chorea and athetosis in the same patient is referred to as choreoathetosis. When the movements are fast and flinging (with a higher amplitude) and involve the proximal limbs, the term ballism is used. Although the description of this patient’s movements was not clearly suggestive of ballism, hemichorea and hemiballismus often occur together.

The term dyskinesia can refer to any abnormal movements and is often used to describe hyperkinetic disorders that are induced by specific drugs, such as tardive dyskinesia induced by dopamine antagonists or dyskinesia induced by levodopa in patients with Parkinson’s disease. Often, dyskinesia manifests as chorea or choreoathetoid movements, but chorea and dyskinesia are not synonymous. This patient appears to have involuntary dyskinesia with choreoathetosis as the primary phenomenology. Before constructing a differential diagnosis for dyskinesia in this patient, I will consider two conditions that mimic dyskinesia: seizures and functional movement disorder.

Seizures

Various movement disorders may be mistaken for seizures, although these movement disorders are not associated with EEG abnormalities during the episode. Patients with some forms of epilepsy may present with abnormal movements without other features that are typically associated with seizures, such as aura, change in responsiveness, incontinence, or a postictal state.^3,4 Seizures were initially suspected in this patient, and he was referred to the epilepsy clinic. Recurrent focal seizures were probably suspected because of the transient nature of the episodes. Initial MRI had shown a small abnormality in the right middle frontal gyrus, but this finding was not seen on follow-up imaging, which makes it unlikely to be related to the overall presentation. Baseline EEG had shown only brief left temporal slowing, without epileptiform abnormalities. The EEG was an interictal study, so the findings do not rule out seizures. However, the slowing was ipsilateral to the abnormal movements, so it is unlikely to be related to the episodes. In addition, the patient’s involuntary movements were nonstereotyped and nonrhythmic, which makes his presentation unlikely to be due to a seizure disorder.

Functional Movement Disorder

Because this patient’s movements diminished with the use of distraction techniques, a diagnosis of functional movement disorder was considered. Most cases of functional movement disorder begin abruptly after a trigger, such as a mild physical injury or illness; a psychological stressor can be present but is not required for diagnosis. Symptoms are typically most severe around the time of onset and may wax and wane over time. Although distractibility is a finding associated with functional disorders, abnormal movements that occur with nonfunctional syndromes can sometimes be suppressed by action or incorporated into voluntary movements in a manner that may appear distractible. Several clinical features in this patient make a diagnosis of functional disorder unlikely. Functional movement disorder is more common in women than in men, and the average age at onset is 40 years.⁵ In addition, tremor is the most common clinical phenotype seen in patients with functional movement disorder; chorea or choreoathetosis, which was seen in this patient, is very unusual in patients with functional movement disorder. Overall, functional movement disorder is unlikely to explain this patient’s presentation.

Dyskinesia

Primary paroxysmal dyskinesia refers to a group of heterogeneous syndromes characterized by recurrent involuntary movements that occur episodically and abruptly, without loss of consciousness.⁶ These disorders usually begin in childhood or young adulthood. Both the age of this patient and the described phenomenology make a diagnosis of primary paroxysmal dyskinesia unlikely.

The differential diagnosis in this case is therefore focused on causes of secondary dyskinesia, of which there are many.⁷ MRI ruled out the presence of a mass lesion suggestive of cancer. The patient had no history of acute illness suggestive of a viral or other infectious encephalitis, and there was no history of trauma or exposure to drugs or other toxins. Although his daughter mentioned trouble with memory, there was no compelling history suggestive of a neurodegenerative disease.

A common metabolic cause of secondary dyskinesia is diabetic striatopathy, a syndrome involving the acute-to-subacute onset of chorea and ballism in the context of hyperglycemia.⁸ This syndrome can occur as the initial manifestation of type 2 diabetes mellitus or as a complication of poorly controlled diabetes. Diabetic striatopathy is more likely to develop in women than in men, and the average age at onset is 70 years. Most patients present with hemichorea and hemiballismus, rather than bilateral symptoms. CT shows hyperdensity, and T1-weighted MRI shows hyperintensity, in the contralateral basal ganglia. However, this patient had no history of diabetes and had a normal blood glycated hemoglobin level, features that rule out a diagnosis of diabetic striatopathy.

Choreiform movements can also be a manifestation of autoimmune conditions.⁹ This patient’s initial presentation with unilateral shoulder and face movements would have suggested the possibility of faciobrachial dystonic seizures associated with anti–leucine-rich, glioma-inactivated 1 (anti-LGI1) encephalitis.¹⁰ This condition is often associated with hyponatremia, which was present in this patient. However, as the case evolved, leg involvement and sensory changes developed that would be atypical for anti-LGI1 encephalitis.

One key clue in this case is that the patient did not have an isolated movement disorder. In addition to motor symptoms, he had a variety of sensory symptoms involving both the left arm and the left leg. His first hospital admission was precipitated by an episode of unresponsiveness. The clinical event that led to his second presentation to the emergency department was distinctly different: an acute onset of speech difficulty accompanied by left hemiparesis and right gaze deviation that was worrisome for an acute right middle cerebral artery (MCA) syndrome. The symptoms resolved without intervention, which indicates that he may have had an acute transient ischemic attack (TIA). The most relevant imaging finding was severe cerebrovascular disease, including severe stenosis of the distal right CCA and proximal right ICA. Could this patient’s movement disorder be explained by a vascular lesion?

Limb-Shaking TIAs

Limb-shaking TIAs were first described by C. Miller Fisher in 1962.¹¹ In most case reports, these episodes are associated with high-grade stenosis of the ICA, which was seen in this patient.^12,13 The mechanism is thought to be cerebral hypoperfusion, and changes in posture or head position that decrease cerebral blood flow can precipitate these episodes. In this patient, the first episode of unresponsiveness that led to hospital admission occurred when he was sitting. He then had an acute episode involving right gaze preference that was provoked by exercise and was very suggestive of a TIA in the right MCA territory. These findings are highly suggestive of a diagnosis of limb-shaking TIAs, and I would refer this patient for emergency carotid endarterectomy.

Clinical Impression and Initial Management

Dr. Scott B. Silverman: When I evaluated this patient, his transient right gaze preference and left hemiparesis were consistent with a right MCA syndrome due to a TIA from symptomatic severe stenosis of the right ICA. The mechanism of this event was either artery-to-artery embolism or hypoperfusion. His previous, recurrent episodes of transient choreoathetosis on the left side that had occurred mainly while he was sitting, standing, or exercising were consistent with limb-shaking TIAs from hypoperfusion or low flow.

The pathogenesis of a low-flow state related to severe carotid stenosis resulting in limb-shaking TIAs is described in a small case series.¹⁴ In six out of eight patients, the transient, stereotyped, involuntary movements were eliminated with carotid artery revascularization. Positional cerebral ischemia in patients without orthostatic hypotension has been described.¹⁵

Treatment with atorvastatin was continued, the dose of aspirin was increased to 325 mg per day, and an intravenous heparin infusion was started. The strategy of permissive hypertension was used, with high blood pressure allowed to a maximum systolic blood pressure of 180 mm Hg. The patient was admitted to the stroke service, and carotid artery duplex ultrasonography was performed.

Dr. Gupta: Doppler ultrasonography of the carotid arteries (Figure 2) revealed markedly elevated Doppler flow velocities within the proximal right ICA. There was a parvus et tardus waveform in the distal right ICA, a finding indicative of low flow related to the more proximal high-grade stenosis. The Doppler waveform contours had poststenotic turbulence.

Figure 2

Doppler Ultrasound Image.

Dr. Silverman: The vascular surgery service was consulted, and the patient underwent right carotid endarterectomy.

Clinical Diagnosis

Limb-shaking transient ischemic attacks.

Dr. Albert Y. Hung’s Diagnosis

Limb-shaking transient ischemic attacks due to severe carotid stenosis, with secondary paroxysmal dyskinesia.

Pathological Discussion

Dr. Caroline F. Hilburn: The endarterectomy specimen included the carotid bifurcation and was notable for firm arterial walls, a finding consistent with calcification. On gross examination (Figure 3A), a large plaque was centered at the carotid bifurcation and protruded into the lumen, resulting in a maximal luminal stenosis of 80%. The plaque had an irregular and focally friable surface. On microscopic examination (Figure 3B), the plaque was characterized by extensive calcification. Some regions of the plaque had a smooth, healed fibrous cap, whereas other regions had an irregular surface suggestive of ulceration, which indicated potential sites of plaque rupture. Multiple smaller calcified plaques were present, affecting both branches of the artery.

Figure 3

Endarterectomy Specimen.

Pathological Diagnosis

Complex atherosclerotic plaque with portions of attached media.

Additional Management

Dr. Silverman: After the procedure, the patient had an uneventful recovery and was discharged home on the fifth hospital day. He was seen 1 month after discharge in the stroke prevention clinic. There had been no further episodes of involuntary movements or choreoathetosis and no stroke or TIA. The patient continues to take aspirin, atorvastatin, and antihypertensive medications.

Final Diagnosis

Limb-shaking transient ischemic attacks.

病例28-2024：一名75岁女性，患有水肿、关节炎和蛋白尿

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Christine M. Parsons (Medicine): A 75-year-old woman was evaluated at this hospital because of arthritis, abdominal pain, edema, malaise, and fever.

Three weeks before the current admission, the patient noticed waxing and waning “throbbing” pain in the right upper abdomen, which she rated at 9 (on a scale of 0 to 10, with 10 indicating the most severe pain) at its maximal intensity. The pain was associated with nausea and fever with a temperature of up to 39.0°C. Pain worsened after food consumption and was relieved with acetaminophen. During the 3 weeks before the current admission, edema developed in both legs; it had started at the ankles and gradually progressed upward to the hips. When the edema began to affect her ambulation, she presented to the emergency department of this hospital.

A review of systems that was obtained from the patient and her family was notable for intermittent fever, abdominal bloating, anorexia, and fatigue that had progressed during the previous 3 weeks. The patient reported new orthopnea and nonproductive cough. Approximately 4 weeks earlier, she had had diarrhea for several days. During the 6 weeks before the current admission, the patient had lost 9 kg unintentionally; she also had had pain in the wrists and hands, 3 days of burning and dryness of the eyes, and diffuse myalgias. She had not had night sweats, dry mouth, jaw claudication, vision changes, urinary symptoms, or oral, nasal, or genital ulcers.

The patient’s medical history was notable for multiple myeloma (for which treatment with thalidomide and melphalan had been initiated 2 years earlier and was stopped approximately 1 year before the current admission); hypothyroidism; chikungunya virus infection (diagnosed 7 years earlier); seropositive erosive rheumatoid arthritis affecting the hands, wrists, elbows, and shoulders (diagnosed 3 years earlier); vitiligo; and osteoarthritis of the right hip, for which she had undergone arthroplasty. Evidence of gastritis was reportedly seen on endoscopy that had been performed 6 months earlier. Medications included daily treatment with levothyroxine and acetaminophen and pipazethate hydrochloride as needed for cough. The patient consumed chamomile and horsetail herbal teas. She had no known allergies to medications, but she had been advised not to take nonsteroidal antiinflammatory drugs after her diagnosis of multiple myeloma.

Approximately 5 months before the current admission, the patient had emigrated from Central America. She lived with her daughter and grandchildren in an urban area of New England. She had previously worked in health care. She had no history of alcohol, tobacco, or other substance use. There was no family history of cancer or autoimmune, renal, gastrointestinal, pulmonary, or cardiac disease.

On examination, the temporal temperature was 37.1°C, the heart rate 106 beats per minute, the blood pressure 152/67 mm Hg, and the oxygen saturation 100% while the patient was breathing ambient air. She had a frail appearance and bitemporal cachexia. The weight was 41 kg and the body-mass index (the weight in kilograms divided by the square of the height in meters) 15.2. Her dentition was poor; most of the teeth were missing, caries were present in the remaining teeth, and the mucous membranes were dry. She had abdominal tenderness on the right side and mild abdominal distention, without organomegaly or guarding. Bilateral axillary lymphadenopathy was palpable. Infrequent inspiratory wheezing was noted.

The patient had swan-neck deformity, boutonnière deformity, ulnar deviation, and distal hyperextensibility of the thumbs (Fig. 1). Subcutaneous nodules were observed on the proximal interphalangeal joints of the second and third fingers of the right hand and on the proximal interphalangeal joint of the fourth finger of the left hand. Synovial thickening of the metacarpophalangeal joints of the second fingers was noted. There was mild swelling and tenderness of the wrists. She had pain with flexion of the shoulders and right hip, and there was subtle swelling of the shoulders and right knee. Pitting edema (3+) and vitiligo were noted on the legs. No sclerodactyly, digital pitting, telangiectasias, appreciable calcinosis, nodules, nail changes (including pitting), or tophi were present. The remainder of the examination was normal.

Figure 1

Photograph of the Hands.

The blood levels of glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin, globulin, lactate, lipase, magnesium, and phosphorus were normal, as were the prothrombin time and international normalized ratio; other laboratory test results are shown in Table 1. Urinalysis showed 3+ protein and 3+ blood, and microscopic examination of the sediment revealed 5 to 10 red cells per high-power field and granular casts. Urine and blood were obtained for culture. An electrocardiogram met (at a borderline level) the voltage criteria for left ventricular hypertrophy.

Table 1

Laboratory Data.

Dr. Rene Balza Romero: Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous administration of contrast material, revealed scattered subcentimeter pulmonary nodules (including clusters in the right middle lobe and patchy and ground-glass opacities in the left upper lobe), trace pleural effusion in the left lung, coronary and valvular calcifications, and trace pericardial effusion, ascites, and anasarca. The scans also showed slight enlargement of the axillary lymph nodes (up to 11 mm in the short axis) bilaterally and a chronic-appearing compression fracture involving the T12 vertebral body.

Dr. Parsons: Morphine and lactated Ringer’s solution were administered intravenously. On the second day in the emergency department (also referred to as hospital day 2), the blood levels of haptoglobin, folate, and vitamin B₁₂ were normal; other laboratory test results are shown in Table 1. A rapid antigen test for malaria was positive. Wright–Giemsa staining of thick and thin peripheral-blood smears was negative for parasites; the smears also showed Döhle bodies and basophilic stippling. Antigliadin antibodies and anti–tissue transglutaminase antibodies were not detected. Tests for hepatitis A IgG and hepatitis C antibodies were positive. Tests for hepatitis B core and surface antibodies were negative. A test for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was negative.

Findings on abdominal ultrasound imaging performed on the second day (Fig. 2A and 2B) were notable for a small volume of ascites and kidneys with echogenic parenchyma. Ultrasonography of the legs showed no deep venous thrombosis. An echocardiogram showed normal ventricular size and function, aortic sclerosis with mild aortic insufficiency, moderate tricuspid regurgitation, a right ventricular systolic pressure of 39 mm Hg, and a small circumferential pericardial effusion. Intravenous hydromorphone was administered, and the patient was admitted to the hospital.

Figure 2

Imaging Studies of the Abdomen and Hands.

On the third day (also referred to as hospital day 3), nucleic acid testing for cytomegalovirus, Epstein–Barr virus, and hepatitis C virus was negative, and a stool antigen test for Helicobacter pylori was negative. An interferon-γ release assay for Mycobacterium tuberculosis was also negative. Oral acetaminophen and ivermectin and intravenous hydromorphone and furosemide were administered.

Dr. Balza Romero: Radiographs of the hands (Fig. 2C through 2F) showed joint-space narrowing of both radiocarpal joints and proximal interphalangeal erosions involving both hands. Radiographs of the shoulders showed arthritis of the glenohumeral joint and alignment suggestive of a tear of the right rotator cuff. A radiograph of the pelvis showed diffuse joint-space narrowing of the left hip, without osteophytosis, and an intact right hip prosthesis.

Dr. Parsons: Diagnostic tests were performed, and management decisions were made.

Differential Diagnosis

Dr. Beth L. Jonas: This patient is a 75-year-old woman who recently emigrated from Central America. She presented to this hospital with a multisystem disease involving the respiratory, gastrointestinal, renal, and musculoskeletal systems. Her medical history is notable for seropositive erosive rheumatoid arthritis and multiple myeloma, which had been treated with melphalan and thalidomide. Relevant clinical features on presentation include unintended weight loss and cachexia, axillary lymphadenopathy, serositis, cytopenia in two cell lines, hypocomplementemia, and elevated serum free kappa and lambda light-chain levels (with a normal free light-chain ratio) with no monoclonal spike. The white-cell count was elevated, but she had no eosinophilia. CT images of the chest showed scattered subcentimeter pulmonary nodules. With respect to the patient’s anemia, no schistocytes were present, the haptoglobin level was normal, and the iron studies were unremarkable. These findings, in combination with the elevated ferritin level, indicate anemia of chronic inflammation. The renal findings are most salient in the context of the patient’s hypertension, anasarca, elevated cystatin C level, active urinary sediment with proteinuria in the nephrotic range, and small, echogenic kidneys on ultrasonography.

In constructing a differential diagnosis, I will consider medication use, cancer, infectious disease, and autoimmune disease. Medications can be eliminated as the cause of this patient’s illness, since she was taking only levothyroxine, acetaminophen, and the antitussive agent pipazethate.

Cancer

The patient has a history of multiple myeloma, which may manifest with a multisystem disease involving the kidneys, but serum protein electrophoresis showed no monoclonal protein. Given the presence of nephrotic syndrome in the context of multiple myeloma, systemic immunoglobulin light-chain amyloidosis would be highest on the differential diagnosis with respect to cancer; however, the patient’s normal light-chain ratio makes this diagnosis unlikely. The development of myeloid neoplasms, such as acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, is important to consider in the context of previous treatment with alkylating agents,¹ which this patient had received. However, the peripheral-blood smear showed no findings that would indicate a hematologic cancer, and such a diagnosis would not explain the patient’s acute kidney injury with nephrotic-range proteinuria.

Infectious Disease

Several features of this patient’s case warrant special consideration, including her history of immunosuppression due to rheumatoid arthritis and to previously treated myeloma, along with the fact that she had emigrated from Central America, where certain infections may be prevalent. Infection with hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV-1 and HIV-2, cytomegalovirus, Epstein–Barr virus, H. pylori, and M. tuberculosis can be ruled out on the basis of laboratory studies. A rapid antigen test for plasmodium species was reported to be positive, but this assay has a known cross-reactivity with rheumatoid factor.² Moreover, the thick and thin peripheral-blood smears were negative. Thus, malaria would be an unlikely diagnosis.

The patient has a history of infection with chikungunya virus, an arbovirus transmitted by a mosquito vector that has been responsible for large epidemics in the Americas since 2013.³ Acute symptoms include fever, rash, arthralgia, and myalgia. The development of a chronic arthritis that may meet the classification criteria for rheumatoid arthritis, as defined by the American College of Rheumatology and the European Alliance of Associations for Rheumatology, has been reported in up to 60% of patients infected with chikungunya virus.^4,5 In the context of this discussion, I considered whether chikungunya virus infection could be the cause of this patient’s symptoms, since this infection occurred before the diagnosis of rheumatoid arthritis. However, the degree of erosion and loss of joint space that was visible on radiographs would be most unusual for arthritis associated with chikungunya virus infection and would not explain the renal manifestations.

Strongyloidiasis is a helminth infection (caused by Strongyloides stercoralis) that is widespread in developing countries. Infection usually occurs through contact with soil, and most affected persons are asymptomatic. However, in immunosuppressed persons, strongyloides hyperinfection syndrome or a disseminated infection can develop as a consequence of accelerated autoinfection.⁶ The clinical presentation of strongyloides hyperinfection syndrome can include gastrointestinal symptoms (diarrhea, constipation, nausea, or vomiting), respiratory symptoms (cough, dyspnea, or wheezing), and rash due to migration of larvae through the subcutaneous tissues. Of note, only a minority of patients present with eosinophilia. Several case reports describe the development of nephrotic-range proteinuria, thrombotic microangiopathy, and IgA vasculitis in patients with strongyloides hyperinfection syndrome.^7-9 However, strongyloidiasis would not explain this patient’s cytopenias and hypocomplementemia.

Autoimmune Disease

The patient has a 3-year history of rheumatoid arthritis, although her clinical features of swan-neck deformity, boutonnière deformity, and joint instability suggest a longer duration of disease. We do not know whether she had received previous treatment with disease-modifying antirheumatic drugs or biologic agents, but the possible use of such treatments may be a consideration with respect to her progression of disease and overall degree of immunosuppression. The blood levels of rheumatoid factor and anti–cyclic citrullinated peptide antibodies were elevated, and radiographs of the hands showed erosive disease, although there was a relative paucity of metacarpophalangeal findings. A review of systems was negative for dry mouth, but her physical examination showed poor dentition and dry mouth — findings that make secondary Sjögren’s syndrome a consideration.

Renal disease can occur in patients with Sjögren’s syndrome. The two most typical presentations are tubulointerstitial nephritis and, less commonly, nephritic syndrome (membranoproliferative glomerulonephritis related to cryoglobulinemia). Tubulointerstitial nephritis may manifest with renal disease of varying severity, usually with a bland urinary sediment and often with abnormalities of tubular function such as distal renal tubular acidosis. Membranoproliferative glomerulonephritis caused by cryoglobulinemia is the most common glomerular disease associated with Sjögren’s syndrome. Although nephrotic-range proteinuria can occur with Sjögren’s syndrome, it is relatively uncommon.¹⁰ Renal disease is uncommon in patients with rheumatoid arthritis and is usually related to coexisting cardiovascular conditions. Medications used in the treatment of autoimmune disease — mainly nonsteroidal antiinflammatory drugs — may be associated with renal disease, but I would not expect the presence of an active urinary sediment, as was seen in this patient.

Amyloid A (AA) amyloidosis, a condition that is rare in the era of aggressive management of rheumatoid arthritis, has been described in patients with severe, long-standing seropositive erosive rheumatoid arthritis. Serum amyloid A (SAA) is a protein that is produced in the liver in response to chronic inflammation associated with interleukin-1, interleukin-6, and tumor necrosis factor α (TNF-α) in the context of chronic infections, autoimmune disease (classically rheumatoid arthritis), autoinflammatory disease, and cancers including renal cell carcinoma and non-Hodgkin’s lymphoma.¹¹ Signs and symptoms of AA amyloidosis are related to the deposition of the protein in organs, and patients often present with multisystem signs and symptoms. The kidney is the organ that is most often affected, but deposition can occur in the heart, gastrointestinal tract, nervous system, musculoskeletal system, and lungs. Proteinuria is the first clinical manifestation in almost 95% of patients with AA amyloidosis, and 50% of affected patients present with nephrotic syndrome.¹² The urinary sediment is generally bland, and complement levels in the blood are normal. AA amyloidosis remains on the differential diagnosis in this patient, but it would not completely explain her renal disease.

Hypocomplementemia

The key to this case is understanding the cause of this patient’s hypocomplementemia. Hypocomplementemia can be due to decreased complement production in the context of liver disease, congenital complement deficiency, or increased complement consumption resulting from activation of the innate immune system. This patient has no history of chronic liver disease and her laboratory test results indicated good hepatic synthetic function. Classical complement deficiency (including C4 deficiency) that begins early in life is associated with autoimmune disease, and early C3 deficiency is characterized by severe pyogenic infections. It would be unusual for a patient of this age to be deficient in both C3 and C4 without earlier clinical consequences. I therefore concluded that the hypocomplementemia in this case was related to complement consumption.

Rheumatic diseases that may be associated with prominent renal manifestations include antineutrophil cytoplasmic antibody–associated vasculitis, systemic sclerosis with renal crisis, cryoglobulinemic vasculitis, antiglomerular basement membrane disease, and systemic lupus erythematosus (SLE). Of those conditions, SLE would be the most likely to be manifested by an active urinary sediment and nephrotic-range proteinuria with consumption of both C3 and C4 in the context of fever, thrombocytopenia, and serositis. This patient’s fever, thrombocytopenia, and serositis also fit with this diagnosis.¹³

Because the patient has long-standing seropositive erosive rheumatoid arthritis, a diagnosis of AA amyloidosis is strongly suspected. Moreover, given the presence of thrombocytopenia, hypocomplementemia, and an active urinary sediment, I would recommend a kidney biopsy to evaluate for lupus nephritis and AA amyloidosis.

Dr. Beth L. Jonas’s Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus with amyloid A amyloidosis.

Pathological Discussion

Dr. Claire Trivin-Avillach: Testing for autoimmune antibodies was performed. A test for antinuclear antibodies was positive at a titer of 1:5120 with a homogeneous pattern, and a test for anti–double-stranded DNA antibodies was positive at a titer of 1:2560.

The diagnostic procedure in this case was a core-needle biopsy of the kidney. Examination of the specimen with light microscopy revealed 20 glomeruli, 45% of which were globally sclerosed, along with fibrosis involving approximately 60% of the interstitium and tubular atrophy. Diffusely enlarged glomeruli with thickened capillary walls and an expanded mesangium were weakly positive on periodic acid–Schiff staining; the glomeruli stained pale blue on Masson’s trichrome staining. Congo red staining revealed metachromatic salmon-colored deposition involving the glomeruli, the blood-vessel walls, and the interstitium, which was associated with apple-green birefringence when viewed under polarized light (Fig. 3A). In addition, mesangial and endocapillary hypercellularity was identified in approximately 30% of the nonsclerosed glomeruli and was associated with karyorrhexis (Fig. 3B). One cellular crescent was also detected. These features are characteristic of active proliferative glomerulonephritis.

Figure 3

Biopsy Specimen of the Kidney.

Immunofluorescence microscopy revealed prominent granular staining for IgG (4+), IgM (4+), C3 (3+), C1q (3+), IgA (1+), kappa (3+), and lambda (3+) along the glomerular basement membranes and within the mesangium, as well as focal granular deposits of IgG and C3 along the tubular basement membrane (Fig. 3C and 3D). Additional immunofluorescence studies showed strong positivity (4+) for SAA within the glomeruli, the blood-vessel walls, and the interstitium (Fig. 3E), whereas staining for beta₂-microglobulin, transthyretin, and apolipoprotein A1 was faint.

Electron microscopy revealed the presence of subendothelial and mesangial electron-dense deposits (with no substructure identified) adjacent to randomly arranged fibrils (measuring 8.2 to 10.6 nm in diameter) within the glomerular basement membranes and the mesangium (Fig. 3F). Glomerular endothelial cells appeared reactive and contained tubuloreticular inclusions, features that were suggestive of interferon-mediated activation.

The findings on Congo red staining were characteristic of amyloidosis with typical birefringent material. The strong positivity of SAA within the deposits as compared with the faint staining of other reactants identified the type of amyloid as SAA, which is consistent with the patient’s history of rheumatoid arthritis. The biopsy also showed an immune complex–mediated proliferative glomerulonephritis with a “full house” pattern (defined as positivity for the three immunoglobulin classes IgG, IgM, and IgA and the two complement components C3 and C1q, in reference to the “full house” hand in a poker game). Immune complex–mediated proliferative glomerulonephritis has been reported in patients with rheumatoid arthritis who were receiving anti–TNF-α therapy,¹⁴ which was not the case in this patient. The positive test for hepatitis C antibodies prompted consideration of hepatitis C–related membranoproliferative glomerulonephritis. However, taken together, the negative nucleic acid test for hepatitis C virus, the full house pattern on immunofluorescence, the tubular basement membrane deposits, and the positive test for anti–double-stranded DNA antibodies favor a diagnosis of lupus nephritis of at least class III (defined as focal proliferative glomerulonephritis), according to the criteria of the International Society of Nephrology and the Renal Pathology Society, superimposed on AA amyloidosis.

Pathological Diagnosis

Proliferative lupus nephritis of International Society of Nephrology and Renal Pathology Society class III, superimposed on amyloid A amyloidosis.

Discussion of Management

Dr. Pui W. Cheung: On the basis of the finding of echogenic kidneys on ultrasonography and the findings of extensive interstitial fibrosis and tubular atrophy on kidney biopsy, we know that this patient has advanced chronic kidney disease that is unlikely to be reversible. The patient is also noted to have a markedly lower glomerular filtration rate (GFR) than that predicted by the blood creatinine level owing to the presence of cachexia, and this is substantiated by the cystatin C–based GFR and a 24-hour creatinine clearance of 22 ml per minute per 1.73 m² of body-surface area. The typical induction therapy for stage III or IV lupus nephritis consists of high-dose glucocorticoids and either mycophenolate mofetil or cyclophosphamide. Other reasonable alternatives for initial therapy include mycophenolate mofetil in combination with either a calcineurin inhibitor or belimumab, or cyclophosphamide in combination with belimumab.¹⁵ Hydroxychloroquine is also recommended as part of the therapy, since it has shown benefits in improving the response to treatment and reducing disease flare.¹⁶ Mycophenolate mofetil and cyclophosphamide have similar efficacy with respect to clinical response, which includes a reduction in proteinuria and either an improvement in renal function or stabilization of renal function; the risks of infections and adverse events associated with these medications are also similar.^17,18

Given the severity of the lupus nephritis with overlying AA amyloidosis from active rheumatoid arthritis, the treatment options proposed were high-dose glucocorticoids and rituximab with either mycophenolate mofetil or cyclophosphamide.¹⁹ After discussions with multidisciplinary consultants from rheumatology, infectious diseases, and nephrology, lingering concerns were raised about infection and patient frailty; ultimately, the decision was made to initiate high-dose glucocorticoid therapy in combination with mycophenolate mofetil, rituximab, and hydroxychloroquine.

The patient’s mycophenolate mofetil dose regimen was inconsistent owing to gastrointestinal side effects, and the treatment was eventually withheld because of pancytopenia and fever. Unfortunately, her kidney function worsened, and renal replacement therapy was initiated within 3 weeks after the start of the induction therapy. The cause of her renal failure was thought to be disease progression, compounded by hemodynamically mediated tubular injury in the context of infection. While the administration of mycophenolate mofetil was stopped, treatment with rituximab was continued, with slow tapering of the glucocorticoid dose at the direction of the rheumatologist. She remained dependent on dialysis and was deemed to have end-stage kidney disease after 3 months of dialysis.

Dr. Lisa G. Criscione-Schreiber: The patient has SLE with nephritis, seropositive erosive rheumatoid arthritis, and systemic AA amyloidosis. AA amyloidosis is rare owing to the availability of effective therapies for rheumatoid arthritis and is managed through aggressive treatment of inflammation due to rheumatoid arthritis. Reports addressing the management of rheumatoid arthritis–induced AA amyloidosis generally cite stability of end-organ damage caused by AA amyloid as evidence of effective management of the condition (through treatment of the inflammation of rheumatoid arthritis). Methotrexate, the cornerstone of treatment for rheumatoid arthritis, is contraindicated in this case owing to the presence of kidney disease. The alkylating agent cyclophosphamide has been reported to be effective for the treatment of AA amyloidosis from rheumatoid arthritis²⁰ and has known efficacy in patients with lupus nephritis, both of which make it a viable treatment option. Rituximab has also been reported to be effective for managing rheumatoid arthritis–induced AA amyloidosis,²¹ is approved for the treatment of rheumatoid arthritis, and is used for manifestations of SLE, including thrombocytopenia and nephritis. Although anti–TNF-α agents, abatacept, and Janus kinase inhibitors are reported to be effective for the treatment of AA amyloidosis in patients with rheumatoid arthritis,²² recent publications have coalesced on the ability of anti–interleukin-6 therapy to block interleukin-6–induced hepatic production of SAA.^23-25

The overlap of seropositive erosive rheumatoid arthritis and SLE (sometimes termed “rhupus”) usually resembles rheumatoid arthritis more than SLE; manifestations include thrombocytosis, leukocytosis, an elevated erythrocyte sedimentation rate, an elevated blood level of C-reactive protein, and the presence of marginal erosions on radiographs.²⁶ In contrast, SLE without seropositive erosive rheumatoid arthritis characteristically manifests with thrombocytopenia, leukopenia, and an elevated erythrocyte sedimentation rate but usually not an elevated C-reactive protein level; in addition, nonerosive inflammatory arthritis with reversible deformities is commonly observed. This patient had a mixed laboratory profile, on the basis of the results of antinuclear antibody and anti–double-stranded DNA antibody tests. The challenge of treating an overlap syndrome of rheumatoid arthritis and SLE is choosing disease-modifying antirheumatic drugs that are effective and safe in both conditions. This patient’s most severe disease manifestation is lupus nephritis; therefore, the treatment regimen must target nephritis along with the AA amyloidosis and inflammatory arthritis.

As noted earlier, current induction therapy for lupus nephritis includes either mycophenolate mofetil or cyclophosphamide. Mycophenolate mofetil may provide inadequate treatment of the rheumatoid arthritis and amyloidosis, whereas cyclophosphamide would treat the lupus nephritis, has possible efficacy for treatment of the AA amyloidosis, and would treat the rheumatoid arthritis. Rituximab could be added to cyclophosphamide or mycophenolate mofetil to treat the rheumatoid arthritis and resultant AA amyloidosis and could also possibly help treat the lupus nephritis. The addition of anti–interleukin-6 therapy to mycophenolate mofetil or cyclophosphamide is an intriguing option that may effectively treat the rheumatoid arthritis and subsequent AA amyloidosis. The addition of belimumab to mycophenolate mofetil or cyclophosphamide has been reported to improve renal response in patients with lupus nephritis,²⁷ as has the addition of voclosporin to mycophenolate mofetil.²⁸ However, belimumab is ineffective for the treatment of rheumatoid arthritis, and voclosporin has not been studied in patients with rheumatoid arthritis or in those with a GFR of 45 milliliters per minute or less. The high-dose glucocorticoids that are used in induction therapy for lupus nephritis will effectively manage this patient’s inflammatory arthritis and probably also the subsequent AA amyloidosis. Finally, it is important that every patient with lupus nephritis receive hydroxychloroquine, which improves the treatment response to induction therapy.²⁹

Follow-up

Dr. Parsons: The patient’s hospital course was further complicated by suspected immune-mediated thrombocytopenia, for which she received intravenous immune globulin. Her pancytopenia and arthritis ultimately abated. Unfortunately, she did not have renal recovery and continues to receive hemodialysis. After a prolonged hospital course, she was discharged home.

Final Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.

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