兽研1. 引言
尿路上皮癌（UC）是起源于膀胱、尿道、输尿管黏膜表面以及肾小管、肾盏和肾盂的肿瘤。该病在人类和犬中均有常见报道，分别最常起源于膀胱侧壁和膀胱三角区[1]。
相比之下，猫的报道发病率较低，较大的病例系列提示其起源部位更为多变[2,3,4,5]；其余文献仅限于单例病例报告。虽然猫UC的危险因素仍缺乏充分记录，但已在其他物种中确定了若干因素。在犬中，这些因素包括接触杀虫剂、肥胖、环磷酰胺给药、雌性性别和品种易感性[6,7]。在人类中，危险因素包括吸烟和饮酒、化学物质暴露、化疗和放疗、男性性别、高龄和遗传[8]。重要的是，慢性膀胱炎症、尿液潴留、尿石症和泌尿道先天性异常已被提出是人类泌尿道肿瘤形成的特定促发因素[9,10]。
异位输尿管是一种先天性异常，其中一条或两条输尿管终止于膀胱三角区正常插入部位的远端，常导致尿失禁[11]。虽然据认为异位输尿管导致犬多达23%的尿失禁[12]，但在猫中罕有报道。目前尚不清楚这是否反映了真实的物种差异，还是代表了猫中的诊断不足和报告不足。在一项回顾性病例系列中，19只表现为先天性尿失禁的猫中有10只发现输尿管异位[13]，而另一项研究报告在35只尿失禁猫的队列中未发现输尿管异位的证据[14]。除尿失禁外，异位输尿管还易导致尿液潴留和膀胱输尿管反流，从而增加感染和尿石症的风险[15]。由此产生的慢性炎症可导致细胞化生，在人类中，这被认为是肿瘤转化的易感因素[16]。事实上，人类文献中有多篇报道UC与异位输尿管相关发生[17,18,19,20,21,22]。
相比之下，在兽医物种中尚未确定这种关联，仅有一篇病例报告描述了一只犬同时患有输尿管UC和原位输尿管囊肿[23]。本报告描述了首例记录在案的猫异位输尿管与UC共存病例。
2. 病例描述
一只10岁、体重7.2 kg的已绝育雌性缅因猫被转诊至英国一家兽医医院，有为期一个月的血尿、排尿困难、尿频、体重减轻、多尿、多饮和进行性氮质血症病史。该患者有五年轻度氮质血症和等渗尿病史，先前归因于慢性肾病。就诊时，她仅饲喂肾脏处方粮，并接受贝那普利（0.7 mg/kg 口服 每24小时一次）治疗。就诊前两周，该患者在尿液培养阳性后完成了14天的头孢氨苄疗程（15 mg/kg 口服 每12小时一次）。尽管猫的食欲有所改善，但持续的血尿和恶化的氮质血症促使后续转诊。
就诊时，该猫精神活泼、警觉、反应灵敏，体况评分为5/9，并有轻度全身性肌肉萎缩。心肺听诊无异常。患者的性情妨碍了全面的清醒检查，但麻醉下的进一步评估无异常。特别是，外生殖器检查未发现异常。全血细胞计数显示轻度正细胞性、正色素性、非再生性贫血（血细胞比容22.2% [参考区间30.3–42.3]），血清生化显示轻度氮质血症（肌酐272 µmol/L [参考区间0–150]；尿素20.6 mmol/L [参考区间2.70–9.2]），电解质在正常范围内。还记录到轻度离子化低钙血症（1.12 mmol/L，参考区间1.20–1.32）。根据ISFM共识指南[24]使用示波法设备测量的血压指示为高血压前期[25]：平均收缩压153 mmHg，舒张压97 mmHg，平均压111 mmHg。眼科检查未发现高血压性视网膜病变的证据。
在镇静状态下由委员会认证的放射科医师进行的腹部超声检查（GE Logic S7，韩国城南）显示双肾不对称，皮髓质分界减弱。双侧肾盂中度扩张（最大达0.8 cm），右侧肾盂内可见一枚小结石（0.2 × 0.3 cm）。左肾大小其余方面无异常，结合品种和体重考虑为正常（长度5.0 cm）[26]。右肾明显较小（长度3.7 cm），边缘不规则。肾周脂肪中度增厚且回声增强，伴有少量相关腹膜后积液。双侧输尿管弥漫性中度扩张（直径最大达0.4 cm），呈异位走行，向尾侧延伸超过膀胱颈，在三角区远端附近进入近端尿道。未见壁内段，膀胱内未见输尿管喷尿。膀胱中度充盈，尿液无回声，膀胱壁厚度和结构无异常。泌尿系统异常的示意图见图1。
由于双侧肾盂扩张和腹膜后改变怀疑肾盂肾炎，遂行膀胱穿刺和双侧肾盂穿刺。患者取仰卧位，在超声引导下用22G针头从膀胱抽吸尿液。随后在超声引导下经腰旁入路将22G针头经皮刺入各肾盂。超声确认针尖位置正确后抽吸尿液，无相关并发症。三个部位的尿液分析均提示明显血尿和脓尿；右肾盂样本异常最为显著，包括明显蛋白尿、碱性pH和活跃沉渣。膀胱和左肾盂尿液培养提示大肠埃希菌生长（表1）。患者住院24小时，接受马波沙星静脉注射（2 mg/kg 每日一次），作为等待尿培养和药敏结果期间的经验性治疗，符合ISCAID指南[27]。停用贝那普利。出院时根据药敏结果继续口服马波沙星（2 mg/kg 每日一次）。一周随访时，主人报告精神状态和食欲明显改善，下泌尿道症状完全消失。抗生素治疗再持续三周，直至完成四周疗程。
四周复评时，猫仍在接受马波沙星治疗，主人报告无临床异常，体格检查无异常。然而，血液学检查显示正细胞正色素非再生性贫血进展（HCT 17.8% [参考区间30.3–42.3]），血清生化显示氮质血症显著恶化（肌酐494 µmol/L [参考区间0–150]；尿素36.2 mmol/L [参考区间2.70–9.2]）。重复腹部超声显示泌尿系统异常进展。左肾盂扩张增至2.1 cm，近端输尿管扩张加重（0.35–0.5 cm），内容物无回声，并伴轻度壁增厚。右肾仍小（3.7 cm）且形态异常，肾盂扩张加重（1.3 cm），髓质回声增强，头极皮髓质萎缩。右输尿管扩张（5 mm），伴轻度壁增厚。双侧输尿管在近端尿道水平的异位终止如先前所见。右侧腹膜后改变持续存在，脂肪回声严重增强且质地不均。按前述方法经超声引导行膀胱穿刺和双侧肾盂穿刺采集尿液样本，所有样本均显示活跃沉渣但培养阴性。
次日记录到氮质血症进一步恶化（肌酐916 µmol/L [参考区间0–150]；尿素61.23 mmol/L [参考区间2.7–9.2]），鉴于进行性肾盂扩张，在麻醉下进行了超声引导下顺行肾盂造影以寻找潜在的尿路梗阻。患者取仰卧位，通过腰旁入路将22 G针头经皮双侧刺入肾盂。使用凸阵探头维持超声引导，向每侧肾盂注入5 ml碘化对比剂（Iohexol 300 mg I/mL Omnipaque®，GE Healthcare，芝加哥，伊利诺伊州，美国），无并发症。注射时及注射后5、10和15分钟拍摄的正交腹部X线片证实双侧肾盂扩张，并显示对比剂依次充盈于持续扩张的输尿管内，输尿管轮廓不规则、略呈囊状。右侧输尿管近端和尾侧段边缘明显不规则、界限不清，而其余输尿管部分 delineation 良好。尽管远端输尿管充盈，但在15分钟成像窗口内持续存在双侧输尿管终末段狭窄，且膀胱和尿道内无对比剂，提示膀胱输尿管连接处水平的尿路梗阻。然而，不能完全排除与肾功能损害相关的延迟性尿液排泄。
基于双侧输尿管梗阻的怀疑，进行了中线开腹术以探查尿路。行腹侧膀胱切开术并延伸至近端尿道，以识别和观察异位输尿管膀胱连接处，两者均位于预期解剖位置的远端，在前列腺部尿道水平进入，无壁内段。双侧输尿管明显扩张，右侧输尿管远端可触及增厚。在输尿管异位进入近端尿道的入口点也可触及坚实的增厚，引起对潜在浸润性病变与慢性炎症改变的担忧（图2）。膀胱壁弥漫性增厚。右肾明显增大，有少量同侧肾周积液，右侧腹膜后间隙水肿。除尿路病变外，大网膜上散布着小的苍白结节（图3）。
双侧输尿管尽可能在远端靠近其异位插入处进行结扎和横断。横断后观察到左侧输尿管立即有尿液流出，但右侧输尿管产生的尿液极少。将公猫导管逆行插入每侧肾盂，以用生理盐水冲洗并检查输尿管通畅性。随后进行双侧输尿管膀胱再植术，将输尿管开口重新定位至解剖上适当的位置：将双侧输尿管重新植入膀胱背侧靠近膀胱顶处，输尿管末端纵行切开，使用4-0聚卡普隆（Monocryl，Ethicon，萨默维尔，新泽西州，美国）以简单间断模式与膀胱黏膜吻合。整个手术过程中未观察到输尿管蠕动活动。基于吻合口可见尿液流出，左侧再植术被认为技术上成功。右侧输尿管流量极少归因于既存肾脏病变的严重程度而非再植术的技术失败，但尽管冲洗时通畅，右侧输尿管膀胱再植术的功能在术中无法完全确认。将大网膜结节和膀胱壁活检连同从异位连接处采集的异常右侧输尿管组织送检组织病理学。膀胱切开术以3-0 Monocryl简单连续模式闭合，腹腔用温生理盐水灌洗后按常规三层闭合，皮内皮肤缝合。麻醉苏醒前放置导尿管和食管造口管，分别用于持续监测尿量和营养支持。
麻醉苏醒平稳，猫接受静脉输液治疗（复方乳酸钠）、马罗匹坦（1 mg/kg IV q24h）和丁丙诺啡（0.02 mg/kg IV q6h）。夜间，患者保持安静、警觉、反应灵敏，疼痛评分为2/10。生命体征、血压和电解质保持在正常范围内。密切监测液体平衡，根据测得的尿量、估计的持续丢失量和水合状态调整静脉输液。尿液仍呈肉眼血尿，尿量从苏醒后1.4 mL/kg/h降至次日0.9 mL/kg/h。苏醒后48小时，患者仍少尿（尿量0.8 mL/kg/h），持续氮质血症（肌酐907 µmol/L [参考区间：0–150]；尿素61.2 mmol/L [参考区间：2.7–9.2]），根据主人意愿实施安乐死。
除了对手术活检组织进行评估外，还进行了完整的尸检，以系统评估原发疾病的范围和转移扩散的证据。对皮下组织以及呼吸、心血管、消化、造血、生殖、内分泌、肌肉骨骼和神经系统均进行了肉眼和组织学检查，未发现肿瘤累及的证据；在肝脏与右肾头极之间偶然发现一条冗余的后腔静脉，属于血管异常。大网膜可见多灶性结节，泌尿系统证实存在明显的肉眼异常，病变累及肾脏、膀胱、输尿管和尿道。右肾体积小且形态不规则，与肝脏及右肾上腺粘连。切面显示皮髓质交界消失及多灶性变色，符合浸润性疾病（图4）。左右输尿管明显且弥漫性扩张，膀胱三角处可见手术吻合口。膀胱壁增厚，并可见多灶性至融合性小出血点。尸检肉眼特征的完整描述见表2。
组织学上，可见一个无包膜、边界不清、细胞密集、具有浸润性的肿瘤，符合癌的特征，由多边形上皮细胞排列成索状和小梁状，起源于异位输尿管膀胱交界水平处的右侧输尿管和尿道尿路上皮（图5），并浸润膀胱壁。右肾及大网膜结节内可见形态相似的具有恶性特征的尿路上皮细胞（图6）。所检查的切片中未发现鳞状或腺性分化的组织学证据。右肾结构几乎完全被凝固性坏死和纤维化所取代，仅在该促结缔组织增生性间质中可见散在的肿瘤细胞。左肾显示多灶性中度慢性淋巴浆细胞性间质性肾炎，伴有肾小管坏死、纤维化及肾小管内草酸钙结晶，未见肿瘤浸润的证据。组织病理学特征的完整描述见表2，其结论提示最终诊断为尿路上皮癌，累及右侧输尿管、膀胱、尿道及右肾，伴大网膜转移。
3. 讨论
尿路上皮癌（UC）在猫中是一种罕有报道的恶性肿瘤，累及输尿管者尤为少见[2,4,28]。本病例描述了一例此前未见报道的UC与双侧异位输尿管共存的病例，后者是一种在猫中不常见的先天性异常。进行性下泌尿道症状的临床表现是两种疾病共有的典型表现，所观察到的输尿管积水、肾积水和泌尿道感染的发生也是如此[2,13]。虽然异位输尿管在雌性犬中更为常见，且某些犬种发病率过高[29,30,31]，但猫异位输尿管尚未确定性别或品种易感性。然而，多篇病例报告描述了缅因猫品种中的异位输尿管[32,33,34,35,36]。同样，与犬不同——在犬中某些品种明显易患UC——报道猫UC的病例系列描述了多个受影响品种[37]。
长期以来，人们一直假设慢性炎症参与致癌过程[38]，并且在人类中，慢性泌尿系统病变与泌尿道肿瘤发病率之间存在充分文献记载的关联[9,10]。此外，人类文献的证据支持肾脏和泌尿道先天性异常（CAKUT）与随后的泌尿道恶性肿瘤之间存在特定关联。例如，一项基于人群的队列研究对超过150万名受试者进行了长达30年的随访，发现儿童期诊断CAKUT与成年后发生肾脏、输尿管和膀胱恶性肿瘤的风险显著增加相关[39]。值得注意的是，这种关联的 proposed 机制不仅限于慢性尿路上皮炎症，因为调控正常肾发生和输尿管芽成熟的相同基因在受到破坏时可能导致CAKUT。因此，也有人提出异常肾发生可独立地使受累尿路上皮易发生肿瘤发生[39]。尽管在异位输尿管患者中尚未确定具体的遗传联系，但多个人类病例研究描述了患有这种先天性异常的患者发生尿路上皮癌[17,18,21,22,40,41]。
这些关联的兽医证据稀少，仅有一篇病例报告描述了一只犬同时患有原位输尿管囊肿和尿路上皮癌[6]。因此，无法确定其他兽医物种中是否存在类似的因果关系；然而，该患者中UC与异位输尿管的共存提出了这种可能性。另外，也应考虑几种非互斥的解释。肿瘤可能独立发生，这两种情况代表的是巧合而非机制相关的病理。事实上，已有报道猫尿路上皮癌可在没有任何可识别易感原因的情况下发生[37]。虽然亚临床异位输尿管可与持续性尿液淤滞和感染相关[13,17,18]，但值得注意的是，未报告尿失禁、反复感染和尿石症等既往下尿路症状，使得其在此患者中的先前意义不确定。由局部肿瘤进展导致的尿液淤滞、尿路上皮破坏和局部防御受损，可独立解释所见的炎症、感染、输尿管积水和肾积水；因此，前因关系未得到确认[42,43]。尽管如此，因果联系的假设提出了可能需要对先天性泌尿道畸形动物进行更积极管理和早期干预的必要性。
鉴于大体和组织病理学发现，肿瘤似乎很可能起源于异位输尿管膀胱连接处附近，局部延伸至相邻的右输尿管、尿道和膀胱，并随后扩散至右肾和大网膜。事实上，肿瘤病变的分布可能反映了UC播散的几种公认机制。尿路上皮癌以其通过种植转移播散的倾向而广为人知，即尿液中的脱落肿瘤细胞在远离原发肿瘤部位的尿路上皮表面种植；这一机制可合理解释异位输尿管膀胱连接处区域和右肾盂的受累。此外，组织学鉴定出与相邻动脉和静脉结构不同的肿瘤血栓栓子，支持淋巴管侵犯作为局部及潜在远处播散的进一步途径。这与癌通常倾向于通过淋巴管而非血行途径转移的一般规律一致[44]。最后，大网膜内存在形态相同的肿瘤细胞，与经体腔种植一致，这是起源于或侵犯浆膜表面的癌已知的腹膜播散途径[45,46]。因此，该猫观察到的疾病模式与局部浸润、尿液种植、淋巴管侵犯和腹膜播种的联合效应一致，并突显了猫UC的侵袭性。事实上，如该患者所示，预后通常较差，据报道猫的中位生存时间在部分膀胱切除加NSAID治疗下为176天，未经治疗为46天[2]。虽然UC浸润导致右输尿管和尿道阻塞被认为是该猫临床恶化的主要驱动因素，但尽管尿培养阴性，仍不能排除持续性细菌性肾盂肾炎的存在。考虑到该猫慢性轻度氮质血症和等渗尿的病史以及对侧（左）肾明显的组织病理学变化，既往存在的慢性肾病和肾结石也可能在总体结局中发挥了作用。
本病例报告强调了在既往无症状的老年患者中考虑先天性泌尿道异常可能性的重要性[17,18]。输尿管异位的慢性后遗症是否如人类文献所提出的那样促进了恶性转化仍属推测，但也突显了在出现进行性或无反应临床症状的异位输尿管患者中考虑肿瘤可能性的重要性。
4. 结论
本病例报告记录了猫中异位输尿管与UC的罕见共存，强调了在先天性泌尿异常且临床症状进行性加重的患者鉴别诊断中纳入肿瘤的重要性。它突显了UC的侵袭性以及晚期疾病相关的诊断和治疗挑战。鉴于人类医学的大量证据，它也提出了这样一种可能性：猫的先天性泌尿道解剖异常通过尿动力学改变和连接异常肾发生与肿瘤发生的共同异常发育途径的组合，赋予了恶性肿瘤风险。
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1. Introduction
Urothelial carcinoma (UC) is a neoplasm arising from the mucosal surface of the urinary bladder, urethra, ureters, and the renal tubules, calyces and pelvis. It is commonly documented in humans and dogs, most often arising from the lateral bladder wall and bladder trigone respectively [1].
In contrast, it has a low reported incidence in cats, with the larger case series suggesting a more variable site of origin [2,3,4,5]; the remaining literature is restricted to single case reports. Whilst risk factors for UC in cats remain poorly documented, several factors have been identified in other species. In dogs, these include exposure to insecticides, obesity, cyclophosphamide administration, female sex, and breed predisposition [6,7]. In humans, risk factors include tobacco and alcohol use, chemical exposure, chemotherapy and radiotherapy, male sex, advanced age and genetics [8]. Importantly, chronic bladder inflammation, urinary stasis, urolithiasis and congenital abnormalities of the urinary tract have been proposed as specific contributors to urinary tract neoplasia in humans [9,10].
Ectopic ureters are a congenital anomaly in which one or both ureters terminate distal to the normal insertion at the bladder trigone, often resulting in urinary incontinence [11]. Whilst considered responsible for up to 23% of urinary incontinence in dogs [12], ectopic ureters are rarely reported in cats. It is unclear whether this reflects a true species difference, or whether it represents underdiagnosis and under-reporting in cats. In one retrospective case series, ureteral ectopia was identified in 10 of 19 cats presenting with congenital urinary incontinence [13], while a separate study reported no evidence of ureteral ectopia in a cohort of 35 cats with incontinence [14]. In addition to urinary incontinence, ectopic ureters predispose to urinary stasis and vesicoureteral reflux, leading to an increased risk of infection and urolithiasis [15]. Consequent chronic inflammation can result cellular metaplasia which, in humans, is proposed as a predisposing factor for neoplastic transformation [16]. Indeed, there are multiple reports in the human literature of UC occurring in association with ectopic ureters [17,18,19,20,21,22].
In contrast, no association has been ascertained in veterinary species, with only a single case report describing a dog with concurrent ureteral UC and an orthotopic ureterocele [23]. This report describes the first documented incidence of coexistent ectopic ureters and UC in a cat.
2. Case Description
A 10-year-old, 7.2 kg, spayed female Maine Coon was referred to a veterinary hospital in the United Kingdom with a one-month history of haematuria, stranguria, pollakiuria, weight loss, polyuria, polydipsia, and progressive azotaemia. The patient had a five-year history of mild azotaemia and isosthenuria, previously attributed to chronic kidney disease. At the time of presentation, she was fed a renal diet exclusively and was receiving benazepril (0.7 mg/kg PO q24h). Two weeks prior to presentation, the patient had completed a 14-day course of cephalexin (15 mg/kg PO q12h) following a positive voided urine culture. Although the cat’s appetite had improved, ongoing haematuria and worsening azotaemia prompted subsequent referral.
On presentation, the cat was bright, alert and responsive, with a body condition score of 5/9 and mild generalised muscle atrophy. Cardiorespiratory auscultation was unremarkable. The patient’s temperament precluded comprehensive conscious examination, but further evaluation under anaesthesia was unremarkable. In particular, examination of the external genitalia revealed no abnormalities. A complete blood count identified mild normocytic, normochromic, non-regenerative anaemia (haematocrit 22.2% [RI 30.3–42.3]), serum biochemistry revealed mild azotaemia (creatinine 272 µmol/L [RI 0–150]; urea 20.6 mmol/L [RI 2.70–9.2]), and electrolytes were within normal limits. Mild ionised hypocalcaemia was also documented (1.12 mmol/L, RI 1.20–1.32). Blood pressure measured using an oscillometric device according to the ISFM Consensus Guidelines [24] indicated a prehypertensive state [25]: average systolic 153 mmHg, diastolic 97 mmHg, mean 111 mmHg. No evidence of hypertensive retinopathy was identified on ophthalmic examination.
Abdominal ultrasound performed under sedation by a board-certified radiologist (GE Logic S7, Seongnam, Republic of Korea) revealed bilateral asymmetrical kidneys with reduced corticomedullary distinction. Both renal pelvises were moderately distended (up to 0.8 cm), and a small nephrolith (0.2 × 0.3 cm) was identified within the right renal pelvis. The left kidney size was otherwise unremarkable, being considered normal considering the breed and body weight (length 5.0 cm) [26]. The right kidney was significantly smaller (length 3.7 cm) with irregular margins. The perirenal fat was moderately thickened and hyperechoic, with minimal associated retroperitoneal effusion. Both ureters were diffusely and moderately distended (up to 0.4 cm in diameter) and displayed ectopic positioning, coursing caudally beyond the bladder neck and entering the proximal urethra just distal to the trigone. No intramural segment was evident, and no ureteral jets were identified within the bladder. The urinary bladder was moderately distended with anechoic urine, and the bladder wall was unremarkable in thickness and architecture. A schematic illustration of the urinary tract abnormalities is shown in Figure 1.
Since the bilateral pelvic dilation and retroperitoneal changes raised suspicion of pyelonephritis, cystocentesis and bilateral pyelocentesis were performed. The patient was positioned in dorsal recumbency, and urine was aspirated from the urinary bladder using a 22-gauge needle under ultrasound guidance. A 22-gauge needle was then percutaneously advanced into each renal pelvis under ultrasound guidance via a paralumbar approach. Urine was aspirated following sonographic confirmation of correct needle tip positioning, with no associated complications. Urinalysis from all three sites indicated marked haematuria and pyuria; the sample from the right renal pelvis exhibited the most pronounced abnormalities, including marked proteinuria, alkaline pH, and active sediment. Culture of the urine from the bladder and from the left renal pelvis indicated growth of E. coli (Table 1). The patient was hospitalised for 24 h and received intravenous marbofloxacin (2 mg/kg SID), selected as empirical therapy pending the urine culture and susceptibility results, in accordance with ISCAID guidelines [27]. Benazepril was discontinued. Oral marbofloxacin (2 mg/kg SID) was continued at the time of discharge, supported by the antibiogram results. At the one-week follow-up, the owner reported marked improvement in demeanour and appetite, with complete resolution of the lower urinary tract signs. Antibiotic therapy was continued for an additional three weeks, until completion of a four-week course.
At the four-week re-evaluation, whilst the cat was still receiving marbofloxacin, the owner reported no clinical concerns, and physical examination was unremarkable. However, haematology showed progression of the normocytic, normochromic, non-regenerative anaemia (HCT 17.8% [RI 30.3–42.3]), and serum biochemistry revealed significant worsening of the azotaemia (creatinine 494 µmol/L [RI 0–150]; urea 36.2 mmol/L [RI 2.70–9.2]). Repeat abdominal ultrasonography revealed progression of the urinary tract abnormalities. The left renal pelvic dilation had increased to 2.1 cm, with worsened proximal ureteral dilation (0.35–0.5 cm) and anechoic content as well as mild wall thickening. The right kidney remained small (3.7 cm) and misshapen, with greater pelvic dilation (1.3 cm), medullary hyperechogenicity, and corticomedullary atrophy of the cranial pole. The right ureter was dilated (5 mm) with mild wall thickening. Ectopic termination of both ureters at the level of the proximal urethra was visualised as previously. Marked right-sided retroperitoneal changes persisted, with severe hyperechogenicity and heterogeneous fat. Urine samples were collected via ultrasound-guided cystocentesis and bilateral pyelocentesis as previously described, with all samples showing an active sediment but negative cultures.
Further worsening of the azotaemia was documented the following day (creatinine 916 µmol/L [RI 0–150]; urea 61.23 mmol/L [RI 2.7–9.2]), and, given the progressive renal pelvic dilation, ultrasound-guided antegrade pyelography was performed under anaesthesia to search for potential urinary obstruction. The patient was positioned in dorsal recumbency, and 22 g needles were percutaneously directed into the renal pelvises bilaterally via a paralumbar approach. Maintaining ultrasound guidance using a convex array probe, 5 ml of iodinated contrast medium (Iohexol 300 mg I/mL Omnipaque®, GE Healthcare, Chicago, IL, USA) was instilled into each renal pelvis, without complications. Orthogonal abdominal radiographs taken at the time of injection, and at 5, 10, and 15 min post-injection, confirmed bilateral pelvic dilation and identified sequential contrast filling throughout persistently dilated ureters with an irregular, slightly saccular contour. The proximal and caudal segments of the right ureter showed markedly irregular, ill-defined margins, while the remaining ureteral portions were well-delineated. Persistent bilateral narrowing of the terminal ureteral segments and an absence of contrast within the urinary bladder and urethra throughout the 15 min imaging window despite filling of the distal ureters was suggestive of urinary obstruction at the level of the vesicoureteral junctions. However, delayed urinary excretion associated with renal compromise could not be completely excluded.
Based on the suspicion of bilateral ureteral obstruction, a midline coeliotomy was performed for urinary tract exploration. A ventral cystotomy extending to the proximal urethra was performed to identify and visualise the ectopic ureterovesical junctions, both of which were located distal to the expected anatomical position, entering at the level of the proximal urethra with no intramural segment. Both ureters were markedly dilated, with the distal right ureter being palpably thickened. A palpable firm thickening was also present at the ectopic entry point of the ureters into the proximal urethra, raising concern of an underlying infiltrative lesion versus chronic inflammatory change (Figure 2). The bladder wall was diffusely thickened. The right kidney was grossly distended, there was a small amount of ipsilateral perirenal fluid, and the right retroperitoneal space was oedematous. In additional to the urinary tract pathology, small pale nodules were scattered throughout the omentum (Figure 3).
Both ureters were ligated and transected as distally as possible, close to their ectopic insertion. An immediate flow of urine was observed from the left ureter following transection, but minimal urine production was visualised from the right ureter. A tomcat catheter was passed in a retrograde fashion into each renal pelvis to allow flushing with saline and check patency of the ureters. Bilateral ureteroneocystostomy was then performed to relocate the ureteral openings to an anatomically appropriate site: both ureters were reimplanted into the dorsal aspect of the bladder near the apex, with the ureteral ends spatulated and anastomosed to the bladder mucosa using 4-0 poliglecaprone (Monocryl, Ethicon, Somerville, NJ, USA) in a simple interrupted pattern. No peristaltic ureteral activity was observed throughout the procedure. Reimplantation was considered technically successful on the left side based on visible urine flow through the anastomosis. Minimal flow from the right ureter was attributed to the severity of pre-existing renal pathology rather than a technical failure of the reimplantation, but, although patent whilst flushing, the function of the right ureteroneocystostomy could not be fully confirmed intraoperatively. Biopsies of the omental nodules and bladder wall were submitted for histopathology along with the abnormal right ureteral tissue harvested from the ectopic junction. The cystotomy was closed with 3-0 Monocryl in a simple continuous pattern, and the abdomen was lavaged with warm saline prior to routine three-layer closure with intradermal skin sutures. A urinary catheter and oesophagostomy tube were placed prior to anaesthetic recovery for ongoing monitoring of urine output and nutritional support respectively.
Anaesthetic recovery was uneventful, and the cat received intravenous fluid therapy (compound sodium lactate), maropitant (1 mg/kg IV q24h) and buprenorphine (0.02 mg/kg IV q6h). Overnight, the patient remained quiet, alert, and responsive, with a pain score of 2/10. Vital parameters, blood pressure and electrolytes remained within normal limits. Fluid balance was closely monitored, with intravenous fluid administration adjusted according to measured urine output, estimated ongoing losses, and hydration status. The urine remained grossly haematuric, and urine output reduced from 1.4 mL/kg/h post recovery to 0.9 mL/kg/h the following day. Forty-eight hours post recovery, the patient remained oliguric (urine output 0.8 mL/kg/h), with persistent azotaemia (creatinine 907 µmol/L [RI: 0–150]; urea 61.2 mmol/L [RI: 2.7–9.2]) prompting euthanasia according to the owner’s wishes.
A full post mortem examination was performed, in addition to an evaluation of the surgical biopsies, to systematically assess for primary disease extent and evidence of metastatic spread. The subcutaneous tissues, as well as respiratory, cardiovascular, alimentary, hematopoietic, reproductive, endocrine, musculoskeletal, and nervous systems were all examined grossly and histologically, with no evidence of neoplastic involvement; a redundant caudal vena cava was noted as an incidental vascular anomaly between the liver and the cranial pole of the right kidney. Multifocal omental nodules were noted, and the urinary system was confirmed to be grossly abnormal, with pathology affecting the kidneys, bladder, ureters and urethra. The right kidney was small and irregular and was adhered to the liver and right adrenal gland. The cut surface exhibited obliteration of the corticomedullary junction and multifocal discolouration, consistent with infiltrative disease (Figure 4). The right and left ureters were markedly and diffusely dilated, and surgical anastomosis at the bladder trigone was evident. The urinary bladder wall was thickened and exhibited multifocal to coalescing small haemorrhages. A full description of the gross post mortem features is given in Table 2.
Histologically, an unencapsulated, poorly demarcated, densely cellular, infiltrative neoplasm compatible with carcinoma, composed of polygonal epithelial cells arranged in cords and trabeculae, was identified arising from the right ureteral and urethral urothelium at the level of the ectopic ureterovescical junction (Figure 5) and infiltrating the bladder wall. Similar urothelial cells with features of malignancy were noted in the right kidney and within the omental nodules (Figure 6). No histologic evidence of squamous or glandular differentiation was identified in the examined sections. The right kidney showed near-complete architectural effacement by coagulative necrosis and fibrosis, with only scattered neoplastic cells identified within this desmoplastic stroma. The left kidney showed multifocal moderate chronic lymphoplasmacytic interstitial nephritis with tubular necrosis, fibrosis, and intratubular calcium oxalate crystals, with no evidence of neoplastic infiltration. A full description of the histopathologic features is given in Table 2, the conclusions from which indicated a final diagnosis of urothelial carcinoma affecting the right ureter, bladder, urethra and right kidney with omental metastasis.
3. Discussion
Urothelial carcinoma (UC) is a rarely reported malignancy in cats, with ureteral involvement being particularly uncommon [2,4,28]. This case describes a previously unreported coexistence of UC with bilateral ectopic ureters, a congenital anomaly uncommonly reported in cats. The clinical presentation of progressive lower urinary tract signs is typical of both conditions, as is the noted development of hydroureters, hydronephrosis and urinary tract infection [2,13]. Whilst ectopic ureters are more common in female dogs, and certain dogs breeds are over-represented [29,30,31], no sex or breed predispositions have been established for ectopic ureters in cats. Nevertheless, multiple case reports have described ectopic ureters in the Maine Coon breed [32,33,34,35,36]. Similarly, unlike in dogs, where certain breeds are clearly over-represented for developing UC, case series reporting UC in cats describe a range of affected breeds [37].
Chronic inflammation has long been hypothesised to contribute to carcinogenesis [38], and, in humans, there is a well-documented association between chronic urinary pathology and the incidence of urinary tract neoplasia [9,10]. Moreover, evidence from the human literature supports a specific association between congenital anomalies of the kidney and urinary tract (CAKUT) and subsequent urinary tract malignancy. For example, one population-based cohort study following over 1.5 million recruits for up to 30 years found that a childhood diagnosis of CAKUT was associated with a significantly increased risk of developing renal, ureteral, and bladder malignancy in adulthood [39]. Notably, the proposed mechanism underlying this association extends beyond chronic urothelial inflammation, as the same genes governing normal nephrogenesis and ureteric bud maturation may, when disrupted, give rise to CAKUT. Thus, aberrant nephrogenesis has also been proposed to independently predispose the affected urothelium to tumorigenesis [39]. Although a specific genetic link has not been defined in patients with ectopic ureters, multiple human case studies have described urothelial carcinoma in patients with this congenital abnormality [17,18,21,22,40,41].
Veterinary evidence for these associations is sparce, consisting of a single case report describing an orthotopic ureterocele with concurrent urothelial carcinoma in a dog [6]. Whether a similar causal relationship exists in other veterinary species can therefore not be determined; however, the coexistence of UC and ectopic ureters in this patient raises this possibility. Alternatively, several non-mutually exclusive explanations should also be considered. The neoplasm may have arisen independently, with the two conditions representing coincidental rather than mechanistically linked pathology. Indeed, feline urothelial carcinoma has been reported to occur in the absence of any identifiable predisposing cause [37]. Whilst subclinical ectopic ureters can be associated with persistent urinary stasis and infection [13,17,18], it is notable that historical lower urinary tract signs such as incontinence, recurrent infection and urolithiasis were not reported, making their prior significance in this patient uncertain. Urinary stasis, urothelial disruption and compromised local defences, resulting from local tumour progression, could independently explain the presence of noted inflammation, infection, hydroureter and hydronephrosis; thus, anteriority is not confirmed [42,43]. Nevertheless, the hypothesis of a causal link raises the possible need for more proactive management and earlier intervention in animals with congenital urinary tract malformations.
Given the gross and histopathologic findings, it seems likely that the tumour arose in the vicinity of the ectopic ureterovesicular junction, with local extension into the adjacent right ureter, urethra and bladder, and with subsequent spread to the right kidney and omentum. Indeed, the distribution of neoplastic lesions likely reflects several recognised mechanisms of UC dissemination. Urothelial carcinoma is well-recognised for its propensity to disseminate via implantation metastasis, in which exfoliated neoplastic cells within the urine seed and implant along the urothelial surface at sites distant from the original tumour site; this mechanism plausibly explains the involvement of both the ectopic ureterovesicular junction region and right renal pelvis. In addition, histological identification of a tumour thromboembolus distinct from adjacent arterial and venous structures supports lymphatic invasion as a further route of local and potentially distant spread. This is consistent with the general tendency of carcinomas to metastasize preferentially via lymphatic rather than haematogenous pathways [44]. Finally, the presence of morphologically identical neoplastic cells within the omentum is consistent with transcoelomic implantation, a recognised route of peritoneal dissemination for carcinomas arising from or invading through a serosal surface [45,46]. The pattern of disease observed in this cat is therefore consistent with the combined effects of local infiltration, urinary implantation, lymphatic invasion, and peritoneal seeding and highlights the aggressive nature of feline UC. Indeed, as noted in this patient, the prognosis is generally poor, with reported median survival times in cats of 176 days with partially cystectomy and NSAID therapy or 46 days without treatment [2]. Whilst UC infiltration resulting in obstruction of the right ureter and urethra is assumed to have been the main driver of clinical deterioration in this cat, the presence of ongoing bacterial pyelonephritis cannot be excluded despite the negative urine cultures. Considering the cat’s history of chronic mild azotaemia and isosthenuria and the histopathologic changes evident in the contralateral (left) kidney, pre-existing chronic kidney disease and nephrolithiasis may have also played a role in the overall outcome.
This case report underscores the importance of considering the possibility of congenital urinary tract anomalies in older patients that have previously remained asymptomatic [17,18]. Whether the chronic sequalae of ureteral ectopia contributed to malignant transformation as has been proposed in the human literature remains speculative, but the importance of considering neoplasia as a possibility in patients with ectopic ureters experiencing progressive or non-responsive clinical signs is also highlighted.
4. Conclusions
This case report documents an unusual coexistence of ectopic ureters and UC in a cat, stressing the importance of including neoplasia in the differential diagnosis for patients with congenital urinary anomalies and progressive clinical signs. It highlights the aggressive nature of UC and the diagnostic and treatment challenges associated with late-stage disease. Given the body of evidence in human medicine, it also raises the possibility that congenital anatomic anomalies of the urinary tract in cats confer a risk of malignancy through a combination of altered urodynamics and a shared aberrant developmental pathway linking abnormal nephrogenesis to oncogenesis.