Introduction

Primary bladder cancer is a frequently occurring malignancy. It is the tenth most common cancer globally, with an estimate of 549,000 new cases and 200,000 deaths reported in 2018, making it the most prevalent among the urothelial cancers worldwide.¹ However, secondary bladder cancers are quite rare, constituting only 2% of all the bladder tumors.² They can either reach the bladder by direct invasion from the surrounding organs, or by lymphatic, transcoelomic or hematogenous spread from distant sources.³ The majority of data on secondary bladder neoplasms are based on autopsy series. Bates and Baithun’s report on 282 patients showed that the tumors that metastasize to the bladder by direct invasion are mainly from the colon, prostate, rectum, and cervix.⁴ Bladder metastasis from distant primary foci is relatively rare, with the most commonly reported origin of primary tumor being stomach (4.3% of metastatic bladder cancers), followed by skin (3.9%), lung (2.8%), and breast (2.5%).⁵

Case Presentation

A 61-year-old Caucasian male was referred to our urology department from the accident and emergency services with a history of sudden-onset gradually progressive right flank pain for 3 days, associated with lethargy. He had no history of hematuria or chronic lower urinary tract symptoms. Three years ago, he was treated with neoadjuvant chemotherapy and total gastrectomy for grade 3 pT3 N0MxR0 gastric adenocarcinoma. Following completion of the treatment, he attended the gastrointestinal surgery clinic at 6 months, where the surveillance evaluation revealed no local recurrence or dissemination, after which he was lost to follow-up. He had no other known medical comorbidities. However, along with his presenting symptoms, he also complained of ongoing loss of appetite and loss of weight. Laboratory investigations revealed hemoglobin of 140 g/L (normal value: 130-180), and estimated glomerular filtration rate of 53 mL/min (previous for the patient: > 90 mL/min, normal value: > 90 mL/min).

Further evaluation with CT scan of the abdomen and pelvis revealed an obstructive 5-mm distal right ureteric calculus with upstream hydroureteronephrosis and thickened right lateral bladder wall that was thought to be likely associated with the tissue reaction caused by the distal ureteric obstruction (Figure 1, A-D). There was no bladder mass seen on the CT scan. Alongside these findings, there was bowel-wall thickening in the ascending and proximal transverse colon with surrounding fat stranding, and marked multifocal soft tissue stranding in the omentum, all suggestive of a metastatic picture keeping in view the patient’s clinical history. In view of the clinical presentation with acute kidney injury, he underwent cystoscopy and ureteric stent insertion under general anesthesia for the management of ureteric obstruction. Intraoperatively he was found to have a tight right ureteric orifice, due to which ureteroscopy-guided stone removal was deferred. There was no obvious protuberant growth seen, but a diffusely inflamed patchy area was found on the right posterolateral wall away from the right ureteric orifice, from where a few cold-cup biopsies were taken. Histopathological examination revealed small fragments of bladder wall mucosa with normal and intact overlying urothelium, but the submucosa was extensively infiltrated by a poorly differentiated carcinoma in which there were several signet ring cells containing intracellular mucin (Figure 2, A and B).

Figure 3. Immunoprofile of the tumor. A, Strong diffuse expression of epithelial immunohistochemical marker AE1/AE3 (original magnification ×400). B, Moderate expression of gastrointestinal marker CDX2 (original magnification ×400)

Immunohistochemistry studies revealed strong expression of epithelial marker AE1/AE3 and gastrointestinal marker CDX2 (Figure 3, A and B). There was no expression of the urothelial marker, thrombomodulin. The nuclear expression of CDX2 confirms gastrointestinal origin, and in view of the history, the appearances point toward metastasis to the bladder from a primary gastric adenocarcinoma. The case details of the patient were further discussed in the urology and gastrointestinal surgery multidisciplinary team meetings, and management with palliative chemoradiotherapy was planned and the patient was referred to the oncology team. The right ureteric calculus was planned for management with ureteroscopy, laser lithotripsy, and stone removal in 4 to 6 weeks.

Discussion

Primary adenocarcinoma of the bladder is a rare occurrence, accounting for only 1% of all primary bladder tumors, while among the secondary bladder tumors, more than 50% are histologically proven to be adenocarcinomas.⁴ In our patient, there was no history of chronic urinary symptoms, making bladder outlet obstruction a less likely differential for diffuse thickening of the bladder wall. Besides this, although hydronephrosis can be likely due to obstructive ureteric calculus, preoperative imaging showing omental and gastrointestinal involvement along with bladder wall thickening, and a positive history of a preceding high-grade gastric adenocarcinoma, motivated us to obtain cystoscopy-guided biopsies from the diffusely suspicious area of the bladder. Despite all the clinical clues being present, in our patient and also on review of the available literature, we found that it might not be fully plausible to clearly distinguish between a primary and secondary bladder adenocarcinoma. Mostofi et al suggested that primary bladder origin is more likely when there is a coexistence of transitional cell carcinoma.⁶ A submucosal, nonulcerative nature of the tumors is more suggestive of secondary bladder neoplasm.⁷ The absence of overlying transitional cell carcinoma in situ, and the presence of a normal intact urothelium in our patient, favors metastasis over a rarer primary signet ring cell carcinoma of the bladder. Similar to our case, a series of 16 cases reviewed by Okutur et al suggested that positivity for CDX2 on immunohistochemistry studies can help as an adjunct in arriving at the diagnosis of secondary bladder tumor of gastrointestinal origin.⁸

With regard to management, unlike primary bladder tumors where curative cystectomy is considered the mainstay, treatment planning with a palliative intent is more frequently warranted among patients with secondary bladder tumors in view of possibly present disseminated hematogenous, peritoneal, and lymphatic spread.⁵ Overall, signet ring cell carcinomas in particular are known to belong to a poorly differentiated subset with more aggressive disease course with a poor disease prognosis.⁸