When clinicians performed a transurethral resection of the bladder lesion, histopathological examination showed an infiltrative high-grade carcinoma arranged in irregular nests and cords within desmoplastic stroma. Immunohistochemistry told a decisive story: the tumor cells expressed CK20, GATA3, and p63, partially expressed CK7 and Uroplakin III, and were negative for PSA and NKX3.1. That combination is the classic immunophenotype of urothelial carcinoma, the malignancy that arises from the transitional epithelium of the urinary tract. GATA3 is a highly sensitive marker of urothelial differentiation in high-grade tumors, while NKX3.1 is considered a sensitive and specific marker of prostatic origin. The tumor was not a prostate cancer at all. It was bladder cancer that had crossed the bladder neck and invaded the prostate, and the normal PSA level had provided no protection against the misdiagnosis that nearly followed.

Two weeks after admission, the patient underwent radical cystectomy, ileal conduit urinary diversion, and pelvic lymph-node dissection. The postoperative pathology revealed a tumor measuring approximately 4.5 by 4.0 by 1.0 centimeters that had invaded the full thickness of the bladder wall and extended directly into the prostatic stroma and capsule. Fourteen pelvic lymph nodes were negative for carcinoma, but the distal prostatic urethral margin was positive, and the tumor showed both lymphovascular invasion and perineural invasion. The pathological stage was assigned as pT4aN0M0, a designation that reflects the direct, contiguous extension of the bladder primary into the prostatic parenchyma. In the AJCC TNM staging system, prostatic stromal invasion by bladder urothelial carcinoma is classified as pT4a disease, and it is regarded as an important pathological feature of aggressive tumor biology.

PD-L1 immunohistochemistry performed on the primary lesion showed a tumor proportion score below 1 percent and an immune-cell score below 1 percent, indicating low expression. HER2 was negative. Because no neoadjuvant systemic therapy had been given and the final pathology showed pT4a disease with a positive margin, a multidisciplinary discussion concluded that adjuvant systemic therapy was indicated. Current guideline-based options support adjuvant cisplatin-based combination chemotherapy for patients with pT3/4 and/or pN+ disease when no neoadjuvant systemic therapy has been administered, while adjuvant nivolumab is a recommended alternative for high-risk muscle-invasive urothelial carcinoma when cisplatin-based chemotherapy is not feasible or is declined. The planned regimen was gemcitabine at 1,000 milligrams per square meter on days 1 and 8 plus cisplatin at 70 milligrams per square meter on day 1, repeated every 21 days for up to four cycles.

What actually happened next exposes a gap between what oncology guidelines recommend and what patients can tolerate. The patient received only approximately one week of platinum-based chemotherapy plus immunotherapy before treatment was discontinued after renewed shared decision-making, driven by poor tolerance and substantial financial burden. The authors of the case report acknowledge that the inability to deliver complete perioperative or adjuvant systemic therapy is a major limitation of the case and an important context for interpreting what followed. Approximately three months after radical cystectomy, the patient developed low back pain and was evaluated in the oncology department.

Whole-body bone scintigraphy and SPECT/CT fusion imaging demonstrated multiple osteolytic bone metastases involving the L2 and L4 vertebrae and their posterior elements, the bilateral iliac bones, the left acetabular rim, and the right inferior pubic ramus. The distribution is striking: despite negative pelvic lymph nodes at the time of surgery, the cancer had already seeded the axial and pelvic skeleton within a quarter of a year. The authors suggest that occult micrometastases not detectable on routine preoperative imaging may already have been present at the time of cystectomy, and that lymphovascular invasion, perineural invasion, and a positive prostatic urethral margin together indicated highly aggressive tumor biology that routine staging had underestimated.

Soon after the diagnosis of bone metastases, the patient received denosumab at 120 milligrams by subcutaneous injection every 4 weeks to reduce the risk of skeletal-related events, combined with intensity-modulated radiotherapy to the vertebral metastatic lesions at a prescribed dose of 30 Gy in 10 fractions. The choice of denosumab is supported by a phase III randomized controlled trial showing that it was non-inferior to zoledronic acid in delaying skeletal-related events in patients with bone metastases from advanced solid tumors, with a lower incidence of renal toxicity. However, in patients with symptomatic bone metastases, antiresorptive therapy alone is often insufficient to control local pain and maintain skeletal stability, and palliative radiotherapy is usually required as part of comprehensive treatment, consistent with ASTRO evidence-based guidance indicating that palliative radiation can effectively relieve pain associated with bone metastases and help achieve local lesion control.

The deeper lesson of this case lies in the diagnostic pitfall that nearly derailed the workup. Bladder urothelial carcinoma involving the prostate can spread through three major pathways: prostatic urethral mucosal involvement, prostatic ductal involvement, and direct stromal invasion. Among these patterns, stromal invasion represents the most clinically significant form because it reflects tumor infiltration into the prostatic parenchyma and is associated with advanced pathological stage and poorer oncological outcomes. Retrospective analyses of patients with bladder cancer and prostatic involvement have shown that prostatic stromal invasion is closely associated with decreased cancer-specific and overall survival and represents an independent adverse prognostic indicator. Compared with mucosal or ductal involvement alone, prostatic stromal invasion is associated with a higher risk of local recurrence and distant metastasis, and the depth of prostatic involvement independently predicts poor overall survival. Prognosis is determined primarily by the presence of stromal invasion rather than by whether prostatic involvement is contiguous or non-contiguous.

Previous studies have shown that PSA is often normal or only mildly elevated when bladder-derived urothelial carcinoma involves the prostate, which means a normal serum PSA level cannot be used to exclude urothelial carcinoma involving the prostate. Secondary prostatic involvement by bladder urothelial carcinoma has been reported in approximately 12 to 40 percent of radical cystectomy specimens, while primary prostatic urothelial carcinoma is rare, accounting for only 1 to 4 percent of prostate malignancies. Because some high-grade prostatic adenocarcinomas may exhibit solid, nested, or pseudopapillary growth patterns that closely mimic urothelial carcinoma morphologically, particularly in tumors involving the bladder neck or prostatic urethra, careful correlation with immunohistochemical findings is required to establish the correct tumor origin. A single immunomarker is insufficient for reliably distinguishing between these two tumor types, and the combined use of urothelial markers such as GATA3, p63, and Uroplakin III alongside prostatic markers such as PSA and NKX3.1 provides higher diagnostic accuracy than any single marker alone.

From a molecular perspective, urothelial carcinoma is characterized by a highly heterogeneous genomic landscape involving alterations in pathways related to chromatin remodeling, DNA damage repair, cell-cycle regulation, and receptor tyrosine kinase signaling. Comprehensive genomic analyses have demonstrated that muscle-invasive bladder cancer frequently harbors alterations in TP53, RB1, ERCC2, FGFR3, PIK3CA, and ARID1A, which contribute to genomic instability, tumor progression, and biological heterogeneity. Recent molecular classification studies have divided muscle-invasive bladder cancer into distinct subtypes, including basal/squamous and luminal categories, which demonstrate different biological characteristics and prognostic implications. Although comprehensive genomic sequencing was not performed in this patient, the rapid postoperative metastatic progression and extensive pathological risk factors may indicate underlying molecular abnormalities associated with aggressive tumor behavior, and future genomic profiling may help clarify the mechanisms responsible for prostatic stromal invasion and early distant dissemination in this rare subgroup.

For patients with a normal serum PSA level but a mass at the bladder neck or prostatic region, clinicians should remain alert to the possibility of prostatic involvement by bladder-derived urothelial carcinoma, and a routine immunohistochemical panel including GATA3, CK7, CK20, p63, Uroplakin III, PSA, and NKX3.1 should be used early for differential diagnosis. Prostatic stromal invasion combined with lymphovascular invasion, perineural invasion, and a positive surgical margin may indicate highly aggressive disease and an increased risk of early distant metastasis, requiring more active postoperative risk assessment, systemic treatment decision-making, and close follow-up. When perioperative or adjuvant systemic therapy cannot be administered or completed, any deviation from the recommended treatment plan should be thoroughly documented, discussed with the patient, and taken into consideration when interpreting early recurrence. In this case, the early bone metastases are best interpreted as a consequence of both aggressive pathological risk factors and the incomplete delivery of systemic therapy, rather than as a novel diagnostic entity. The patient is currently continuing treatment and follow-up.

Subject of Research: Case report of bladder urothelial carcinoma with prostatic stromal invasion and early postoperative bone metastases

Article Title: Urothelial carcinoma of the bladder with prostatic stromal invasion and early postoperative bone metastases: a case report

Article References: Wang, C., Wang, M., & He, Y. (2026). Urothelial carcinoma of the bladder with prostatic stromal invasion and early postoperative bone metastases: a case report. Frontiers in Urology, 6, Article 1910163. https://doi.org/10.3389/fruro.2026.1910163

Image Credits: AI Generated

DOI: 10.3389/fruro.2026.1910163

Keywords: urothelial carcinoma, prostatic stromal invasion, bone metastases, immunohistochemistry, PSA, radical cystectomy, denosumab, case report, Urothelial, carcinoma, bladder, prostatic