Advances in Therapy for Urothelial and Non-Urothelial Subtype Histologies of Advanced Bladder Cancer: From Etiology to Current Development

Abstract

Urothelial carcinoma (UC) is the most common histological subtype of bladder tumors; however, bladder cancer represents a heterogeneous group of diseases with at least 40 distinct histological subtypes. Among these, the 2022 World Health Organization classification of urinary tract tumors identifies a range of less common subtypes of invasive UC, formerly known as variants, which are considered high-grade tumors, including squamous cell, small-cell, sarcomatoid urothelial, micropapillary, plasmacytoid, and urachal carcinomas, and adenocarcinoma. Their accurate histological diagnosis is critical for risk stratification and therapeutic decision-making, as most subtype histologies are associated with poorer outcomes than conventional UC. Despite the importance of a precise diagnosis, high-quality evidence on optimal treatments for subtype histologies remains limited owing to their rarity. In particular, neoadjuvant and adjuvant chemotherapy have not been well characterized, and prospective data are scarce. For advanced-stage diseases, clinical trial participation is strongly recommended to address the lack of robust evidence. Advances in molecular pathology and the development of targeted therapies and immunotherapies have reshaped our understanding and classification of bladder cancer subtypes, spurring efforts to identify predictive biomarkers to guide personalized treatment strategies. Nevertheless, the management of rare bladder cancer subgroups remains challenging because they are frequently excluded from clinical trials. For localized disease, curative options such as surgical resection or radiotherapy are available; however, treatment options become more limited in recurrence or metastasis, where systemic therapy is primarily used to control disease progression and palliate symptoms. Herein, we present recent advances in the management of urothelial and non-urothelial bladder cancer subtypes and also explore the current evidence guiding their treatment and emphasize the challenges and perspectives of future therapeutic strategies.

Keywords: FGFR inhibitors; antibody–drug conjugates; bladder cancer; chemotherapy; immunotherapy; non-urothelial cancer; subtype histologies; urothelial cancer.

Figure 1

(A) Micropapillary subtype of UC (H&E); multiple small nests of tumor cells with surrounding lacunar (empty) space are a classic feature and may be the most helpful feature in making the diagnosis. (B) Plasmacytoid subtype of UC (H&E); discohesive single cells with eccentrically placed nuclei and abundant eosinophilic cytoplasm, which are often deeply infiltrative but with minimal stromal reaction. (C) Sarcomatoid urothelial carcinoma (H&E); malignant spindled cells with a nonspecific morphologic appearance and a mesenchymal-like growth pattern. The most common component is an undifferentiated high-grade spindle cell sarcoma, as in this figure. (D) Bladder squamous cell carcinoma (H&E); keratinization and intercellular bridges, features consistent with squamous differentiation. (E) Neuroendocrine bladder cancer (H&E); small, round cells with a high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and fine chromatin, typical of neuroendocrine differentiation. (F) Bladder adenocarcinoma (H&E); prominent glandular formation of columnar cells and potential mucin production, raising the differential diagnosis of spread from the gastrointestinal tract or other primary sites. Abbreviations: UC, urothelial carcinoma; H&E, hematoxylin and eosin.

Figure 1

(A) Micropapillary subtype of UC (H&E); multiple small nests of tumor cells with surrounding lacunar (empty) space are a classic feature and may be the most helpful feature in making the diagnosis. (B) Plasmacytoid subtype of UC (H&E); discohesive single cells with eccentrically placed nuclei and abundant eosinophilic cytoplasm, which are often deeply infiltrative but with minimal stromal reaction. (C) Sarcomatoid urothelial carcinoma (H&E); malignant spindled cells with a nonspecific morphologic appearance and a mesenchymal-like growth pattern. The most common component is an undifferentiated high-grade spindle cell sarcoma, as in this figure. (D) Bladder squamous cell carcinoma (H&E); keratinization and intercellular bridges, features consistent with squamous differentiation. (E) Neuroendocrine bladder cancer (H&E); small, round cells with a high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and fine chromatin, typical of neuroendocrine differentiation. (F) Bladder adenocarcinoma (H&E); prominent glandular formation of columnar cells and potential mucin production, raising the differential diagnosis of spread from the gastrointestinal tract or other primary sites. Abbreviations: UC, urothelial carcinoma; H&E, hematoxylin and eosin.