Challenges in Pathologic Staging of Bladder Cancer: Proposals for Fresh Approaches of Assessing Pathologic Stage in Light of Recent Studies and Observations Pertaining to Bladder Histoanatomic Variances

The paradigm of pathologic stage (pT) categorization in bladder cancer remains the depth of invasion into the different histologic layers of the bladder wall. However, the approaches to assigning pT stage category toward an enhanced outcome stratification have been marked by challenges and innovations, due in part to our growing appreciation of the surprisingly perplexing bladder histoanatomy. Upstaging of pT1 tumors after radical cystectomy is substantial and underscores the potential value of pT1 substaging in transurethral resection (TUR) specimens. The 2017 American Joint Committee on Cancer tumor-node-metastasis system recommends pT1 substaging but recognizes the need to optimize the approach. Over the years, the cut-off for microinvasion has been significantly lowered to 0.5mm and is now a promising scheme for pT1 (micrometric) substaging. Unlike the micrometric approach, histoanatomic substaging using muscularis mucosae (MM) and vascular plexus as landmarks is less feasible in TUR specimens and inconsistent in stratifying the outcome of pT1 tumors. The lamina propria possesses inherent variations in depth, MM, and vascular plexus dispositions that should be factored in future pT1 substaging proposals. Histoanatomic variations among the bladder regions also occur, and studies suggest that trigone and bladder neck cancers may have more adverse outcomes. The muscularis propria (MP), besides being the essential histologic landmark for assigning pT2 stage category, is also considered a surrogate for the adequacy of TUR, furthering the importance of identifying its presence in TUR specimens. MP, however, may be mimicked by hyperplastic or isolated MP-like MM muscle bundles in the lamina propria with overstaging implications, and caution should be exercised in distinguishing these 2 muscle types morphologically and immunohistochemically. Presence of additional superficial MP unique from the detrusor muscle proper may also complicate staging at the trigone and ureter insertion sites. With regard to the depth of MP invasion, large and multicenter studies have reaffirmed the prognostic significance of pT2a/b subcategories. It is revealed that there are at least 3 ways used to demarcate the irregular MP to perivesical soft tissue junction, and use of a common criterion indicates improvement in pT2b/pT3a staging reproducibility. Although studies have shown significantly poorer outcome in pT3b compared with pT3a tumors, this designation has a substantial reliance on the prosector's gross assessment of perivesical soft tissue invasion which if performed incorrectly may lead to staging inaccuracy of pT3 tumors. The 8th edition of the American Joint Committee on Cancer has updated the staging schema for bladder cancers with concomitant prostatic stromal invasion and cancers within bladder diverticula. Because of 2 possible pT designations, prostatic stromal invasion in TUR specimens should not be automatically staged as either pT4a or pT2 (urethral). Recent data support that bladder cancer invading into the seminal vesicle has comparable outcome to pT4b tumors. Interestingly, several studies in pT4a tumors, which are staged based on sex-specific organs, have shown poorer outcome in females than males after radical cystectomy, and while there are possibly several reasons, they may also include anatomic factors. Despite the progress has been made, work remains to be done to inform future bladder cancer pT category definitions and their reproducibility in application and prognostication.