910 E D I T O R I A L Reply to Counterpoint Progression of T1 Bladder Tumors: Better Staging or Better Biology? Reply Liang Cheng, M.D.1 David G. Bostwick, 2 M.D. 1 Department of Pathology and Urology, Indiana University School of Medicine, Indianapolis, Indiana. 2 Department of Pathology and Urology, Mayo Clinic, Rochester, Minnesota. I See editorial counterpoint on pages 908 –9 and referenced original article on pages 1035– 43. Dr. Bostwick is now at Bostwick Laboratories, 6722 Patterson Avenue, Richmond, VA 23226. E-mail: email@example.com Address for reprints: Liang Cheng, M.D., Department of Pathology and Urology, UH 3465, Indiana University School of Medicine, 550 North University Blvd., Indianapolis, IN 46202. E-mail: firstname.lastname@example.org Received June 9, 1999; accepted June 9, 1999. © 1999 American Cancer Society t has been recognized that T1 bladder carcinoma represents a heterogeneity of disease with different biologic potentials. Up to 50% of patients with T1 bladder carcinoma diagnosed using transurethral resection specimens will develop cancer progression within 5 years after the diagnosis. It is critical to distinguish patients who will develop cancer progression from those who will not, considering that many nonsurgical approaches are now available for patients who want to preserve their bladder function. Several proposals for the subclassification of T1 bladder carcinoma were made in recent years. Essentially, all these proposals were based on the identification of invasion of the muscularis mucosae. The use of an ill-defined histologic landmark for staging is problematic. In one study, only 15% of carefully examined biopsy specimens were found to contain muscularis mucosae. A significant number of patients will not have muscularis mucosae present at all. It is not surprising to find that 48% of patients could not be staged based on muscularis mucosae invasion in one study. Evidence emerged that the depth of invasion based on the assessment of muscularis mucosae may not be as important as initially believed.1–3 More recently, it was recommended by the World Health Organization and International Society of Urologic Pathology that “substage tumor invading the lamina propria based on the relationship of tumor to the muscularis mucosae (above, at or below) should not be universally adopted or advocated to pathologists.”4 There is a substantial need for a universal, practical, and clinically useful staging system for the classification of T1 bladder carcinoma. We studied 55 patients with T1 bladder carcinoma that was detected by transurethral resection of the bladder (TURB) prior to the Bacille Calmette-Gúerin (BCG) era.5 All the patients subsequently were treated by cystectomy. The depth of invasion in TURB specimens was measured by ocular micrometer. We found that the depth of invasion predicted final pathologic stage. Approximately 95% of patients with a depth of invasion of $1.5 mm were found to have Reply to Counterpoint/Cheng and Bostwick muscle invasive or higher stage bladder carcinoma in the cystectomy specimens. Our data suggest that the depth of invasion, measured by micrometer, may provide a more accurate indication of tumor spread at the time of diagnosis than the use of depth of invasion determined by invasion at the level of muscularis mucosae. We previously reported that the mean thickness of the lamina propria in the bladder was 1.4 mm,6 suggesting that patients with a depth of invasion $1.5 mm may harbor more advanced bladder carcinoma that was not sampled. We recognize that our study may have several potential limitations. The study cohort was highly selected and the majority of patients (93%) had high grade carcinoma. All patients received cystectomy after the diagnosis of T1 bladder carcinoma (median interval from TURB to cystectomy, 10 days). The factors that influenced the decision to proceed with cystectomy in these patients were varied and selection criteria were not standardized. We found that a significant number of patients were understaged. Approximately 40% of patients were clinically understaged in other studies.7–12 Dr. Herr claims that 90% of tumors can be staged correctly by experienced urologists and experienced pathologists. However, this is not supported by existing data.7–12 The patients in our series were from a pre-BCG era as stated, and may not be fully representative of the earlier stage detection observed in many of the contemporary patients. Nonetheless, staging of bladder urothelial carcinoma remains a serious issue, and we do not accept that only 10% of cases are understaged, even at this time. In this study, the muscularis propria was present in the biopsy specimens in 19 patients (35%). It may be difficult to sample muscle wall or demonstrate muscle wall invasion in the TURB specimens when the tumor is deeply invasive and extensively destroying adjacent normal tissues. It is not well recognized that the distribution of muscle layers is not uniform or continuous in the normal bladder. A variable amount of fibrous connective tissue exists in the muscle wall, compounding the diagnosis of muscularis propria invasion. Furthermore, the tumor may elicit a prominent desmoplastic reaction surrounding the tumor cells. The distinction of muscle wall invasion from desmoplastic stromal reaction may not always be straightforward. The tumor borders may not always be infiltrative, further compounding the interpretation of biopsy specimens. Identification of tumor in the adipose tissue should not be equated as extravesical extension because adipose tissue normally is present in the lamina propria and muscle wall.13 The use of “large vessels” as a substitute for muscularis mucosae for staging1,14 –18 is subject to error. We agree that 911 adequate sampling should be undertaken as the initial step in the management of patients with bladder carcinoma. A repeat biopsy may be indicated for patients who initially are diagnosed with T1 bladder carcinoma. With recent advances in immunotherapy for bladder carcinoma, many patients choose bladder preservation. However, radical cystectomy offers the best opportunity of cure for patients with early stage bladder carcinoma. The key issue in the management of T1 bladder carcinoma is to identify prospectively patients at risk of disease (or stage) progression. We recently validated the proposed classification system in a large series of patients with biopsy-proven T1 tumors who were treated by contemporary therapeutic modalities.19 Among 83 patients with T1 bladder carcinoma who had a median follow-up of 5.4 years, the 5-year disease (stage) progression free survival rate was 67% for patients with a depth of invasion $1.5 mm, compared with a 5-year progression free survival rate of 93% in patients with a depth of invasion ,1.5 mm (P 5 0.009).19 Additional confirmatory studies of this micrometer-based measurement of depth of invasion will be needed before its adoption into the TNM classification system. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. Platz CE, Cohen MB, Jones MP, Olson DB, Lynch CF. Is microstaging of early invasive cancer of the urinary bladder possible or useful? Mod Pathol 1996;11:1035–9. Kondylis F, Emirci S, Ladaga L, Kolm P, Schellhammer P. Outcome after intravesical BCG is not affected by T1a/T1b substage. J Urol 1999;161:284A. 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