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Reply to Counterpoint
Progression of T1 Bladder
Tumors: Better Staging or Better
Liang Cheng, M.D.1
David G. Bostwick,
Department of Pathology and Urology, Indiana University School of Medicine, Indianapolis,
Department of Pathology and Urology, Mayo Clinic, Rochester, Minnesota.
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.
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:
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
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.
Platz CE, Cohen MB, Jones MP, Olson DB, Lynch CF. Is
microstaging of early invasive cancer of the urinary bladder
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Kondylis F, Emirci S, Ladaga L, Kolm P, Schellhammer P.
Outcome after intravesical BCG is not affected by T1a/T1b
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Weizer A, Green A, Shaw C, Wheeler T, Lerner S. Risk assessment of T1 transitional cell carcinoma of the bladder
using p53 immunohistochemistry and pathologic substaging. J Urol 1999;161:315A.
Epstein JI, Amin MB, Reuter VR, Mostofi FK, and the Bladder
Consensus Conference Committee. The World Health Organization/International Society of Urologic Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 1998;22:
1435– 48.
Cheng L, Weaver AL, Neumann RM, Scherer BG, Bostwick
DG. Substaging of T1 bladder carcinoma based on the depth
of invasion measured by micrometer: a new proposal. Cancer 1999;86:1035– 43.
Cheng L, Neumann RM, Scherer BG, Weaver AL, Leibovich
BC, Nehra A, et al. Tumor size predicts the survival of
patients with pathologic stage T2 bladder carcinoma: a critical evaluation of the depth of muscle invasion. Cancer
1999;85:2638 – 47.
Soloway MS, Lopez AE, Patel J, Lu Y. Results of radical
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and the effect of chemotherapy. Cancer 1994;73:1926 –31.
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CANCER September 15, 1999 / Volume 86 / Number 6
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WR. Neoadjuvant chemotherapy in invasive bladder cancer:
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19. Cheng L, Neumann RM, Weaver AL, Spotts BE, Bostwick
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