—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 4 - pT1 Urothelial Carcinoma of the Bladder

Rafael Jimenez
Mayo Clinic
Rochester, MN





Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:



under each thumbnail image below. You must have Aperio ImageScope installed on your PC.
If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy:  
Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.

If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.



Introduction
Stage is the most powerful prognostic indicator in urothelial carcinoma, and a major defining parameter in the management of this disease [1]. The TNM staging system defines pT1 tumors as those invading into the lamina propria (LP), but not the muscularis propria (MP) [2]. Although it has been demonstrated in several studies that pT1 tumors bear a less favorable prognosis than pTa (non invasive) neoplasms [3, 4, 5, 6], clinically they are both usually lumped together under the term "superficial" or "non-muscle invasive" bladder tumors. Beside the fact that tumors classified in these two stages traditionally have been managed conservatively, another possible factor contributing to the clinicians' rationale in grouping pTa and pT1 tumors as "superficial" is the pathologists' difficulty in accurately recognizing LP invasion. On the contrary, those tumors with involvement of the MP and beyond (pT2-4, or "invasive" tumors) are usually managed with aggressive surgical therapy (i.e. cystectomy). While an argument in favor of cystectomy for LP invasive tumors of high grade has been made [7, 8, 9], others have focused in attempting to identify additional pathologic prognostic markers in LP invasive disease. This has made accurate histopathology recognition of invasion into LP even more important, and has inevitably raised an important question as to whether the pathologist should sub-stage pT1 disease.


Case 4 - Slide 1
Click to view with ImageScope
Click to view with a Web-Based Viewer

Histology of the Superficial Bladder Wall
The subepithelial layer of the bladder wall is divided by a thin layer of smooth muscle fibers (muscularis mucosae [MM]) into a LP, which is superficial, and a submucosal layer, located between the MM and MP. It was not until relatively recently that the MM layer of the urinary bladder was described [10, 11, 12], alerting pathologists and urologists of the importance of its recognition and differentiation from the underlying compact smooth muscle bundles of MP. MM fibers are usually thin, often discontinuous, wispy and wavy fascicles of smooth muscle, which are frequently associated with large caliber blood vessels, and surrounded by loose fibroconnective tissue. Most studies have identified some degree of this layer in 94-100% of cystectomy specimens [11, 12], and in about a third of specimens from biopsies or TURBT [13, 14]. MP fascicles, on the other hand, are usually thick and compact, divided into distinct bundles surrounded by perimysium. Occasionally, MM bundles may undergo hypertrophy and the distinction between MM and MP, especially in biopsy or TURBT specimens, may be difficult. Significant variations in thickness, distribution, and depth of the MM, as well as its relationship with the vascular plexus associated with it, have been recently described, complicating its differentiation from MP and raising concerns about its potential use as topographic landmarks for staging neoplasms [15, 16].

Diagnosis of Lamina Propria Invasion
Recognition of LP invasion by urothelial carcinoma is one of the most challenging diagnoses in surgical pathology [17]. Often faced with distorted, cauterized, and tangentially sectioned specimens, the pathologist should follow strict criteria to diagnose LP invasion. While evaluating tumors for invasion, it is important to focus in the following features: a) histologic grade of tumor, b) characteristics of the invading epithelium, c) the stromal response, d) the histologic pattern of invasion and e) possible pitfalls.
  1. Histologic grade: LP invasion should be carefully looked for in all high grade papillary carcinomas. While invasion is not necessarily an unexpected finding in low grade tumors, it is much more common in high grade lesions. In Jordan et al.'s series [18], 96.5% of invasive carcinomas were grade III (1973 WHO classification). Similarly, of 53 patients with pT1 disease in Malmström et al.'s series [19], 37 (70%) were grades 2b and higher, which roughly equate to the high grade papillary urothelial carcinomas of the 2004 WHO [20, 21]. Thus, while clear cut histologic signs of invasion are required for the diagnosis of invasion into LP, the level of suspicion should be higher in those cases with a high histologic grade.

  2. Invading epithelium: The invasive front of the neoplasm may show one of several features: single cells or irregularly shaped nests of tumor within the stroma, architectural complexity not conforming to the usual regularity of papillary neoplasms, or an irregular, disrupted, or absent basement membrane. Sometimes tentacular or finger-like extensions can be seen arising from the base of the papillary tumor. Frequently the invading nests appear morphologically different from the cells at the base of the non-invasive component of the tumor, with more abundant cytoplasm and often with a higher degree of pleomorphism.

  3. Stromal response: The LP may react to invasion in one or more of the following forms:
    • Desmoplastic or sclerotic stroma

    • Retraction artifact

    • Inflamed stroma

    • Myxoid stroma

    • Pseudosarcomatous stroma

    • Absent stromal response

Histologic Patterns of Lamina Propria Invasion
LP invasive tumors may be classified from their morphologic perspective according to several patterns. Awareness of these patterns may be important to the surgical pathologist in order to focus on particular areas of the tumor while assessing for invasion, thus facilitating its recognition, even when it is extremely focal.
  1. Carcinoma in situ (CIS) with microinvasion: Isolated CIS (i.e. in the absence of papillary and/or invasive neoplasm) is rare, representing approximately 1% of bladder neoplasms [22]. Microinvasion by CIS is defined by Farrow et al. [6] as an invasive component measuring less than 5 mm in depth. In their study, these authors found microinvasion in 34% of a series of entirely-submitted bladders harboring CIS, and in 5.8% of these cases metastatic disease developed, causing the patients' demise.

  2. Papillary urothelial carcinoma with microinvasion: Microinvasion of papillary tumors can be similarly defined as in cases with CIS, and should be mentioned in the diagnosis, in order to document minimal, focal or early invasion.

  3. Papillary urothelial carcinoma with invasion into stalk: Very rarely papillary urothelial carcinomas may invade into the stalk of a tumor. Appreciation of this pattern requires optimal orientation of the entire papillary tumor, which may not always be the case, especially in TURBT specimens.

  4. Well-established invasion into underlying LP: In the overwhelming majority of cases, invasion is seen at the base of the papillary neoplasm.

  5. Urothelial carcinoma with endophytic or broad front growth pattern: A more problematic pattern is seen in large papillary tumors which display a prominent endophytic growth, and thus "invade" the LP with a pushing border, much akin to cutaneous and mucosal verrucous carcinoma [23]. Unless this pattern is accompanied by true destructive stromal invasion (as defined above), the likelihood of metastasis in tumors with this histology is minimal, because the basement membrane is not truly breached.
Problems and Pitfalls in the diagnosis of pT1 carcinoma
Diagnosis of LP invasion is often difficult, and the problem is well exemplified in the data from the French Association of Urology Cancer Committee study [24], which revealed that seven experienced pathologists could agree on LP invasion in only 61% of cases after 3 assessments. In 10% of cases, no consensus was achieved despite 4 evaluations. In another study by Abel et al. [25], 15% of lesions initially diagnosed as pT1 were downstaged to pTa by a "dedicated" pathologist. In order to improve the concordance rates among pathologists, it is imperative to be aware and understand the possible pitfalls in the diagnosis of LP invasion. The most common ones are:
  1. Tangential sectioning and poor orientation: TURBT specimens are excised in a piece-meal fashion. This renders fragmented specimens, which are usually poorly oriented. Further, due to their complex architecture, papillary tumors are inevitably tangentially sectioned in multiple planes, resulting in isolated nests of tumor cells within connective tissue. Smooth, round, and regular contours favor tangential sectioning, whereas irregular, jagged nests with haphazard arrangement favors stromal invasion.

  2. Thermal injury: Thermal injury or cautery artifact produces severely distorted morphology in TURBT specimens, and is a frequent source of distress for the pathologist. Unfortunately, pathologists have no control over this problem, although occasionally deeper levels may display better preserved areas. When this is not helpful, the pathologist should express its inability to render a definitive diagnosis due to thermal effect.

  3. Obscuring inflammation: Papillary tumors may show variable, often brisk inflammation at the tumor-stromal interface, which may obscure isolated cells or nests of invasive tumor.

  4. CIS involving von Brunn's nests: Flat lesions, when they involve von Brunn's nests may mimic LP invasion by the mere presence of high grade cells in a submucosal location. This is especially problematic in prominent nests or those that have been distorted by an inflammatory process.

  5. Muscle invasion indeterminate for type of muscle: In these cases invasive tumor is seen juxtaposed to muscle fibers, but due to obscuring factors (i.e. inflammation, tangential sectioning, cautery artifact, strong desmoplastic response, or poor orientation), the pathologist is unable to determine whether the muscle involved belongs to the MM or the MP. It is recommended that when faced with this situation, the pathologist should clearly state their uncertainty in establishing the depth of invasion, rather than to commit to a particular type of muscle involvement-MM (pT1) or MP (pT2). This distinction is critical, as MP invasion is currently regarded as the crossroads between conservative management and aggressive therapy. Recently, Paner et al. [26] described a novel antibody, smoothelin, which is strongly expressed in smooth muscle from the MP, but not from the MM. When only strong and diffuse immunoreactivity was considered positive, these authors obtained 100% specificity and positive predictive value of smoothelin for MP vs. MM. The potential use of this marker in the clinical setting to facilitate adequate staging of bladder tumors is evident. Current studies are in progress to test this marker in the clinical setting.

  6. Prominent demoplastic reaction: Some invasive tumors elicit a strong desmoplastic reaction that can be on occasion confused with invasion of muscle tissue. The problem is further complicated when traditional muscle markers, such as desmin or smooth muscle actin, are use to evaluate these specimens, as this myofibroblast-rich proliferation frequently expresses these markers. A suburothelial band of myofibroblasts in the LP has recently been described [26], which could be partially responsible for this sometimes exuberant desmoplastic reaction. In this study, these fibers were negative for smoothelin expression, which could potentially avoid their misinterpretation as fibers from the MP.

  7. Deceptively bland variants of urothelial carcinomas: When limited to the LP, deceptively bland patterns of invasive urothelial carcinoma such as microcystic urothelial carcinoma or the "nested" pattern may make the recognition of pT1 disease extremely difficult [27, 28].

  8. Potential for understaging: pT1 disease diagnosed on TUR specimens can be associated with significant understaging of the tumor. Cheng et al. [29] in a series of matched TURB and cystectomy specimens, found that 43 of 55 patients with stage T1 carcinoma at TURB had advanced-stage carcinoma at cystectomy, including 34 who had extravesicular extension (pT3 or more). Similarly, Chang et al. [30] found that 45% of their pT1 tumors on TURBT were upstaged on the cystectomy specimen. These findings are likely complicated by the fact that MP is not included in the sample of TURBT specimens in up to 51% of cases. [31]
Applying strict morphologic criteria for the diagnosis of LP invasion should minimize diagnostic discrepancies among pathologists. Admission of the inability to definitively identify invasion is appropriate in difficult cases with suboptimal tissue preservation or orientation.

Substaging of pT1 disease
Several studies have looked at the issue of substaging pT1 urothelial carcinomas (See table). In 1990 Younes et al. [32] found a 75% all-cause 5 year survival for tumors invading above or into the MM, compared to a 11% survival for those tumors invading below the MM. Similarly, Hasui et al. [33], Angulo et al. [13], and more recently Orsola et al. [34] were able to find different progression rates and/or, 5-year all-cause survival for those tumors with invasion above and below the MM (see below). The main problem with this method of substaging pT1 urothelial carcinomas, is that the MM, as mentioned before, is not a consistent histologic finding in bladder tumor resection specimens. Most of the above mentioned authors have at least partially overcome this problem by using the large blood vessels in the submucosa as a substitute anatomical landmark when MM was not present. For example, Angulo et al. [13] were able to identify MM in 39% of their cases, and used the blood vessels landmark in a remaining 26%. Thus, in 35% of their cases, substaging could not be performed. Paner et al. [15] recently described significant inconsistencies in the anatomy of MM among different specimens and among different regions of the bladder. Among these are the very superficial location of the MM in the trigone, and occurrence of deeply situated bundles of hyperplastic MM beyond the vascular plexus. These findings have prompted recent questioning of whether substaging pT1 disease based on the MM is recommended. In 1999, Cheng et al. [35] proposed a system of substaging pT1 tumors based on the micrometrical measurement of the depth of invasion. By using 1.5 mm of depth of invasion, they were able to predict advanced stage in the cystectomy with a sensitivity of 81%, a specificity of 83%, and a positive and negative predictive value of 95% and 56%, respectively. They further applied the same criteria to a group of 83 consecutive patients diagnosed with pT1 bladder cancer and found a 5-year progression free survival of 67% in patients with a tumor >1.5 mm in depth, compared to 93% for those tumor with a depth of <1.5 mm. This method is limited, however, by its practicality. Further, cauterized, maloriented, and fragmented specimens may prove challenging to measure. The collective data implies that deep LP (i.e. submucosal) invasion, whether assessed by the relation of the tumor to the MM, or by direct micrometrical measurement, identifies a subset of patients with pT1 disease with a more adverse prognosis. However, so far there appears to exist no consensus regarding the best way to determine and report the extent of invasion.

Proposed Substaging Systems for pT1 Urothelial Carcinoma

Authors Susbstaging system Outcome Endpoint
Younes et al. [32] T1a: Invasion above muscularis mucosae 75% 5 year all-cause survival
T1b: Invasion at muscularis mucosae
T1c: Invasion below muscularis mucosae 11%
Hasui et al. [33] T1a: Invasion above muscularis mucosae 7% Progression rate
T1b: Invasion below muscularis mucosae 54%
Angulo et al. [13] T1a: Invasion above or at muscularis mucosae 86% 5-year all-cause survival
T1b: Invasion below muscularis mucosae 52%
Platz et al. [14] T1a: Invasion above muscularis mucosae 65% 10-year cancer-specific survival
T1b: Invasion at muscularis mucosae 54%
T1c: Invasion below muscularis mucosae 60%
Holmang et al. [36] T1a: Invasion above muscularis mucosae 23% Disease-specific demise
T1b: Invasion at or below muscularis mucosae 45%
Hermann et al. [37] T1a: Invasion limited to stalk of papillae 78% 5-year all cause survival
T1b: Invasion above muscularis mucosae 75%
T1c: Invasion at or below muscularis mucosae 55%
Smits et al [38] pT1a: Invasion up to muscularis mucosae 6%3-year risk for progression
pT1b: Invasion into muscularis mucosae 33%
pT1c: Invasion beyond muscularis mucosae 55%
Orsola et al [34] pT1a: Invasion up to muscularis mucosae 8% Recurrence rate
pT1b: Invasion into muscularis mucosae 30%
pT1c: Invasion beyond muscularis mucosae 35%
Cheng et al. [35] Depth of invasion measured by micrometer < 1.5 mm 93% 5-year progression-free survival
> 1.5 mm 67%

Other prognostic factors
The reasons for heterogeneous behavior in patients with pT1 tumors may be explained by factors besides the extent of invasion.
  1. Grading : Grading of urothelial carcinomas has been identified as a significant predictor of subsequent progression to muscle-invasive disease. Invasive tumors should not be automatically regarded as high grade, as Angulo et al. [13] reported 41% of their pT1a tumors, and 18% of their pT1b tumors to be grade I, and 45% and 60%, respectively, to be grade II (1973 WHO classification). Hermann et al. [37] found no grade 0 or 1 in their series of pT1 tumors, but 21%, 19% and 8% of their pT1a, pT1b and pT1c tumors, respectively, were grade 2 (modified Bergvist system). Kaubisch et al. [39] found progression to muscle-invasive disease in 0% grade I, 22% of grades II, and 50% of grade III pT1 tumors (1973 WHO classification). These data support that pT1 tumors should be graded in the same fashion as pTa tumors, and that LP invasion does not necessarily equate a high grade disease.

  2. Vascular invasion: Data on the impact of vascular invasion in urothelial carcinoma is conflicting and difficult to interpret, due mostly to the fact that in the urinary bladder vascular invasion is difficult to recognize histologically and easily overdiagnosed. As discussed earlier, invasion into LP by carcinoma is usually associated with a retraction artifact of the stroma which can easily be interpreted as lymphatic vessel invasion. Vascular invasion was confirmed with endothelial markers in only 14% and 40% of cases in two studies in which it was originally suspected with routine light microscopy [40, 41]. These data raises questions regarding previously reported incidence of vascular invasion and its impact on prognosis.

  3. Multicentricity and tumor size: Tumor size, as assessed at time of cystoscopy correlates with muscle-invasive disease. In Heney et al.'s series, superficial tumors larger than 5 cm were associated with a risk of progression of 35%, compared to 9% for tumors smaller than 5 cm [42]. Similarly, multicentricity (i.e. presence of multiple tumors at the time of cystoscopy) is related to both recurrence and progression. In one study [43], 46% of solitary superficial tumors recurred, compared to 73% of multifocal tumors; progression was seen in 24% of solitary tumors, compared to 44% of multifocal tumors.

  4. Adjacent CIS: The presence of CIS in the mucosa adjacent to the papillary tumor has been associated with a higher risk of recurrence and progression. Bono et al. [44] reported recurrence rates of 85% and 44% in patients with pT1 grade 3-tumors, with and without associated CIS, respectively. Further, the incidence of progression to invasive disease was 36% in patients with associated CIS, compared to 18% for patients without this association. In Orsola et al.'s series [34] 47% of tumors associated with CIS progressed compared to 14% of tumors without CIS. CIS remained an independent prognostic factor on multivariate analysis.

Clinical Management of pT1 Disease
pT1 urothelial carcinoma is managerially different from muscle-invasive urothelial carcinoma. Similarly, its management may be significantly different from that of non-invasive urothelial carcinoma (i.e. pTa or pTis). Thus, the main implication of a diagnosis of pT1 disease is that it defines a unique management for the patient with bladder cancer. The baseline treatment for pT1 urothelial carcinoma (and for that matter, for pTa carcinoma) is TUR of the tumor. This resection should attempt to:
  • provide adequate tissue for pathologic analysis

  • remove all visible disease

  • provide tissue from the MP for adequate staging. If no MP is identified in the sample, repeat resection should be performed prior to additional therapy.
However, pT1 and other "high risk" neoplasms (i.e. high grade, CIS) only treated with TUR recur within the first year in up to 60% of cases [45]. Thus, pT1 tumors are usually managed with a combination of TUR and postoperative intravesical therapy, as the latter significantly drops the recurrence rate to around 15%. There seems to be a more dramatic drop in patients treated with BCG (i.e. immunotherapy) vs. patients treated with intravesical chemotherapy (e.g mytomycin) [45]. Further, there is evidence that BCG may prevent progression in the setting of pT1 disease [46]. However, this potential benefit may be outweighed by the higher incidence of side effects and cost of BCG therapy, compared to intravesical chemotherapy.

Cystectomy may be considered as first line therapy in select patients with pT1 disease. The rationale for radical therapy in these cases includes the relatively high risk of understaging, the relatively high rate of progression, and the high cure rate associated with cystectomy. Patients with pT1 tumors who may benefit from this approach include patients with large tumor size, tumor location in poorly accessible areas, diffuse disease, associated CIS, lymphovascular invasion, and prostatic urethral involvement [7, 8, 9, 45]. The role of cystectomy appears clearer in patients with pT1 disease that recur after prior intravesical therapy. While there is some evidence that a select group of patients may respond to second induction regimens of intravesical therapy (particularly BCG) [47], due to the high likelihood of progression and the adverse consequences of delaying radical surgery, cystectomy appears the preferred treatment for these patients [45].

References
  1. Mazzucchelli, L., et al., Invasion depth is the most important prognostic factor for transitional- cell carcinoma in a prospective trial of radical cystectomy and adjuvant chemotherapy. Int J Cancer, 1994. 57(1): p. 15-20.

  2. American, J.C.C., AJCC cancer staging manual. 6 ed. 2002: Lippincott-Raven. 302.

  3. Anderstrom, C., S. Johansson, and S. Nilsson, The significance of lamina propria invasion on the prognosis of patients with bladder tumors. J Urol, 1980. 124(1): p. 23-6.

  4. Williams, J.L., J.C. Hammonds, and N. Saunders, T1 bladder tumours. Br J Urol, 1977. 49(7): p. 663-8.

  5. Kiemeney, L.A., et al., The clinical epidemiology of superficial bladder cancer. Dutch South- East Cooperative Urological Group. Br J Cancer, 1993. 67(4): p. 806-12.

  6. Farrow, G.M. and D.C. Utz, Observations on microinvasive transitional cell carcinoma of the urinary bladder. Clin Oncol, 1982. 1: p. 609-14.

  7. Esrig, D., et al., Early cystectomy for clinical stage T1 transitional cell carcinoma of the bladder. Seminars in Urologic Oncology, 1997. 15(3): p. 154-60.

  8. Takashi, M., et al., Grade 3 bladder cancer with lamina propria invasion (pT1): characteristics of tumor and clinical course. Nagoya J Med Sci, 1991. 53(1-4): p. 1-8.

  9. Bianco, F.J., Jr., et al., Management of clinical T1 bladder transitional cell carcinoma by radical cystectomy. Urol Oncol, 2004. 22(4): p. 290-4.

  10. Dixon, J.S. and J.A. Gosling, Histology and fine structure of the muscularis mucosae of the human urinary bladder. J Anat, 1983. 136(2): p. 265-71.

  11. Ro, J.Y., A.G. Ayala, and A. el-Naggar, Muscularis mucosa of urinary bladder. Importance for staging and treatment. Am J Surg Pathol, 1987. 11(9): p. 668-73.

  12. Keep, J.C., et al., Invasive carcinomas of the urinary bladder. Evaluation of tunica muscularis mucosae involvement. Am J Clin Pathol, 1989. 91(5): p. 575-9.

  13. Angulo, J.C., et al., Muscularis mucosa differentiates two populations with different prognosis in stage T1 bladder cancer. Urology, 1995. 45(1): p. 47-53.

  14. Platz, C.E., et al., Is microstaging of early invasive cancer of the urinary bladder possible or useful? Mod Pathol, 1996. 9(11): p. 1035-9.

  15. Paner, G.P., et al., Further characterization of the muscle layers and lamina propria of the urinary bladder by systematic histologic mapping: implications for pathologic staging of invasive urothelial carcinoma. Am J Surg Pathol, 2007. 31(9): p. 1420-9.

  16. Vakar-Lopez, F., et al., Muscularis mucosae of the urinary bladder revisited with emphasis on its hyperplastic patterns: a study of a large series of cystectomy specimens. Ann Diagn Pathol, 2007. 11(6): p. 395-401.

  17. Amin, M., et al., Controversies in the pathology of transitional cell carcinoma of the urinary bladder. Part II., in Reviews of Pathology, P.P. Rosen and R.E. Fechner, Editors. 1997, ASCP press: Chicago, IL. p. 72-100.

  18. Jordan, A.M., J. Weingarten, and W.M. Murphy, Transitional cell neoplasms of the urinary bladder. Can biologic potential be predicted from histologic grading? [published erratum appears in Cancer 1988 Apr 1;61(7):1385]. Cancer, 1987. 60(11): p. 2766-74.

  19. Malmstrom, P.U., C. Busch, and B.J. Norlen, Recurrence, progression and survival in bladder cancer. A retrospective analysis of 232 patients with greater than or equal to 5-year follow-up. Scand J Urol Nephrol, 1987. 21(3): p. 185-95.

  20. Eble, J.N., et al., WHO Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. 2004, Lyon: IARC Press.

  21. Epstein, J.I., et al., The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol, 1998. 22(12): p. 1435-48.

  22. Orozco, R.E., A.A. Martin, and W.M. Murphy, Carcinoma in situ of the urinary bladder. Clues to host involvement in human carcinogenesis. Cancer, 1994. 74(1): p. 115-22.

  23. Amin, M.B., J.A. Gomez, and R.H. Young, Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol, 1997. 21(9): p. 1057-68.

  24. Lamina propria microinvasion of bladder tumors, incidence on stage allocation (pTa vs pT1): recommended approach. Pathologists of the French Association of Urology Cancer Committee. World J Urol, 1993. 11(3): p. 161-4.

  25. Abel, P.D., et al., Differing interpretations by pathologists of the pT category and grade of transitional cell cancer of the bladder. Br J Urol, 1988. 62(4): p. 339-42.

  26. Paner, G.P., et al., Diagnostic utility of antibody to smoothelin in the distinction of muscularis propria from muscularis mucosae of the urinary bladder: a potential ancillary tool in the pathologic staging of invasive urothelial carcinoma. Am J Surg Pathol, 2009. 33(1): p. 91-8.

  27. Young, R.H. and L.R. Zukerberg, Microcystic transitional cell carcinomas of the urinary bladder. A report of four cases. Am J Clin Pathol, 1991. 96(5): p. 635-9.

  28. Drew, P.A., et al., The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol, 1996. 9(10): p. 989-94.

  29. Cheng, L., et al., Grading and staging of bladder carcinoma in transurethral resection specimens. Correlation with 105 matched cystectomy specimens. Am J Clin Pathol, 2000. 113(2): p. 275-9.

  30. Chang, B.S., et al., Correlation between biopsy and radical cystectomy in assessing grade and depth of invasion in bladder urothelial carcinoma. Urology, 2001. 57(6): p. 1063-6; discussion 1066-7.

  31. Maruniak, N.A., K. Takezawa, and W.M. Murphy, Accurate pathological staging of urothelial neoplasms requires better cystoscopic sampling. J Urol, 2002. 167(6): p. 2404-7.

  32. Younes, M., J. Sussman, and L.D. True, The usefulness of the level of the muscularis mucosae in the staging of invasive transitional cell carcinoma of the urinary bladder. Cancer, 1990. 66(3): p. 543-8.

  33. Hasui, Y., et al., Significance of invasion to the muscularis mucosae on the progression of superficial bladder cancer. Urology, 1994. 43(6): p. 782-6.

  34. Orsola, A., et al., Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients. Eur Urol, 2005. 48(2): p. 231-8; discussion 238.

  35. Cheng, L., et al., Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol, 1999. 17: p. 3182-3187.

  36. Holmang, S., et al., The importance of the depth of invasion in stage T1 bladder carcinoma: a prospective cohort study. J Urol, 1997. 157(3): p. 800-3; discussion 804.

  37. Hermann, G.G., T. Horn, and K. Steven, The influence of the level of lamina propria invasion and the prevalence of p53 nuclear accumulation on survival in stage T1 transitional cell bladder cancer. Journal of Urology, 1998. 159(1): p. 91-4.

  38. Smits, G., et al., Microstaging of pT1 transitional cell carcinoma of the bladder: identification of subgroups with distinct risks of progression. Urology, 1998. 52(6): p. 1009-13; discussion 1013-4.

  39. Kaubisch, S., et al., Stage T1 bladder cancer: grade is the primary determinant for risk of muscle invasion. J Urol, 1991. 146(1): p. 28-31.

  40. Larsen, M.P., et al., Use of Ulex europaeus agglutinin I (UEAI) to distinguish vascular and "pseudovascular" invasion in transitional cell carcinoma of bladder with lamina propria invasion. Mod Pathol, 1990. 3(1): p. 83-8.

  41. Ramani, P., et al., Evaluation of endothelial markers in detecting blood and lymphatic channel invasion in pT1 transitional carcinoma of bladder. Histopathology, 1991. 19(6): p. 551-4.

  42. Heney, N.M., et al., Superficial bladder cancer: progression and recurrence. J Urol, 1983. 130(6): p. 1083-6.

  43. Lutzeyer, W., H. Rubben, and H. Dahm, Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J Urol, 1982. 127(2): p. 250-2.

  44. Bono, A.V., et al., Results of transurethral resection and intravesical doxorubicin prophylaxis in patients with T1G3 bladder cancer. Urology, 1994. 44(3): p. 329-34; discussion 334-5.

  45. Hall, M.C., et al., Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol, 2007. 178(6): p. 2314-30.

  46. Sylvester, R.J., M.A. van der, and D.L. Lamm, Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol, 2002. 168(5): p. 1964-70.

  47. Lamm, D.L., et al., Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol, 2000. 163(4): p. 1124-9.