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1 Case Presentation 58 year old male with recent history of hematuria, for which he underwent cystoscopy. A 1.5 cm papillary tumor was found in the left lateral wall of the bladder.

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5 Pictures of case

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8 Case presentation Outside diagnosis: Invasive papillary urothelial carcinoma involving muscularis propria. Referred for cystectomy for muscle invasive disease.

9 SMA

10 DES

11 pt1 Urothelial Carcinoma of the Bladder: Criteria for Diagnosis, Pitfalls and Clinical Implications Rafael E. Jimenez, M.D.

12 pt1 Stage Tumor invasive into lamina propria, but not the muscularis propria.

13 Anatomy of the bladder wall MM MP

14 Anatomy of the bladder wall LP SM

15 Terminology TNM Clinical- Managerial ptis pta Superficial Non muscleinvasive Invasive MuscleInvasive pt1 pt2+

16 Patterns of invasion

17 Grade of Papillary Tumor Vast majority of pt1 tumors are high grade G 1 2a 2b 3 Ta T Larsson et al. Scand J Urol Nephrol 37: , 2003.

18 Epithelial changes

19 Stromal changes

20 The Real World

21 Diagnostic pitfalls Underdiagnosis of pt1 Overdiagnosis of pt1 Overdiagnosis of pt2

22 Obscuring Inflammation

23 Deceptively bland UC

24 Difficulty in diagnosis LP invasion frequently overcalled. Interpretation differences: Tangential sectioning Tissue fragmentation Cauterization artifacts Stage Original Consensus pta pt Bol et al. J Urol 169, , 2003.

25 CIS bon Bunn s nests

26 Tangential sectioning

27 Inverted growth pattern

28 Invasion of smooth muscle, indeterminate for type of muscle

29 Smoothelin Smooth muscle protein expressed only in terminally differentiated cells. Absent expression in noncontractile and proliferative smooth muscle fibers.

30 Smoothelin 100% specificity and positive predictive value in identifying MP vs. MM. ACTIN 10 TURBT cases with perfect correlation between smoothelin results and H&E impression. SMTLN Paner et al. Am J Surg Pathol, 2009

31 Prominent desmoplastic reaction

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33 Understaging Cystectomy Stage TURB Ta T1 T2 T3 T4 Total Ta T1 T2 Total of 55 cases (78%) were upstaged on cystectomy Only 34% had muscularis propria Cheng et al. Am J Clin Pathol 113: , 2000.

34 Substaging of pt1 disease Heterogeneous behavior in pt1 disease has been recognized. Higher risk of recurrence may be associated with more extensive invasive disease. Need to differentiate between focal vs. extensive invasion of lamina propria.

35 Substaging of pt1 disease Relationship to muscularis mucosae: MM MM MP

36 Abnormal anatomy MM BV

37 Substaging of pt1 disease Depth of Invasion measured by micrometer: Author Categories Outcome Endpoint Cheng 1999 <1.5 mm 93% 5-year PFS >1.5 mm 67%

38 Substaging of pt1 disease Maximum linear size of invasive front: Author Categories Outcome Endpoint Van der AA 2005 <0.5 mm (1 hpf diameter) 69% 5-year PFS >0.5 mm 50%

39 Clinical Management Baseline treatment Transurethral resection of tumor: Provide adequate tissue for pathologic analysis Remove all visible disease Provide tissue from MP for adequate staging. Repeat resection if no MP identified in the sample

40 Clinical Management Intravesical therapy Progression-free survival 40% at 5-y for patients with TUR only PFS improves 15-23% in patients treated with intravesical chemotherapy BCG may be superior Recurrence-free survival Tolley et al. Journal of Urology 1996;155: in preventing recurrence and progression, but may be associated with worse side effects and higher cost.

41 Clinical Management Cystectomy High risk of understaging in TUR High rate of progression Disease specific survival Herr and Sogani. J Urol 2001; 166:231 High cure rate associated with cystectomy

42 Summary Pathologic diagnosis of pt1 urothelial carcinoma places the patient in an unique managerial category. Pathologists need to be familiarized with the morphologic features associated with lamina propria invasion, as well as the potential pitfalls associated with the diagnosis. Extent of the invasive component is useful information on the management of these patients; however, currently an universally accepted system for substaging has not been agreed upon.

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