Disclosures. The Importance of Pathology? Pathologic, Morphologic and Clinical Features. Pathologic Reproducibility

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1 The Importance of Pathology? Seth P. Lerner, MD, FACS Beth and Dave Swalm Chair in Urologic Oncology Scott Department of Urology Baylor College of Medicine Support for research Disclosures Photocure, Imalux, BMS, Pfizer, Celek Scientific advisory board Imalux, Celek Consultant Spectrum (Allergan) UCSF Bladder Cancer Post Graduate Course April 9, 2010 Pathologic, Morphologic and Clinical Features Accurate determination of stage and grade Surgical quality TURBT and bladder biopsies Recommend re-review and 2 nd TUR for T1G3 Variant histology: micropapillary Focality single vs. multiple Presence of CIS Age Status at 3 month follow-up Size Future: Molecular profiling Pathologic Reproducibility 122 primary Ta,T referee pathologists Bol, et al J Urol 169:1291:2003 1

Pathologic Reproducibility Implications for Central Review Concordance rates Ta

grade affect treatment decisions in high risk group Recommend re-review and 2 nd

G1 well differentiated G2 Moderately differentiated G3 Poorly differentiated

Relationship of 1973 WHO to 1998 WHO/ISUP Epstein, et al Am J Surg Pathol

1973 WHO 2004 Papilloma Papilloma www.pathology.jhu.

2 Pathologic Reproducibility Implications for Central Review Concordance rates Ta - 90% G1-53% T1-43% G2-60% >T2-68% G3-61% TaG1 57% T1G3 50% Errors in stage and grade affect treatment decisions in high risk group Recommend re-review and 2 nd TUR for T1G3 EORTC AUA 2000 (Abstract 661) Grading of Papillary Lesions WHO 1973 G1 well differentiated G2 Moderately differentiated G3 Poorly differentiated WHO/ISUP 1998 Low grade High grade WHO 2004 Identical to WHO/ISUP 1998 Relationship of 1973 WHO to 1998 WHO/ISUP Epstein, et al Am J Surg Pathol 1998;22(12): Lopez-Beltran and Montironi, Eur Urol 46:170, 2004 WHO 1973 WHO 2004 Papilloma Papilloma Papilloma PUNLMP Grade 1 Grade 2 Grade 3 PUNLMP Low grade High grade Low Grade High Grade 2

Relationship of WHO and WHO/ISUP Grade to Progression WHO Samaratunga H and Epstein JI, Urology 60(2),

5 60 60 WHO/ ISUP Cases (%) Progression (%) 45 mo 90 mo Papilloma 2.2 0 0 LMP 21.6 8 8 Low grade 54.

6 23 51 TURBT and Lymphovascular Invasion (LVI) Cho, et al (J Urol 182:2625, 2009) 118 primary T1 LVI in

patients with LVI compared to 34 without LVI Decreased survival and trend to understaging in patients with

all T1 patients at initial diagnosis registered 1987-1988 in western Sweden Number of Nodes (quartile)

3 Relationship of WHO and WHO/ISUP Grade to Progression WHO Samaratunga H and Epstein JI, Urology 60(2), , 2002 Cases (%) Progression (%) 45 mo 90 mo Papilloma G G G WHO/ ISUP Cases (%) Progression (%) 45 mo 90 mo Papilloma LMP Low grade High grade TURBT and Lymphovascular Invasion (LVI) Cho, et al (J Urol 182:2625, 2009) 118 primary T1 LVI in 28% Only risk factor independently associated with progression Streeper, et al (BJUI 103:475, 2009) 69 patients with LVI compared to 34 without LVI Decreased survival and trend to understaging in patients with LVI T1 Prognostic Factors Andius, et al Urology 2007 Lymphatic and Vascular Invasion Prospective study of all T1 patients at initial diagnosis registered in western Sweden Number of Nodes (quartile) Lotan, et al JCO 2005 Bladder cancer Specific Mortality (98/551) Parameter Hazard Ratio 95% CI p Value LVI Stage T1 1 - T T T

EORTC Chemotherapy Trials Factors Affecting Recurrence and Progression Factor Rec HR Prog HR Primary vs. Recurrent NS 1.48 Primary vs. Recurrent 1y vs. > 1y 1.

4 EORTC Chemotherapy Trials Factors Affecting Recurrence and Progression Factor Rec HR Prog HR Primary vs. Recurrent NS 1.48 Primary vs. Recurrent 1y vs. > 1y 1.35 NS Number tumors: single, multiple NS 1.70 Number tumors: single, 2-7, NS Size < 3cm vs. 3cm Ta vs. T CIS NS 3.41 Grade 1, 2, NS Grade G3: no, yes NS 2.67 Sylvester et al Eur Urol 49:466, Sylvester et al Eur Urol 49:466, Risk Tables Pathology Makes a Difference Ta first occurrence, 3 tumors, < 3cm 3 yr Recurrence 3 yr Progression G1-2 40% 4% G3 56% 11% CIS 56% 30% T1 first occurrence, one tumor, < 3cm G1-2 40% 4% G3 40% 11% CIS 40% 30% Stage and Grade Accuracy Take Home Message Surgical quality and pathologic reproducibility directly affect accurate determination of stage and grade. With the highest quality data we can accurately assess risk of recurrence and progression and determine the appropriate course of treatment. 4

Histologic Variants MDACC series 1246 patients with urothelial cancer 1985-2006 Squamous or glandular components 13.3% Small cell 3.3% Micropapillary 3.6% Sarcoma 3.

5 Histologic Variants MDACC series 1246 patients with urothelial cancer Squamous or glandular components 13.3% Small cell 3.3% Micropapillary 3.6% Sarcoma 3.3% All originate from urothelial progenitor cells Black, et al Urol Oncol 27:3-7, 2009 A17 DO MIXED HISTOLOGIC FEATURES AFFECT SURVIVAL BENEFIT FROM NEOADJUVANT PLATINUM-BASED COMBINATION CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED BLADDER CANCER? E.M. Messing, E. Scosyrev, B.W. Ely, V.O. Speights, H.B. Grossman, D.P. Wood, R.W. deverewhite, N.J. Vogelzang, D.L. Trump, R.B. Natale, C. Tangen, E.D. Crawford, I.M. Thompson GU ASCO March 2010 Mixed Histology Bladder Cancer 30-40% T2+ urothelial cancers are MH usually UC + SCC or adeno 1 Metastatic BC: MH BCs respond slightly less well (25-34%) than pure UCs (39-44%, CR or PR) to PBCC 2,3 Some evidence that pure SCC and pure adeno CA are poorly responsive to MVAC and other PBCCs 4,5 PBCC platinum based combination chemotherapy 1 Wasco, et al. Urology 70:69, 2007; 2 Logethitis, et al. J Urol 141:33, 1989; 3- Kastritis, et al. Anticancer Res 26:3865, 2006; 4 DeSantis and Bachner. Curr Opinion Urol 17:363, 2007; 5 Black, et al. Urologic Onc 27:3, 2009 Hypothesis MH BCs respond less well to MVAC than pure UCs Possibly should forego neoadjuvant chemorx to avoid dangerous delay in cystectomy (e.g. > 3 mos) for MH BC Gore, et al. Cancer 115:988,

Downstage to pt0 Histology Rx N N(%) pt0 P value 5 yr Survival* Probabilities MH MVAC + cystec 32 11 (34%) MH Cystec 27 1 (4%) Pure UC MVAC + cystec 115 33 (29%) Pure UC Cystec 121 17 (14%) p = 0.

6 Downstage to pt0 Histology Rx N N(%) pt0 P value 5 yr Survival* Probabilities MH MVAC + cystec (34%) MH Cystec 27 1 (4%) Pure UC MVAC + cystec (29%) Pure UC Cystec (14%) p = p = Clinical stage Rx MH Pure UC ct2 MVAC + cystec ct2 Cystec ct3-4a MVAC + cystec ct3-4a Cystec D-S to pt0 UC + SCC 6/20 (30%) UC + adeno 5/10 (50%) UC + SCC + adeno 0/2 * 5 yr survival adjusted for age by conditional standardization Summary MH BCs had better response to MVAC than pure UCs - ADE to pt0: 28% (MH) vs. 15% (pure UC) - HR for survival:0.46 (0.28, 0.87) for MH (p=0.02) 0.90(.67, 1.21) for pure UC (p=0.48) UC + SCC and UC + adenoca both responded to MVAC All of the benefit of neoadjuvant MVAC seen in SWOG 8710/INT 0080 (HR = 0.78) occurred in pts with MH BCs Neuroendocrine Tumors of the Bladder Small Cell May comprise a component of TCC or be the predominant morphology High grade by definition Large Cell Rare variant that is high grade Carcinoid Primary origin in bladder rare 7 well documented cases Secondary involvement from appendix origin ADE: additive downstage effect standardized to distribution of clincal T stage 6

7 Histology Variants Small Cell Bladder Cancer Small Cell May be predominant or mixed with TCC Aggressive, prognosis poor, paraneoplastic syndromes ACTH, hypercalcemia, hypophosphatemia Treatment requires neoadjuvant chemotherapy (cisplatin and etoposide) followed by radical cystectomy or radiation therapy. Small cell Synaptophysin Chromogranin MDACC (88 patients) 46 treated with cystectomy 25 initial cystectomy ± adjuvant chemotherapy 36% 5-year disease-specific survival 21 neo-adjuvant chemotherapy 12 with residual disease at cystectomy 78% 5-year disease-specific survival Downstaged to T2 no cancer deaths Chemotherapy etoposide/cisplatin or ifosfamide/doxorubicin or M-VAC Siefker-Radtke, AO, et al J Urol 172:481, 2004 Small Cell Bladder Cancer Initial cystectomy vs. initial chemotherapy Neoadjuvant chemotx Initial cystectomy pt2 vs pt3 pt0-2 pt3 Optimal results are achieved via integration of local and systemic treatment Small Cell Bladder Cancer Chemotherapy and Radiation Bex (World J Urol, 2009) 42 patients 17 with local disease Chemoradiation 12 patients progressed/8 DOD/1 AWD Distant progression 3-15 months Local progression 18, 24, 44, 45 months 3/4 free of disease; cystectomy (3), bcg (1) Siefker-Radtke, AO, et al J Urol 172:481,

8 Micropapillary Micropapillary Variant of high grade TCC Lymphovascular invasion > 50% Early muscle invasion and metastases Not responsive to BCG % micropapillary correlates with prognosis Cystectomy treatment of choice Kamat, et al J Urol 175:881, 2006 Cancer 110:62, A (H&E) 3A (D2-40) 3A (CD34) 3A (CD31) Micropapillary MDACC GU ASCO 09 N = 146 Cystectomy for ct 4a T2 (n = 66) Neoadjuvant chemotherapy (32%) 75% T2 25% T3 No survival benefit to neoadjuvant chemotherapy need for prospective trials of novel agents and regimens. Histology Variants Variants Lymphoepithelioma-like - better prognosis than high grade invasive TCC Nested aggressive despite bland appearance Sarcoma rhabdomyosarcoma (pediatric and adult), leiomyosarcoma Lymphoma primary rare; bladder involved in 10% of systemic cases Lymphoepithelioma Nested 8

9 Summary WHO 2004 grade schema simplifies to low vs. high grade and reliably predicts progression Pathologic reproducibility a significant problem Expert GU pathology review can be helpful Histologic variants may affect response to standard treatments and treatment selection 9

Controversies in the management of Non-muscle invasive bladder cancer

Controversies in the management of Non-muscle invasive bladder cancer Sia Daneshmand, MD Associate Professor of Urology (Clinical Scholar) Director of Urologic Oncology Director of Clinical Research Urologic