Update on bladder neoplasia: 2016 WHO classification and recent developments within the pathologic, molecular & clinical domains of the disease

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Ira Alexander
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1 Update on bladder neoplasia: 2016 WHO classification and recent developments within the pathologic, molecular & clinical domains of the disease

3 Biology of urothelial tumorigenesis: insights from genetically engineered mice Xue-Ru Wu, Cancer Metastases, 2009

4 Urothelial Carcinoma: Two Pathways Manifesting in Two Phenotypes? Superficial non-muscle invasive urothelial carcinoma : 70-80% Majority of UrCa (60-70%) present as non-invasive (pta) tumors at time of first diagnosis 50% will recur as non-invasive tumors, only 5-10% of will progress Muscle Invasive urothelial carcinoma (MIBC): 20-30% 80-90% are primary Muscle invasive urothelial carcinoma Practically all are high grade Despite aggressive Rx (Cystectomy +/- Chemotherapy) <50% overall survival

5 Invasive Genetically Unstable Non Invasive Genetically Stable Hyperplasia Normal Urothelium Dysplasia PUNLMP LG UrCa HG UrCa HG UrCa 5-10% Flat CIS pt1 Eble et al. WHO Pathology & Genetics: Tumors of the Urinary System and Male Genital Organs pt2-4

6 Superficial Non-invasive papillary neoplasia pta Invasive Ca into muscularis propria Flat CIS ptis pt1 Ca invasive into lamina propria, muscularis mucosa & sub mucosa Ca into pericystic fat

7 WHO GRADING IN pta UROTHELIAL CARCINOMA PUNLMP LG CA HG CA Recur Progress Holmäng et al, J Urol 165: , 2001

9 CARCINOMA IN SITU

10 CARCINOMA IN SITU Large cells, pleomorphic nuclei, hyperchromatic nuclei; note size of nuclei compared with other normal tissue cells

11 CIS - DENUDING

12 CIS - UNDERMINING

13 Non invasive Urothelial Neoplasia Papillary (80%) Urothelial papilloma PUNLMP Non-invasive papillary urothelial carcinoma, low-grade Non-invasive papillary urothelial carcinoma, high grade Non-papillary flat (20%) Reactive atypia Atypia of undertermined significance Urothelial dysplasia Urothelial Carcinoma in-situ

14 LG HG Papilloma PUNLMP

16 9q-/9p- Normal Urothelium 70-80% Urothelial Hyperplasia HRAS/FGFR3 PIK3CA-Akt LG URCa 70% Recurrence ~15% 20-30% 9q-/9p- Dysplasia/CIS HG URCa Invasive URCa ~50% Metastasis Modified from Xue-Ru Wu et al Nature Rev 2005

17 Urothelial Carcinoma of the Bladder RTK-HRAS Pathway FGFR3: Receptor Tyrosine Kinase (RTK) function Mutations in 75% of low-grade papillary UrCa while very rare in CIS and only 10% of Invasive UrCa Constitutive activation of FGFR3 by mutation enhance cell growth (HRAS-MEK-ERK network) and angiogenesis

18 Bladder Urothelial Carcinoma RTK-HRAS Pathway Xue-Ru et al Cancer Metastasis Rev 2009

9q-/9p- 70-80% Urothelial Hyperplasia HRAS/FGFR3

P53,Rb 20-30% 9q-/9p- Dysplasia/CIS HG URCa Invasive URCa

19 9q-/9p % Urothelial Hyperplasia HRAS/FGFR3 PIK3CA-Akt LG URCa 70% Recurrence Normal Urothelium ~15% P53,Rb 20-30% 9q-/9p- Dysplasia/CIS HG URCa Invasive URCa ~50% Metastasis P53, Rb Modified from Xue-RuWu et al Nature Rev 2005

20 pta BLADDER CA LONG TERM OUTCOME Progression in stage N=175 N=483 N=129 Pan et al, AJCP 133:788, 2010

21 pta BLADDER CA LONG TERM OUTCOME Cancer-specific mortality N=175 N=483 N=129 Pan et al, AJCP 133:788, 2010

22 WHO/ISUP GRADING IN pta UROTHELIAL CARCINOMA 680 new cases, 363 (53%) pta Grade distribution: PUNLMP 95 (26%) Low grade 160 (44%) High grade 108 (30%) Treatment: TURBT alone358 (98.6%) Follow up: minimum 5-years Holmäng et al, J Urol 165: , 2011

23 WHO/ISUP GRADING IN pta UROTHELIAL CARCINOMA PUNLMP LG CA HG CA Recur Progress Holmäng et al, J Urol 165: , 2001

24 Cao et al., Urology 2010; 76:593-9

25 Cao et al., Urology 2010; 76:593-9

26 HISTOLOGIC FEATURES OF INVASION Loss of smooth BM outline Single cells or irregular clusters of cells haphazardly extending from surface Invading cells with more abundant eosinophilic cytoplasm than non-invasive Retraction artifact Stromal edema - myxoid, desmoplasia or fibrosis Inflammation

27 LAMINA PROPRIA INVASION

28 LAMINA PROPRIA INVASION

29 DIAGNOSIS OF INVASION

30 DIAGNOSIS OF INVASION

31 DIAGNOSIS OF INVASION

32 DIAGNOSIS OF INVASION

33 MUSCULARIS MUCOSAE

34 MUSCULARIS MUCOSAE INVASION

35 pt1 - SUBSTAGING BASED ON MUSCULARIS MUCOSAE

36 SIGNIFICANCE OF MUSCULARIS MUCOSAE Patients treated by TURBT only Younes et al, Cancer 66: , 1990

37 SURVIVAL ACCORDING TO MUSCULARIS MUCOSAE INVASION 151 patients pt1 on TUR Cases centrally reviewed 97 included in study All high-grade with mp in specimen Substaging possible in 85 (88%) Treated by: Orsola et al. Eur Urol 48: , 2006

38 High Risk Superficial Bladder Cancer- Benefits of Cystectomy

39 Risk Stratification Admittedly, cystectomy as a treatment has significant morbidity and impact on quality of life Other factors may also be useful in selection Tumor size Mulifocality Lymphovascular invasion Variant histology Prostatic urethral involvement Depth of T1 invasion Molecular markers

40 High Grade T1- first step Repeat TURBT Significant proportion of cancers are understaged Detection of cancer on repeat TURBT may be a prognostic factor itself Decreased survival with worsening pathology on restaging TUR Herr 2007 J Urol

41 Overall Risk in HG T1 bladder cancer High percentage have upstaging or progression on cystectomy Cystectomy for High Grade T1 Bladder cancer Total 167 Upstaging 50% Extravesicular disease 27.5% Lymph node metastasis 17.5% Recurrence 29.4 Death 18.5 Gupta Urol 2008

42 High Grade T1 patients on BCG therapy 23 center, review of 2,451 patients These patients are at high risk of recurrence, progression, and survival Gontero 2015 Eur Urol

43 High Grade T1 with concomitant CIS 132 consecutive patients treated with BCG Denziger 2007 IJU

44 T1G3 with CIS also fares worse with cystectomy 167 patients treated with cystectomy for HGT1 at 3 centers Recurrence Cancer-specific survival

45 Conclusion High Grade T1 bladder cancer represents a heterogeneous group of patients with high risk for recurrence and progression CIS is associated with BCG failure, upstaging at cystectomy, and cancer death Risk stratification and further investigation into precise markers/prognostic factors are necessary to select patients that should be advised to pursue early cystectomy

46 P53 in Urothelial carcinoma: Clinical studies Sarkis A et al JNCI % of pt1 had p53 overexpression p53 overexpression predicted PFS on multivariate analysis Esrig et al NEJM % tumors had p53 overexpression Hiher recurrence rate in UrCa with p53 overexpression (62%-80% for pt1-3 vs 7-11%) Independently Predict recurrence and survival on multivariate (grade, stage) Sarkis A et al JCO % tumors had p53 overexpression Lower (41% vs 77%) DFS in UrCa with p53 overexpression Independently predict survival on multivariate (grade, stage, tx size)

47 Basal Markers Basal P53-like Luminal P63 STAT3 EGFR Choi et al. Nature reviews 2014

48 Epithelial-to-mesencymal transition (EMT) One of the initial steps in the metastatic journey is the acquisition of an epithelial-to- mesenchymal transition (EMT). Tumor cells acquire molecular and phenotypic changes Resulting in spindle cell morphology and dysfunctional cellcell adhesion Leading to invasion and metastasis. Zhang et al. Modern Pathology 2012

53 Luminal Markers Basal P53-like Luminal PPARr

55 Review of Intrinsic Subtypes of MIBCs at a Glance! Study Study group Study size (n) Study design Intrinsic Subtypes Weinstein et al Choi et al Damraeur et al TCGA 131 Retrospective Cluster I Cluster II Cluster III Cluster IV MDA 73 Retrospective Luminal p53-like Basal UNC 226 Retrospective Luminal Basal

56 Choi et al. Cancer Cell 2014

57 Choi et al. Cancer Cell 2014

Methods: A total of 215 MIBC from the MDACC (n=75) and TCGA (n=140) Results: In total there were 16 and 199 tumors from AA and non-aa patients respectively.

58 Methods: A total of 215 MIBC from the MDACC (n=75) and TCGA (n=140) Results: In total there were 16 and 199 tumors from AA and non-aa patients respectively. In AA patients, there was enrichment of basal tumors (12 basal and 4 luminal) (p=0.03). Conclusions: AA patients are enriched in the basal molecular subtype of UC. Similar findings have been previously documented in AA women with breast cancer. The enrichment of basal UC in AAs suggests that a biological explanation may in part underlie the poor outcomes seen in AA patients. Kados et al. JCO 2015

59 P53-like subtype

60 P53-like MIBCs Characterized by high levels of infiltrating stromal cells, particularly cancer associated fibroblasts. Expressed gene expression signatures consistent with active wild-type p53.

61 Different subtypes show different responses to chemotherapy At least half of all basal MIBCs were chemosensitive, as were half of tumors in the luminal category Tumors in the p53-like subtype were resistant Choi et al. Cancer Cell 2014

62 Mechanism of resistance?? p53-like tumors expressed gene expression signatures characteristic of active, wild-type p53 and low levels of proliferation markers and appear to be relatively quiescent compared with tumors in the other subtypes. This quiescence probably contributes directly to chemoresistance because proliferation is associated with sensitivity to apoptosis.

63 Are there any biomarkers to identify chemosensitive basal and luminal subtypes? Pretreatment gene expression profiles of basal and luminal responders and nonresponders was performed Chemosensitive basal tumors were enriched with immune biomarkers suggestive of infiltration with B and T lymphocytes (TILs) No biomarkers were capable of distinguishing between chemosensitive and chemoresistent luminal tumors.

65 Targeted Therapy for the Molecular Subtypes of MIBC

66 EGFR Basal MIBCs The EGFR gene is amplified in a subset of basal MIBCs which demonstrate high sensitivity to EGFR inhibitors T-cell modulators Immune checkpoint inhibitor, including ipilumumab (a blocking anti- CTLA4 antibody) and PD-L1 inhibitor (Atezolizumab), has been shown to produce immune modulation when used in the neoadjuvant setting

67 Basal MIBCs STAT3 A number of different small-molecule STAT3 inhibitors have been developed that should be evaluated in preclinical models to determine their potential value in treatment of basal MIBCs Debanth et al. J.Med.Chem 2012 Nam et al. Mol Oncol 2013

68 Luminal MIBCs FGFR3 Sensitive to FGFR3 Inhibitors A multicenter Phase II clinical trial of FGFR inhibitor dovitinib (TKI-258) in patients with advanced MIBCs Milwoski et al. J Clin Oncol 2011

69 Luminal MIBCs ERBB2 and ERBB3 Respond well to ERBB2-targeting antibody trastuzamab.

70 PPAR-gamma Luminal MIBCs PPARr activation is a signature feature of luminal bladder cancers (amplified in 15%) A positive role for PPARr in bladder cancer tumor promotion is consistent with preclinical studies demonstrating that PPARr agonists promote bladder cancer in rodents With current concerns about the possible effects of long-term term use of antidiabetic PPARr agonists (pioglitazones) in humans. PPARr could be an emerging therapeutic target

71 Promising Future How urothelial cancers with variant histology (micropapillary, small cell, pure squamous, and so on) relate to the basal and luminal cancers is at present unclear. Develop an immunohistochemical approach to distinguish basal and luminal tumors. Most recent genomics efforts have focused onmibcs, yet more patients present with nonmuscle. These studies will also help us to better define the nonmuscle invasive precursor lesions that give rise to MIBCs

BLADDER CANCER EPIDEMIOLOGY

BLADDER CANCER WHAT IS NEW AND CLINICALLY RELEVANT Canadian Geese - Geist Reservoir (my backyard), Indianapolis, USA BLADDER CANCER EPIDEMIOLOGY Urinary bladder 17,960 2% Urinary bladder 4,390 1.6% Siegel