Morphologic diversity in urothelial carcinoma; pathological and clinical correlates

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1 Morphologic diversity in urothelial carcinoma; pathological and clinical correlates Victor E. Reuter, M.D. Memorial Sloan Kettering Cancer Center A Practical Approach to Genitourinary Pathology Firenze, Italy May 2016

2 Classification of urothelial cancer; morphological diversity, clinical and molecular correlates Outline: Define the morphological spectrum of urothelial carcinoma Correlate selected morphological variants of urothelial carcinoma with their clinical and molecular characteristics

3 Comprehensive molecular characterization of urothelial carcinoma of the bladder The Cancer Genome Atlas Research Network (n = 131)

0524 trial (Her2) BKM10 trial for bladder cancer patients with alterations within the

4 Nature 2014 Targetable aberrations.. Neratinib study - any solid tumor with HER2 mutations Anti-Her2 immunotherapy (DN24-02) RTOG 0524 trial (Her2) BKM10 trial for bladder cancer patients with alterations within the PI3K/Akt/mTOR pathway Mocetinostat (histone deacetylase [HDAC] inhibitor) for UC with CREBBP and/or EP300 alterations Other potential targets: FGFR3, EGFR, ERBB3, etc..

5 Genome sequencing identifies a basis for everolimus sensitivity Fig. 1 (A) Computed tomography images of the index patient demonstrating complete resolution of metastatic disease (arrows). Published by AAAS G Iyer et al. Science 2012;338:221

6 Intensity...C_c.746C/G _1 C G Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma FGFR3_p.S249C_c.746C/G_1 R248C R248C FGFR3 S249C (C746G) TCC>TGC Mass Representative MS and Sanger sequencing traces for a tumor harboring FGFR3 mutation S249C R248C S249C Al-Ahmadie H, et al, J Pathol 2011;224: R248C R248C

R248C ID Mutation Low-grade High-grade B049 S249C S249C S249C B091 Y373C Y373C Y373C B107 S249C S249C S249C ID

7 ID Mutation High-grade non-invasive High-grade invasive B012 G370C G370C G370C B060 S249C S249C S249C B072 R248C R248C R248C B124 S249C S249C S249C B126 S249C S249C S249C B138 S371C S371C S371C B148 S249C S249C WT B085 R248C WT R248C ID Mutation Low-grade High-grade B049 S249C S249C S249C B091 Y373C Y373C Y373C B107 S249C S249C S249C ID Mutation Primary Metastasis B164 S249C S249C S249C B166 Y373C Y373C Y373C Al-Ahmadie H, et al, J Pathol 2011;224:

8 The urothelium

9 Metaplasia of the urothelium

10 UROTHELIAL CARCINOMA OF THE URINARY BLADDER Stage at INCIDENCE in the USA Patients presentation Percent per year Ta/T ,625 T ,700 M+ 5 3,175 Total 63,500 90% of patients who die of bladder cancer present with a locally advanced tumor

11 2004 WHO CLASSIFICATION OF UROTHELIAL TUMORS Blue Book Histologic variants: Invasive UC with squamous differentiation Invasive UC with glandular differentiation Squamous cell carcinoma Adenocarcinoma Nested variant Microcystic variant Micropapillary variant Small cell carcinoma Lymphoepithelioma-like carcinoma Lymphoma-like and plasmacytoid variants Sarcomatoid variant (with and without heterologous elements Urothelial carcinoma with giant cells Urothelial carcinoma with trophoblastic differentiation Clear cell variant Lipid cell variant Undifferentiated carcinoma

12 High grade urothelial carcinoma

13 UROTHELIAL CARCINOMA WITH SQUAMOUS DIFFERENTIATION UROTHELIAL CARCINOMA WITH GLANDULAR DIFFERENTIATION

14 TRANSURETHRAL RESECTION FOR BLADDER CANCER 100 consecutive cases TUR for urothelial carcinoma 100 Conventional UC 93 UC with DD 5 pure DD 2 MSKCC data

15 CYSTECTOMY FOR BLADDER CARCINOMA 300 consecutive cases Residual MP invasive disease 212 Conventional UC 154 (73%) UC with DD 58 (27%) Squamous 37 Glandular 14 SMCL/NE 3 Squamous, glandular 3 SMCL/NE, squamous 1 MSKCC

16 Dalbagni et al, J Urol 2001;165:

17 Reclassification after pathology re-review - radical cystectomy (n=1,211) Mayo Clinic experience (Linder et al. J Urol 2013) (33% of entire cohort )

CSS after RC, stratified by pure UC in 827 patients vs UC with squamous and/or glandular differentiation in 186 in RC

18 THE IMPACT OF OF SQUAMOUS AND GLANDULAR DIFFERENTIATION ON SURVIVAL AFTER RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA Kim SP et al, J Urol 2012;188: Figure 1. CSS after RC, stratified by pure UC in 827 patients vs UC with squamous and/or glandular differentiation in 186 in RC specimen. Figure 2. CSS in 186 patients with squamous and/or glandular differentiation at RC, stratified by degree of histological differentiation in specimen. Median differentiation in this cohort was 30% (IQR 10, 60).

19 THE CLINICAL RELEVANCE OF VARIANT HISTOLOGY IN UROTHELIAL CARCINOMA AFTER RADICAL CYSTECTOMY Soave A et al, Urol Oncol 2015;33:ePub Non-squamous variant histology is associated with inferior survival but are not independent predictors of survival Variant histology is associated with established predictors of aggressive tumor biology Xylinas A et al, Eur J Cancer 2013;49: While variant UCB histology was associated with worse outcomes on univariate analysis, this effect did not remain significant on multivariable analyses

20 Squamous cell carcinoma of the bladder Most common non-urothelial variant (5%) Pure squamous differentiation in the invasive component Keratin formation Intercellular bridges Otherwise, urothelial carcinoma with squamous differentiation Morphology of the in situ component is controversial Schistosomal infection is a risk factor in some regions Immunohistochemistry cannot distinguish 1ary from 2ary tumors p16 HPV GATA3 Colonization of the urothelium from cervical or vaginal primary

21 Squamous cell carcinoma

22 COMPARATIVE OUTCOMES OF PURE SQUAMOUS CELL CARCINOMA AND UROTHELIAL CARCINOMA WITH SQUAMOUS DIFFERENTIATION IN PATIENTS TREATED WITH RADICAL CYSTECTOMY Ehdaie B et al, J Urol 2012;187:74-79 Overall survival (A) and cancer specific survival (B) curves for patients with SqD and SCC treated with RCPLND. TCC, transitional cell carcinoma.

23 P16 EXPRESSION IS NOT ASSOCIATED WITH HUMAN PAPILLOMAVIRUS IN URINARY BLADDER SQUAMOUS CELL CARCINOMA Alexander RE et al, Mod Pathol 2012;25:

Modern Pathology (2012) 25, 1534 1542 UROTHELIAL CARCINOMA WITH PROMINENT SQUAMOUS DIFFERENTIATION IN THE SETTING OF NEUROGENIC BLADDER: ROLE OF HUMAN PAPILLOMAVIRUS INFECTION EB Blochin et al Figure

24 Modern Pathology (2012) 25, UROTHELIAL CARCINOMA WITH PROMINENT SQUAMOUS DIFFERENTIATION IN THE SETTING OF NEUROGENIC BLADDER: ROLE OF HUMAN PAPILLOMAVIRUS INFECTION EB Blochin et al Figure 1 Patient 1: (a) in situ squamous cell carcinoma of bladder resembling high-grade squamous intraepithelial lesion of uteri cervix. (b) Invasive and in situ squamous cell carcinoma showing diffuse p16 positivity. (c) Positive HPV in situ hybridization of no invasive disease showing punctate integrated pattern of staining. (d) Invasive squamous cell carcinoma of bladder with foc keratinization, deeply muscle invasive. (e) Invasive carcinoma with diffusely positive p16. (f) Positive HPV in situ hybridization invasive component showing punctate integrated pattern of staining.

25 Modern Pathology (2012) 25, UROTHELIAL CARCINOMA WITH PROMINENT SQUAMOUS DIFFERENTIATION IN THE SETTING OF NEUROGENIC BLADDER: ROLE OF HUMAN PAPILLOMAVIRUS INFECTION Figure 2 Patient 2: (a) in situ squamous cell carcinoma involving augmented intestinal portion of neobladder. Underlying benign intestinal glands are present. (b) In situ squamous cell carcinoma of bladder resembling high-grade squamous intraepithelial lesion of uterine cervix. (c) Diffusely positive p16 staining of in situ squamous cell carcinoma. (d) Positive HPV in situ hybridization of in situ carcinoma, showing punctate integrated pattern of staining. (e) Invasive urothelial carcinoma with squamous and glandular differentiation. (f) Invasive squamous cell carcinoma component of tumor. (g) Diffusely positive p16 staining of invasive carcinoma. (h) Positive HPV in situ hybridization of invasive squamous and glandular components of the tumor, showing punctate integrated pattern of staining.

28 CARCINOMA OF THE UTERINE CERVIX INVOLVING THE GENITOUTINARY TRACT: a potential diagnostic dilemma Schwartz LE, et al. Am J Surg Pathol (epub) 10 cases (consultations, 1984-present) Challenging differential diagnosis (urothelial versus cervical) Urothelial features Squamous features Adenocarcinoma 6 cases: gynecological hx 4 cases: classified as urothelial Most cases with basaloid morphology, some with CIS Most p16 positive (6 diffuse) GATA3 negative in 6 cases HPV HR positive in 8 cases 2 HPV negative cases (gastric-type endocervical adenocarcinomas)

29 ADENOCARCINOMA Mucinous Papillary NOS

30 I would accept as primary at this site if direct extension or a metastasis from another organ has been ruled out clinically

31 ADENOCARCINOMA OF THE URINARY BLADDER Grignon et al Stage at Presentation Cases(%) Survival(%) pt1 2 ( 4) 100 pt2-pt3a 11 (20) 76 pt3b 12 (23) 28 pt4 24 (45) 20 Cancer 1991;67:

33 Mucinous adenocarcinoma with signet ring cells

34 PLASMACYTOID UROTHELIAL CARCINOMA (signet ring cell / diffuse)

36 Plasmacytoid urothelial carcinoma Figure 2. (A) Overall survival (OS) for all patients (n=31) was 17.7 months. (B) OS by stage (I-III [45.8 months] vs. IV [13.4 months]; P<0.001). Dayyeni F et al, J Urol May ; 189(5):

Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy Keck et al.

37 Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy Keck et al. BMC Cancer 2013, 13:71 Figure 3 Kaplan-Meier analysis: Correlation of histology subtype with overall survival. Patients with a plasmacytoid urothelial cancer (lower curve, N=18) showed with 27.4 months (range: ) the shortest overall survival, patients with a conventional UC (middle curve, N=178) survived in average 62.6 months (range: ) whereas patients with a micropapillary urothelial cancer possessed the longest average survival with 64.2 months (range: ; upper curve N=9). The mean survival was significantly different between patients with plasmacytoid urothelial cancer and those with micropapillary urothelial cancer (P=0.013; log rank test). Censoring of patients (marked with a cross) means mathematically removing a patient from the survival curve at the end of his/her follow-up time.

IHC All cases had loss of e- cadherin except: 1 tumor with

38 Plasmacytoid/Signet Ring Cell Carcinoma of the Bladder Inactivation of CDH1 and loss of E-cadherin expression by IHC All cases had loss of e- cadherin except: 1 tumor with splice site mutation and 1 tumor with missense mutation E-cadherin

39 E-cad

40 Nuclear E-cadherin Expression is Associated with the Loss of Membranous E-cadherin, Plasmacytoid Differentiation and Reduced Overall Survival in Urothelial Carcinoma of the Bladder TABLE 2 Expression of membranous and nuclear E-cadherin in different histological variants of urothelial carcinoma Carcinoma Total Membranous E-cadherin Nuclear E-cadherin Negative a Reduced b Strong c Negative a Positive All UC PUC MPC UC conventional urothelial carcinoma, PUC plasmacytoid urothelial carcinoma, MPC micropapillary urothelial carcinoma a b c Immunoreactive score = 0 Immunoreactive score = 1 8 Immunoreactive score = 9 12 Ann Surg Oncol (2013) 20: Bastian Keck, MD et al.

41 Figure 1 a b c Cadherin pro-domain Cadherin domain Cytoplasmic domain Al-Ahmadie H et al, MSKCC, unpublished

42 Metastatic mammary lobular carcinoma ER

43 Diffuse gastric cancer Lobular breast cancer Al-Ahmadie H et al, MSKCC, unpublished

44 SMALL CELL CARCINOMA sinaptophysin

45 Small cell/neuroendocrine carcinoma

46 Small cell carcinoma CAM5.2

47 SMALL CELL CARCINOMA OF THE BLADDER Overall survival in 55 cases Kaplan-Meier Survival Estimate Survival time in years

48 Summary of alterations in 20 tumors of bladder small cell carcinoma

49 Small cell / neuroendocrine carcinoma as a component of divergent differentiation Potential confounding factor in evaluating response to targeted therapy

50 Micropapillary urothelial carcinoma

51 MICROPAPILLARY CARCINOMA Amin et al. AJSP 1994;18: cases Age: mean= 67 M:F = 5:1 MPC: < 50% = % = 9 >90% = 3 Superficial Component: CIS 10/18 Pap 18/18 grade 3 TCC could not be done Vascular Invasion 100% in area of MPC Stage at Presentaion T1 = 1 T2 = 9 T3 = 6 T4 = 2 Follow-up: mean 44 mos. (6-96) NED = 7 AWD = 4 DWD = 7 Amount of MPC correlated with prognosis (no statistics) a comparison of outcomes of TCC with MPC and conventional invasive could not be done Johansson et al. J Urol 1999;161: cases (incidence = 0.7%) Age: mean = 69 M:F = 2.3:1 MPC: 10% = % = % = 2 Superficial component: CIS 13/20 Pap 11/20 Vascular invasion 75% (15/20) Stage at Presentation T1 = 3 T2 = 9 (modern 2a-2b) T3 = 2 T4 = 6 Follow-up: mean 39 mos (4-156) NED = 3 DOC = 1 DOD = 19 Disease specific survival at 5 years: 25% and there was a close correlation between stage and survival, as descrobed by Amin et al

52 MICROPAPILLARY UROTHELIAL CARCINOMA

53 The Case for Early Cystectomy in the Treatment of Nonmuscle invasive Micropapillary Bladder Cancer Kamat et al, JUrol, 175: ,2006 Of 100 consecutive MPC, 44 were nonmuscle invasive Tumors with any amount MPC component were included Not stated if all patients received an initial TUR or Bx Not stated if any repeat TUR were performed (not likely) 30 patients underwent cystectomy 12 (40%) as initial therapy* 18 (60%) after failed BCG** * selection criteria? ** time interval to progression? Pathological upstaging at cystectomy: 57% (17/30)

54 MICROPAPILLARY CARCINOMA Interobserver reproducibility study 30 cases reviewed by 14 GU pathologists -Classic MPC (10) -UC with retraction artifact (non-classic MPC, 20) Results: -Overall kappa: 0.54 (moderate) -Rate of MPC dx ranged from 9/30 to 20/30 (mean=13/30) -Classic: all correctly classified at least 8/10 (sensitivity = 93%) -Non-classic: 6 pathologists, 2/20 called MPC 5 pathologists, 4-7/20 called MPC 3 pathologists, 9-11/20 called MPC Conclusion: high sensitivity, rather low specificity Sangoi A, et al, Am J Surg Pathol Sep;34(9):

55 MSKCC: acgh: 5 of 97 samples with ERBB2 amplification HER Iyer G et al, J Clin Oncol. 2013;31:

56 MUC-1 HER-2

57 Urothelial carcinoma, micropapillary variant NOS Micropapillary UC NOS Micropapillary UC Her2 Mixed NOS and MP urothelial carcinoma

59 Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy A.S. Fairey et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) Table 3 Multivariable analyses examining predictors of survival Variable Overall survival Recurrence-free survival HR 95% CI P value HR 95% CI P value Histologic type UC MUC , , Age (years) > , 2.22 < , Sex Male Female , , Pathologic TNM stage T2N0M >T3N0M , 2.65 < , 3.82 <0.01 TanyN1 3M , 4.54 < , 7.49 <0.01 LVI No Yes , 1.65 < , 2.01 <0.01 Histologic grade Low High , 1.80 < , 2.38 <0.01 Adjuvant chemotherapy No Yes , 0.54 < , 0.73 <0.01

60 Clinical Outcome of Patients with T1 Micropapillary Urothelial Carcinoma of the Bladder Figure 1. Kaplan-Meier estimated cumulative CSM in patients treated with early cystectomy (dashed curve) and conservative therapy (solid curve). THE JOURNAL OF UROLOGY Vol. 192, , September 2014, Massimiliano Spaliviero, et.al

61 Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome Table 2. Univariate associations with cancer-specific survival among patients with micropapillary urothelial carcinoma Parameter Hazard ratio 95% Confidence interval P-value Age at surgery pt stage (reference < T1) pn stage (reference pn0) ECOG Perioperative chemotherapy ERBB2 amplification < Modern Pathology (2014) 27, Steven A Schneider, et al.

62 Kaplan-Meier Survival Estimate Survival time in years

Clear Cell Carcinoma of the Urinary Bladder Cases 13 M:F 2:11 Age 22-83

63 Clear Cell Carcinoma of the Urinary Bladder Cases 13 M:F 2:11 Age (57) Endometriosis 2 Mullerian-type cysts 2 Oliva et al. AJSP 26:190,2002.

64 Clear cell carcinoma

65 Lipid rich Clear cell (glycogen rich)

66 PSA PAX8 + Nephrogenic adenoma involving prostatic urethra

67 Nephrogenic adenoma vs clear cell adenocarcinoma

69 Clear cell carcinoma associated to Müllerian rests

70 Müllerian and mucinous metaplasia ER ER

71 HNF-ß1 p53

72 HCG Glypican AFP

73 SUMMARY Similar to normal urothelium, urothelial carcinoma exhibits a wide spectrum of morphologic variability Divergent differentiation (DD) within urothelial carcinoma is seen primarily in association with high grade disease The identification of pure divergent histology is relevant The implication of DD on management is important but in evolution Shared genomic abnormalities

74 Thank you!

ACCME/Disclosures. Case History 4/13/2016. USCAP GU Specialty Conference Case 3. Ann Arbor, MI

ACCME/Disclosures. Case History 4/13/2016. USCAP GU Specialty Conference Case 3. Ann Arbor, MI USCAP GU Specialty Conference Case 3 March 2016 L. Priya Kunju, M.D. University of Michigan Health System Ann Arbor, MI University of Michigan Health System ACCME/Disclosures The USCAP requires that anyone