DIAGNOSIS AND MANAGEMENT: WHAT ARE WE STRIVING FOR?

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Christal Hopkins
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1 GUIDING THE SURGEON AFTER THE ABNORMAL CYTOLOGIC INTERPRETATION Victor E. Reuter, MD Department of Pathology Memorial Sloan-Kettering Cancer Center Disclosures: none DIAGNOSIS AND MANAGEMENT: WHAT ARE WE STRIVING FOR? Accuracy (black-grey-white) Consistency Ability to risk-stratify High sensitivity High specificity High reproducibility High exportability Low cost Non-invasive DIAGNOSTIC PITFALLS IN CYTOLOGY False Negative Inflammation Low grade urothelial carcinomas Invasive carcinomas with associated ulceration Nested variant of urothelial carcinoma Error in interpretation False Positive Instrumentation Stent Denuded mucosa * Intravesical chemotherapy Primary site- Upper GU tract Error in interpretation THE PATHOLOGY-CYTOLOGY CORRELATION Prevailing opinion: cytology offers a high degree of specificity but lacks sensitivity Assumes that pathology is the gold standard There is an implicit belief that pathology offers greater accuracy and reproducibility

2 Tumor classification Grading Staging NON-INVASIVE UROTHELIAL CARCINOMA THE GRADING OF PAPILLARY UROTHELIAL CARCINOMA Papillary: Common Benign to high grade Focal or multifocal Flat (CIS): Rare in pure form High grade Focal or multifocal WHO/ISUP CLASSIFICATION OF UROTHELIAL TUMORS PAPILLARY NEOPLASMS Papilloma Inverted papilloma Papillary urothelial neoplasm of low malignant potential Papillary urothelial carcinoma, low grade Papillary urothelial carcinoma, high grade

3 Cytology-Histology Correlation Papillary neoplasms Papilloma Inverted papilloma Papillary neoplasm of low grade malignant potential Papillary carcinoma, low grade Papillary carcinoma, high grade Cytology Negative Negative Negative/Atypia Negative/Atypia/SUS Urothelial Carcinoma A: interval to first recurrence B: interval to progression Holmang et al. J Urol. 165: ,2001 Herr et al. J Urol 178: ,2007

4 GRADING OF PAPILLARY UROTHELIAL TUMORS Good interobserver concordance within a single institution (κ = ) Fair to poor interobserver concordance globally incidence of PUNLMP: 0-12% PUNLMP vs LG LG vs HG Absence of data* on the use of markers to grade lesions in a clinically significant manner 2004 WHO CLASSIFICATION OF UROTHELIAL TUMORS Normal urothelium Reactive atypia Urothelial atypia of unknown significance Dysplasia (low grade intraurothelial neoplasia) Carcinoma in situ Post-radiation therapy Post-cyclophosphamide therapy Cytology-Histology Correlation Flat lesions Reactive atypia Atypia of unknown significance Dysplasia Carcinoma in-situ Cytology Negative Negative/Atypia Atypia/SUS Urothelial Carcinoma

5 UROTHELIAL CARCINOMA IN SITU High grade (by definition) >80% positive cytology Comes in two variations In combination with or subsequent to papillary UC (treated or not) Commonly in association with invasive disease In a pure form Rare (1%) Clinicopathologic entity Commonly multifocal/diffuse Erosive (denuding) cystitis UROTHELIAL CARCINOMA IN SITU useful criteria Pleomorphism (nuclear irregularity) (84%) Nucleomegaly (68%) Irregular chromatin (47%) Loss of polarity (46%) Raised nuclear: cytoplasmic ratio (37%) RESULTS all categories Kappa Degree of Subset of interest statistic agreement Normal Good Reactive atypia Fair Atypia? dysplasia Fair L.G. dysplasia Poor H.G.D./CIS Excellent RESULTS Kappa Degree of Subset of interest statistic agreement Non-H.G.D./CIS Excellent H.G.D./CIS Excellent

6 THE CONCEPT OF UROTHELIAL ATYPIA AND DYSPLASIA Biologic continuum Inflammatory/Reactive changes Repair reaction Instrumentation Pychologic predisposition to find disease Kappa statistics Supporting clinical and laboratory data? FLAT UROTHELIAL LESIONS IMMUNOHISTOCHEMISTRY Normal Reactive CIS CK20 umbrella umbrella all CD44 basal all basal or lost p53 rare, weak rare, weak many, strong Ki-67 no to rare rare, basal increased, levels CK20 CK20 PATHOLOGIC INTERPRETATION OF FLAT UROTHELIAL LESIONS Fair to poor interobserver concordance, except at the extremes False negative rate do to denudation and sampling Precursor lesions are poorly defined and lack clinical validation Lack of validated markers to aid in the classification and risk stratification of lesions WHO CLASSIFICATION OF UROTHELIAL TUMORS: 2004 Blue Book Histologic variants: Invasive UC with squamous differentiation Invasive UC with glandular differentiation 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

7 UROTHELIAL CARCINOMA WITH SQUAMOUS DIFFERENTIATION UROTHELIAL CARCINOMA WITH GLANDULAR DIFFERENTIATION TRANSURETHRAL RESECTION FOR BLADDER CANCER TUR for urothelial carcinoma 100 usual type 93 UC with DD 5 pure DD 2 MSKCC CYSTECTOMY FOR BLADDER CARCINOMA Residual invasive disease 212 usual carcinoma 154 (73%) UC with DD 58 (27%) Squamous 37 Glandular 14 SMCL/NE 3 Squamous, glandular 3 SMCL/NE, squamous 1 MSKCC Pure divergent histology Any amount of divergent differentiation The Case for Early Cystectomy in the Treatment of Nonmuscle invasive Micropapillary Bladder Cancer Kamat et al, JUrol, 175: ,2006 Any amount of MPC Dx based on Bx or TUR? Repeat staging TUR? Other histologies? Selection criteria for immediate cystectomy? Time interval to progression? 57% pathologic upstaging at cystectomy!

8 MORPHOLOGIC CLASSIFICATION OF UROTHELIAL TUMORS Fig 2. Kaplan-Meier survival analysis of overall nomogram patient database. Clinically relevant the more tissue examined the better Morphologic criteria are poorly defined Sometimes we will be unable to establish histogenesis How much divergent differentiation is required for clinical relevance is unknown Clinical relevance will depend on the type of tumor (small cell vs nested vs MPC, etc) SUPERFICIAL BLADDER CANCER Ta T1 Incidence (%): (12-57) 5 year survival (%): Progression (%): (18-75) Herr et al. Sem Urol 8: ,1990. T1 disease paradox: high incidence = high survival low incidence = low survival CRITERIA TO DETERMINE LAMINA PROPRIA INVASION (T 1 ) Pattern of invasion Individual tumor cells or irregularly shaped nests Stromal reaction Presence of myxoid, pseudosarcomatous, inflammatory, or sclerotic stromal response Retraction artefact Retraction surrounding tumor nests, suspicious for vascular or lymphatic invasion Morphologic appearance of basement membrane Inconspicuous. Loss of regular contour. Loss of parallel array of blood vessels which defines the basement membrane Paradoxical differentiation in early invasive tumor cells Ta 2.85 T Progression per 100 person/year Ta T1 T1s T1d Progression per 100 person/year PATHOLOGIC STAGING OF BLADDER CANCER Single most important risk factor Requires evaluation of the blader wall - TUR > Bx > Cyto Morphologic criteria are still evolving (T 1 ) False negative rate: - prior TUR - sampling - error in interpretation PATHOLOGICAL ASSESSMENT OF UROTHELIAL NEOPLASIA Summary Provides critical information for risk stratification - classification, grade and stage Complimentary to cytology - erosive cystitis, sampling Suffers from unmet needs: - invasive and expensive - standardized criteria are lacking in many areas - interobserver reproducibility will always be an issue - operator dependent (including surgeon) Absence of validated markers for early detection, recurrence and progression

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