Post on 27-Sep-2020
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“Southern Alps” South Island, NZ
CRITICAL ROLE OF THE PATHOLOGIST IN THE MANAGEMENT OF BLADDER CANCER
BLADDER CANCER EPIDEMIOLOGY (2014)
Siegel et al. CaA Cancer J Clin 64:9-29, 2014
Urinary bladder 18,300 2.3%
Urinary bladder 4,410 1.6%
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EORTC RISK TABLESPatients presenting with Ta/Tis/T1 tumors
RECURRENCE
• 6 - Number of tumors• 4 - Prior recurrence• 3 - Tumor size• 2 - Grade• 1 - T-category• 1 - CIS
PROGRESSION*
• 6 - CIS• 5 - Grade• 4 - T-category• 3 - Number of tumors• 3 - Tumor size• 2 - Prior recurrence
Sylvester et al. Eur Urol 49:466, 2006
*Progression = development of muscle invasive disease
WHO/ISUP 2004/2016 CLASSIFICATION
• NORMAL• FLAT LESIONS WITH ATYPIA
– Reactive (inflammatory) atypia– Atypia of unknown significance– Dysplasia (low grade intraurothelial neoplasia)– Carcinoma in situ (high grade intraurothelial neoplasia)
• PAPILLARY NEOPLASMS– Papilloma– Inverted papilloma– Papillary neoplasm of low malignant potential– Papillary carcinoma, low grade– Papillary carcinoma, high grade
• INVASIVE NEOPLASMS
NORMAL UROTHELIUM
Cytokeratin 20
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REACTIVE ATYPIA REACTIVE ATYPIA
DYSPLASIA DYSPLASIA
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DYSPLASIA
Or Incipient Papillary Neoplasia?
CIS “flat urothelial lesion…containing cytologically malignant cells”
Cytokeratin 20
CIS - LARGE CELL CIS - LARGE CELL
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CARCINOMA IN SITU
Abundant eosinophilic cytoplasm
CIS – “SMALL CELL”
CIS - DENUDING CIS – DENUDING – VON BRUNN’S NESTS
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CARCINOMA IN SITU
No surface epithelium
CARCINOMA IN SITU
Pagetoid growth
SV: CIS - PAGETOID CARCINOMA IN SITU
Early invasion
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CARCINOMA IN SITU – p53 IHC~ 80% Positive
CARCINOMA IN SITU
CK20
CARCINOMA IN SITUCK20
P53
CARCINOMA IN SITU
AMACR
CK 20
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REACTIVE ATYPIA
CK20
p53
UROTHELIAL CARCINOMA IN SITU - LONG TERM OUTCOME
SURVIVAL-TYPE 10-Year 15-Year
Progression-free 63% 59%
Cancer-specific 79% 74%
All-cause 55% 40%
Cheng et al, Cancer 85:2469, 2000
CLASSIFICATION AND GRADING OF PAPILLARY UROTHELIAL NEOPLASMS
BASED ON TWO KEY FEATURES• Architectural disruption• Degree of cytologic atypia
UROTHELIAL PAPILLOMA
• Most are small• Essentially normal
urothelium• Often vacuolated
umbrella cells
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PAPILLOMA PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL
PUNLMP
PUNLMP LOW GRADE
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LOW GRADE
LOW GRADE HIGH GRADE
HIGH GRADE HIGH GRADE
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HIGH GRADE PAPILLARY BLADDER – PAPILLARY UC
52/164 (32%) papillary UC were grade heterogeneous Cheng et al. Cancer 88:1663-1670, 2000
EARLY PAPILLARY CARCINOMA
WHO 1973 vs WHO 2016
Papilloma Papilloma
Papillary urothelial neoplasm of low malignant potential
Papillary ca, low grade
Papillary ca, high grade
Papillary ca, I
Papillary ca, II
Papillary ca, III
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pTa BLADDER CALONG TERM OUTCOME
Pan et al, AJCP 133:788, 2010
N=175 N=483 N=129
Progression in stage
pTa BLADDER CALONG TERM OUTCOME
Pan et al, AJCP 133:788, 2010
Cancer-specific mortality
N=175 N=483 N=129
Hobbiton as seen from the Green Dragon
STAGING OF BLADDER CANCER (2010 TNM)
• pTa Non-invasive, papillary• pTis Non-invasive, flat• pT1 Invasion of subepithelial connective
tissue (lamina propria)• pT2 Invasion of muscularis propria
– pT2a inner one-half– pT2b outer one-half
• pT3 Invasion of perivesical tissue– pT3a microscopically– pT3b macroscopically
• pT4 Invasion of adjacent structures
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BLADDER CANCER:OUTCOME AFTER CYSTECTOMY
N=1,100
Hautmann et al. Eur Urol 61:1039, 2012
TREATMENT OF T1 DISEASE
“ On the basis of clinical and administrative data, we estimate that between 31.2% and 46.8% of deaths potentially were avoidable.”
Cancer 115:1011, 2009
TREATMENT OF T1 DISEASE
2008;102:270-275
15% 83%
Eur Urol 57:60-70, 2010
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TREATMENT OF T1 DISEASE
2008;102:270-275
RADICAL CYSTECTOMY FOR NON-MUSCLE INVASIVE BLADDER CANCER:
EAU GUIDELINES 2016 UPDATE
“RC should be considered:”
• Multiple and/or large (> 3cm) T1, HG/G3 tumors
• T1, HG/G3 tumors with concurrent CIS• Recurrent T1, HG/G3 tumors• T1, HG/G3 tumors with CIS in prostatic
urethra• Unusual histology of urothelial carcinoma• Lymphvascular invasion present
Babjuk et al. Eur Urol 71:447-461, 2017
DIAGNOSIS OF INVASION
Irregular nestsStromal response
DIAGNOSIS OF INVASIONIncreased cytoplasmRetraction artifact
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DIAGNOSIS OF INVASIONIncreased cytoplasmRetraction artifact
DIAGNOSIS OF INVASION
T1 SUBSTAGING
Cheng et al. J Clin Oncol 17:3182, 1999
pT1m: a single microscopic focus ≤one HPF
pT1e: a single microscopic focus > one HPF or more than one focus
van Rhijn et al. Eur Urol 61:378, 2012
T1 SUBSTAGING
Chang et al. Am J Surg Pathol 36:454, 2012
N=1,515
HGPUC Ta vs T1 ≤ 1mm
HGPUC T1 ≤ 1mm vs > 1mm
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T1 SUBSTAGING(≤ 1 HPF vs > 1 HPF)
Bertz et al. Histopathology 59:722, 2011.
P<0.001P=0.012
N=301 N=301Progression-free survival Cancer-specific survival
MUSCULARIS MUCOSAE
MUSCULARIS MUCOSAE TRIGONE REGION
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TRIGONE REGION MUSCULARIS MUCOSAE INVASION
MUSCULARIS MUCOSAE INVASION MUSCULARIS PROPRIA INVASION
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MM vs MP INVASION pT1 – SUBSTAGING: MUSCULARIS MUCOSAE
“pT1a” “pT1b”
SURVIVAL ACCORDING TO MUSCULARIS MUCOSAE INVASION
• 343 patients -initial treatment
• 170 pT1
• Cases centrally reviewed
• Substaging possible in 99 (58%)
• Treated by:
• TURBT with intravesical tx
Angulo et al, J Cancer Res Clin Oncol 119:578, 1993
P<0.02
“Based on the available data, it is recommended to provide an assessment of the depth and/or extent of subepithelial invasion inT1 cases.”
Grignon et al. Infiltrating urothelial carcinoma (p97)
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COLLEGE OF AMERICAN PATHOLOGISTS: 2017 REPORTING GUIDELINES
URINARY BLADDER (BIOPSY/TRANSURETHRAL RESECTION)
“Depth of invasion is a critical prognostic determinant in invasive urothelial carcinoma. In T1 disease, several substaging methods have been proposed but have been difficult to adopt due in part to the inherent lack of orientation of the specimen.10,13 Pathologists are, however, encouraged to provide some assessment as to the extent of lamina propria invasion(ie, maximum dimension of invasive focus, or depth in millimeters, or by level – above, at, or below muscularis mucosae).”
T1 UC WITH LYMPHVASCULAR INVASION• 118 newly diagnosed T1; all with TURBT +/- intra-vesical tx (85%)• LVI diagnosis based on H&E alone • LVI diagnosed in 33 cases (28%)
Cho et al. J Urol 182:2625-2631, 2009
PROBLEMS WITH IDENTIFICATION OF LYMPHVASCULAR INVASION
“The general use of immunohistochemistry in the rout ine setting, however, cannot be recommended” Amin et al. Patholog y Consensus Guidelines, International Consultation on Urologic Diseases, 2012
GRADE AS A PREDICTOR OF OUTCOME IN pT1 CA TREATED BY TURBT
Kaubisch et al, J Urol 146:28-31, 1991
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GRADE AS A PREDICTOR OF OUTCOME IN pT1 CA TREATED BY TURBT
Kaubisch et al, J Urol 146:28-31, 1991
“The overwhelming majority of invasive urothelial carcinomas are high grade” Grignon et al. WHO 2016, p86
UROTHELIAL CARCINOMA - PATTERN OF INVASION
Jimenez et al, Am J Surg Pathol 24:980, 2000
UROTHELIAL CARCINOMASURVIVAL BY PATTERN OF INVASION
Jimenez et al, Am J Surg Pathol 24:980, 2000
Denzinger et al. Scand J Urol 43:282, 2009
UROTHELIAL CARCINOMAHISTOLOGIC VARIANTS (2016)
• Divergent differentiation– Squamous differentiation– Glandular differentiation– Trophoblastic differentiation– Müllerian differentiation
• Nested variant• Microcystic variant• Micropapillary variant• Plasmacytoid variant• Clear cell type• Lipid-rich• Lymphoepithelioma-like variant• Giant cell• Sarcomatoid carcinoma
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2008;102:270-275
PROGNOSITIC SIGNIFICANCE OF VARIANT HISTOLOGY
Xylinas et al. Eur J Cancer 49:1889-1897, 2013
• Multi-institutional (5)• Radical cystectomy 2000 – 2008• No neoadjuvant treatment
RECOGNITION OF VARIANT HISTOLOGY
VARIANT NUMBER* PERCENT PERCENT NOT RECOGNIZED
Squamous differentiation 32 32% <25%
Small cell differentiation 16 16% 44%
Glandular differentiation 13 13% <25%
Micropapillary 12 12% 83%
Nested 8 8% 87%
Sarcomatoid 6 6% NA
Lymphoepithelioma-like 3 3% 100%
Plasmacytoid 1 1% 100%
Multiple types 10 10% NA
* Variant histology present in 115/589 (20%) of TURBT cases reviewed (2004 – 2008)
Shah et al. Urol Oncol 31:1650, 2013
UROTHELIAL CARCINOMAMICROPAPILLARY TYPE
• CLINICAL– Similar epidemiology to usual TCC– High stage, 50% with + LN at diagnosis– Worse prognosis with high % MP
• PATHOLOGY– Small, tight clusters of cells– Open spaces simulating lymphatic invasion– Deeply invasive
– Suggested to be a form of glandular differentiation– Inversion of MUC1 staining to stromal aspect
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MICROPAPILLARY VARIANT MICROPAPILLARY VARIANT
MICROPAPILLARY VARIANT MICROPAPILLARY VARIANT
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UC - MICROPAPILLARY VARIANT
CD 34
UC - MICROPAPILLARY VARIANT: DIAGNOSTIC CRITERIA
• High degree of agreement with “classical cases” (Kappa value 0.79)• Less agreement for equivocal cases • Key features for diagnosis included:
• Extensive retraction artifact• Multiple nests within the same lacunar space• Epithelial ring forms• Peripheral nuclear orientation
Sangoi et al. Am J Surg Pathol 34:1367, 2010
UC - MICROPAPILLARY VARIANT: DIAGNOSTIC CRITERIA
UC - MICROPAPILLARY VARIANTURETER FROZEN SECTION
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UC - MICROPAPILLARY VARIANT
Lopez-Beltran et al. Hum Pathol 42:1159-1164, 2010
Comperat et al. Pathology 42:650-654, 2010
UC – MICROPAPILLARY VARIANT: OUTCOME
N=24 N=72
UROTHELIAL CARCINOMAPLASMACYTOID CELL TYPE
• CLINICAL– Described by Saphir in 1955 (“monocytoid SRC”)– Highly aggressive tumor– Linitis plastica-like; often no discrete mass but
edematous mucosa in many
• PATHOLOGY– Sheets of poorly cohesive cells– Distinct monocytoid/plasmacytoid morphology with
variable numbers of true signet-ring cells– +/- typical UC component– CK ++ (variable CK7/CK20), p63+, LCA -
PLASMACYTOID CARCINOMA
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PLASMACYTOID CARCINOMA Plasmacytoid variant
PLASMACYTOID CARCINOMA PLASMACYTOID CARCINOMA
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PLASMACYTOID CARCINOMA PLASMACYTOID VARIANT
CK 7 CK 20 CD 138
PLASMACYTOID CARCINOMA
E-CADHERIN
PATTERN OF SPREADRectum
Lymph nodePelvic wall
Fallopian Tube
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Plasmacytoid UC – Ureter Margin Frozen Section Plasmacytoid UC – Ureter Margin Frozen Section
PLASMACYTOID CARCINOMA
Keck et al. BMC Cancer 13:71, 2013 Mirror Lake, South Island, NZ