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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