WHO/ISUP classification of urothelial carcinomauroonkoloji.org/files/kongre_10/47.pdf · WHO/ISUP...
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WHO/ISUP classification of
urothelial carcinoma
Rodolfo Montironi, MD (IT), FRCPath (UK), IFCAP (USA)
Polytechnic University of Marche Region (Ancona)
School of Medicine, Ancona, Italy
and
Arizona Cancer Center, Tucson, AZ, USA
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1. Grading criteria of the 1973 WHO classification
“poorly defined”
• Intra- and inter-observer variation
2. 1973 WHO: subset of non-invasive papillary
carcinomas with no progression and low recurrence
rate
• Not all are “carcinomas”
3. Need for better identification of patients with risk of
progression
• Improved risk assessment
Triggers for the 1998 ISUP/WHO classification
proposal (2004 WHO classification)
Montironi R et al, JCP 2008;61:3-10
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• International standard:
– International Society of Urologic Pathologists
(ISUP)
• Endorsed by:1. WHO 2004 Blue Book
2. 4th Series Armed Forces Institutes of Pathology
Fascicle on Bladder
3. 7th edition AJCC Cancer Staging Manual
4. 2011 ICUD on bladder cancer
2004 WHO classification
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Flat neoplasms
1. Without atypia
– Flat urothelial hyperplasia
2. With atypia
– Urothelial dysplasia (Low-grade intraurothelial
neoplasia)
– Urothelial carcinoma in situ (High-grade
intraurothelial neoplasia)
– Reactive atypia
– Atypia of unknown significance
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Normal Urothelium
CIS with microinvasionCISDysplasia
Hyperplasia
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Flat neoplasms
1.Flat urothelial hyperplasia
• Precursor lesion for a subset of papillary
urothelial neoplasms
2.Urothelial dysplasia
• Few studies, most dated: 5% to 19% risk of
developing cancer
3.Urothelial carcinoma in situ
• Development of invasion is seen in 20 to 30% of the
casesMontironi R et al, JCP 2008;61:3-10
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Papillary neoplasms(other than papilloma)
1. PUNLMP* flat hyperplasia
2. LG papillary UC flat dysplasia
3. HG papillary UC CIS
* Papillary urothelial neoplasm of low malignant potential
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Normal UrotheliumPUNLMP
LG UPC HG UPC
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Papillary neoplasms: prognosis
Does not predict risk at individual patient level ICUD 2011
Papilloma PUNLMP LG Pap UC HG Pap UC
Recurrence 9-18%17-62
(34)
34-78
(50)34-74
Grade
progression2 11 7-12 -
Stage
progression0 0-4 3-18 27-61
Survival 100 93-100 82-96 65-90
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Contributions of the 2004 WHO classification
1. Establishment of detailed criteria of various
preneoplastic conditions and various grades of tumor
2. Identification of a distinct group of patients (HG
papillary UCa) who would be ideal candidates for
intravesical therapy
3. Creation of a category of tumor that identifies a
tumor with a negligible risk of progression
(PUNLMP), whereby patients avoid the label of
having cancer which has psychosocial and financial
implications
ICUD 2011
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“The new proposed classification system for noninvasive urothelial
neoplasms does not increase the reproducibility”
Yorukoglu K et at. Reproducibility of the 1998
WHO/ISUP classification of papillary
urothelial neoplasms of the urinary bladder.
Virchows Arch 2003;443:734-740
% of agreement
PUNLMP 48%
LG papillary Ca 73%
HG papillary Ca 92%
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Grading papillary urothelial neoplasms
with histologic heterogeneity
• Grade heterogeneity is not uncommonly
encountered in papillary urothelial neoplasia
• There are studies showing that pure HG papillary
UC has a higher disease progression rate than
tumors with mixed high grade and low-grade
areas
• The 2004 WHO classification recommends
grading of heterogeneous tumors to be based on
the highest grade present in a tumor
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Grading papillary urothelial neoplasms
with histologic heterogeneity
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Grade heterogeneity of urothelial
neoplasms
Primary Secondary No. (%)
PUNLMP PUNLMP 19 (76)
PUNLMP Low grade 6 (24)
Low grade PUNLMP 7 (6)
Low grade Low grade 79 (73)
Low grade High grade 23 (21)
High grade Low grade 16 (53)
High grade High grade 14 (47)
Adapted from Cheng L, et al. Cancer 2000; 88: 1663-1670
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Grading papillary urothelial neoplasms
with histologic heterogeneity
• There is no current widely acceptable
definition or criteria to provide quantitative
estimate of size of smallest focus required to
“upgrade” a lesion
• Studies are needed to establish
quantitative/semi-quantitative criteria that
need to be present to alter assignment of
grade in tumors with grade heterogeneity
ICUD 2011
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Burçin Tuna et al. Histologic grading of urothelial
papillary neoplasms: impact of combined grading
(two-numbered grading system) on reproducibility.
Virchows Arch (2011) 458:659–664
1. PUNLMP has been shown to be the least
reproducible component of a combined scoring
system even among experienced observers
2. Exclusion of PUNLMP from grading scheme
seems to improve interobserver variability
3. The clinical management of patients with
PUNLMP or LGPUC is currently similar, if not
identical
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What is missing in the 2004 WHO
classification
– Lesions with architectural pattern
intermediate between flat and fully developed
papillary neoplasms
– Morphologic spectrum similar to that of the
flat neoplasms:
1. Papillary urothelial hyperplasia (2004 WHO)
2. Dysplasia with early papillary formation
3. CIS with early papillary formationICUD 2011
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Post-2004 WHO classification
Group No 1. Flat Urothelial hyperplasia Urothelial dysplasiaUrothelial carcinoma
in situ
Group No 2a.
Papillary, precursors
Urothelial papillary
hyperplasia
Dysplasia with early
papillary formation
Carcinoma in situ
with early papillary
formation
Group No 2b.
Papillary
Papillary urothelial
neoplasm of low
malignant potential
Low-grade papillary
carcinoma
High-grade papillary
carcinoma
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What is missing in the 2004 WHO
classification
1. Early phases of fully developed papillary
neoplasms
2. Usually occur in the backdrop of
treatment setting (followup)
3. These terms are only descriptive
diagnosis and outcome studies are not
availableICUD 2011
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Inverted neoplasms (other than inverted papilloma)
• The urothelial neoplasms with an inverted growth
pattern show a spectrum of architectural and
cytological features
• Three subgroups could be defined:
1. neoplasms that have the least degree of cytological atypia
2. neoplasms with the most severe degrees of cytological atypia
3. those that lie in between
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Inverted neoplasms• A classification and terminology consistent with
those of the flat and papillary urothelial lesions and
neoplasms should be adopted (staging: pTa)
• Scant molecular and clinical studies on the urothelial
carcinoma with an inverted growth pattern have been
published, mainly focussing on the differences with
the inverted urothelial papilloma
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Inverted neoplasms
1. Inverted urothelial neoplasm of
low malignant potential
2. Low-grade inverted UC
3. High-grade inverted UC
Montironi et al, Eur Urol 2011 ICUD 2011
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Monti
roni
et a
l, E
ur
Uro
l 2011
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Post-2004 WHO classification
Group No 1. Flat Urothelial hyperplasia Urothelial dysplasiaUrothelial carcinoma
in situ
Group No 2a.
Papillary, precursors
Urothelial papillary
hyperplasia
Dysplasia with early
papillary formation
Carcinoma in situ with
early papillary
formation
Group No 2b.
Papillary
Papillary urothelial
neoplasm of low
malignant potential
Low-grade papillary
carcinoma
High-grade papillary
carcinoma
Group No 3. Inverted
Inverted urothelial
neoplasm of low
malignant potential
Low-grade inverted
urothelial carcinoma
High-grade inverted
urothelial carcinoma
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Conclusions1. 1973 2004 a step forward
2. Towards a revised 2004?
3. The success of clinical detectionmethods is basically hampered by the“incomplete” description of themorphology of the non-invasiveneoplasms before, under andfollowing treatment