Bladder Cancers
Mitra Heidarpour, MD
Associate Professor of Pathology
Isfahan University of Medical Sciences
Epidemiology
• Male female ratio slightly less than 3:1
• 2/3 over the age of 65, rare under age 30
• Overwhelmingly a sporadic disease
Risk Factors
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Genetic and environmental factors
Occupational exposure
Aniline dyes
Cyclophosphamide
Tobacco exposure
Ionizing Radiation
Chronic Infection [stone, catheter]
Phenacetin ingestion
dietary fat
Schistosomia hematobium
Bladder Cancer - Pathology
• Over 90% of lesions are transitional cell carcinoma
• 5-7% of lesions are pure squamous cell carcinoma
– Associated with chronic irritation [stones, catheter,
Schistosomiasis]
• 1-2% Adenocarcinoma
– Rule out metastatic source.
• Metaplastic elements of squamous or
adenocarcinoma in TCC are different than
pure tumor devoid of TCC
Morphologic features: Urothelial Carcinoma
• Multicentrity is common.
– They are consequence of intramucosal seeding of a single tumor
rather than true multicenteric tumors.
Bladder cancer: Entities
• 75-85%
superficial bladder cancer
pTa, pTis, pT1
• 10-15%
muscle-invasive bladder cancer
pT2, pT3, pT4
• 5%
metastatic bladder cancer
N+, M+
Classification of Papillary Urothelial
Neoplasms
No absolute agreement
WHO 1973
Papilloma
Grade 1
Grade 2
Grade 3
WHO/ISUP 98-99
Papilloma
PULMP and low grade
low and high grade
high grade
WHO (2004)/ISUP Classification of Urothelial Tumors
• Papillary Urothelial Lesions
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Papillary hyperplasia
Urothelial papilloma
Papillary urothelial neoplasm of low malignant potential
Low-grade papillary urothelial carcinoma
High-grade papillary urothelial carcinoma
• Flat Urothelial Lesions
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Flat uothelial hyperplasia
Reactive (inflammatory) atypia
Urothelial atypia of unknown significance
Dysplasia
Carcinoma in situ
WHO (2004)/ISUP Classification of Urothelial
Tumors
• Non-invasive urothelial neoplasias
– Urothelial papilloma
– Urothelial papilloma, inverted type
– Non-invasive papillary urothelial neoplasm of
LMP
– Non-invasive papillary urothelial carcinoma
(low grade)
– Non-invasive papillary urothelial carcinoma
(high grade)
WHO (2004)/ISUP Classification of Urothelial Tumors
• Infiltrating urothelial carcinoma
• with squamous differentiation
with glandular differentiation
with squamous and glandular differentiation
Nested variant
Microcystic variant
Micropapillary variant
Lymphoepithelioma-like carcinoma
Lymphoma-like variant
Plasmacytoid variant
Sarcomatoid
Giant cell variant
Undifferentiated carcinoma
Squamous neoplasms
• Squamous cell carcinoma
• Verrucous squamous cell
carcinoma
Glandular neoplasms
• Adenocarcinoma
• Urachal carcinoma
• Clear cell adenocarcinoma
• In situ adenocarcinoma
Neuroendocrine tumors
• Small cell carcinoma
• Paraganglioma
• Carcinoid
Mesenchymal and miscellaneous
tumors
Rhabdomyosarcoma
Leiomyosarcoma
Angiosarcoma
Osteosarcoma
Malignant fibrous
histiocytoma
Leiomyoma
Neurofibroma
Haemangioma
Malignant melanoma
Lymphoma
Urothelial Papilloma
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Benign condition
Rare
typically occurring as a small, isolated growth
commonly in younger patients
A discrete papillary growth with a central fibrovascular core
lined by urothelium of normal thickness and normal cytology
simple branching pattern without fusion
The umbrella cell layer is often prominent and may show
prominent vacuolization, nuclear enlargement, or cytoplasmic
eosinophilia
Papillary Urothelial Neoplasm of Low
Malignant Potential (PUNLMP)
• markedly thickened (hyperplastic) urothelial lining
• minimal to absent cytologic atypia
• normal polarity of the urothelial cells with an orderly,
predominantly linear arrangement perpendicular to the
basement membrane.
• Infrequent mitotic figures , usually limited to the basal
layer.
• Maintained umbrella cell layer
• simple branching pattern of papilla
• increased risk of developing recurrent or new papillary
lesions which occasionally are of higher grade and may
progress.
• The diagnosis of PUNLMP should be carefully
reconsidered in the presence of stromal
invasion because that finding would be highly
unusual.
Papillary Urothelial Carcinoma, Low-Grade
• Overall orderly appearance but with easily
recognizable variation of architectural and or
cytologic features seen at scanning magnification.
• architecture is frequently complex with obvious
anastomosis of adjacent papillae creating fused,
confluent formations
• Variation of polarity and nuclear size, shape, and
chromatin texture
• Mitotic figures are infrequent and usually seen in
the lower half; but may be seen at any level of the
urothelium
Papillary Urothelial Carcinoma, High-Grade
• Complex, disordered architecture
• A spectrum of pleomorphism ranging from
moderate to marked
• The individual neoplastic cells are often more
rounded than in lower grade lesions
• Loss of polarity in relation to the basement
membrane
• Frequent mitotic figures, including atypical forms
• Much higher risk of progression than low-grade
lesions
• High risk of association with invasive disease at
the time of diagnosis.
• A spectrum of cytologic and architectural
abnormalities may exist within a single
lesion, stressing the importance of examining
the entire lesion and noting the highest grade
of abnormality.
WHO/ISUP Classification of Flat
Intraurothelial Lesions
• Hyperplasia
• Flat lesions with atypia
– Reactive (inflammatory type)
– Atypia of unknown significance
– Dysplasia (low-grade intraurothelial lesion)
– Carcinoma in situ (high-grade intraurothelial
lesion)
Carcinoma In Situ (High-grade
Intraurothelial Neoplasia)
• characterized by the presence of cells with large,
irregular, hyperchromatic nuclei that may be either
present in the entire thickness of the epithelium or only
a part of it.
• an umbrella cell layer may still be present
• The urothelium may be denuded (discohesive cells)
• it may be diminished in thickness or hyperplastic
• frequent mitoses
• the lamina propria is frequently hypervascular and
inflamed
Immunoprofiles for CIS, Reactive Atypia, and
Normal Urothelium
CK 20
p53
CD44
CIS
Cytoplasmic
staining in full
thickness (81%)
Strong nuclear
reactivity in full
thickness (57%)
Non-reactive; loss
of normal basal
staining
Reactive atypia
Reactive only in
umbrella cells
Non-reactive
Diffuse
membranous
staining in full
thickness
Normal urothelium Reactive only in
umbrella cells
Non-reactive
Membranous
staining in basal cell
layer only
Invasion to muscle is of great consequence
because of its influence on therapy
1. Care should be exercised not to misinterpret the
inconsistent fascicles of muscularis mucosa (particularly
in women) as belong to muscularis properia.
2. Care should be exercised not to misinterpret the
mature adipose tissue that present in lamina propria as
perivesical fat
3. Some times lymphocytic infiltration obscure the
epithelial component of urothelial carcinoma (specially
squamous ones)
Lymphadenectomy
• Improved survival with number of nodes
• sampled 10-14 nodes suggested as cut point.
Immunohistochemical feature
1. Consistent expression of CK20 (in contrast with
morphologically similar TCC of ovary). Coordinate
expression of ck7 & ck20 is particularly reproducible
feature of UC (particularly in metastatic foci)
2. Trombomodeline is very sensitive but positive in most
SCC & mesotheliomas
3. Uroplakin III is very specific but moderately sensitive
4. CEA, cathepsin B, CA19-9-CD15, CD10,… & TTF1
5. P53 in high proportion of UC (particularly high grade
ones) and correlates well with prognosis.
High grade UC vs Prostatic carcinoma
UC+: Ck34 β E 12, ck7, P53
Prostatic carcinoma+: PSA, PSAP, leu7
UC versus inverted papilloma
–ki67, p53 & ck20 (all of them positive in
urothelial carcinoma)
Staging of bladder cancer
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T0: No evidence of a primary tumor
Ta: Non-invasive papillary carcinoma
Tis: Non-invasive flat carcinoma (or CIS)
T1: The tumor has grown into the connective tissue . It has not grown
into the muscle layer of the bladder.
T2a: The tumor has grown into the inner half of the muscle layer.
T2b: The tumor has grown into the outer half of the muscle layer.
T3: The tumor has grown into the fatty tissue.
T3a: microscopically.
T3b: to be seen on imaging tests or felt by the surgeon.
T4a: The tumor has spread to the stroma of the prostate (in men), or
to the uterus and/or vagina (in women).
T4b: The tumor has spread to the pelvic wall or the abdominal wall.
• Bladder cancer can sometimes affect many
areas of the bladder at the same time. If more
than one tumor is found, the letter m is added
to the appropriate T category.
Nodes
• lymph nodes near the bladder (in the true pelvis) and those
along the blood vessel called the common iliac artery.
These lymph nodes are called regional lymph nodes. Any
other lymph nodes are considered distant lymph nodes.
• NX: Regional lymph nodes cannot be assessed due to lack
of information.
• N0: There is no regional lymph node spread.
• N1: The cancer has spread to a single lymph node in the
true pelvis.
• N2: The cancer has spread to 2 or more lymph nodes in the
true pelvis.
• N3: The cancer has spread to lymph nodes that lie along
the common iliac artery.
Metastasis
• M0: There are no signs of distant spread.
• M1: The cancer has spread to distant parts of
the body. The most common sites are distant
lymph nodes, the bones, the lungs, and the
liver).
Stages of bladder cancer
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Stage 0a (Ta, N0, M0)
Stage 0is (Tis, N0, M0)
Stage I (T1, N0, M0)
Stage II (T2a or T2b, N0, M0)
Stage III (T3a, T3b, or T4a, N0, M0)
Stage IV (T4b, N0, M0 or Any T, N1 to N3, M0
or Any T, any N, M1)
The pathology report of a bladder biopsy should
include the following informations:
1. Grade
2. Configuration (papillary or solid)
3. Depth of penetration
4. Presence of muscle
5. Lymphatic invasion
6. Blood vessel invasion
7. Margins and TNM staging in cystectomy specimens