1. Bladder Cancers Mitra Heidarpour, MD Associate Professor of Pathology
Isfahan University of Medical Sciences

2. Epidemiology Male female ratio slightly less than 3:1
2/3 over the age of 65, rare under age 30
Overwhelmingly a sporadic disease

3. Risk Factors Genetic and environmental factors Occupational exposure
Aniline dyes
Cyclophosphamide
Tobacco exposure
Ionizing Radiation
Chronic Infection [stone, catheter]
Phenacetin ingestion
dietary fat
Schistosomia hematobium

4. 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.

5. • Metaplastic elements of squamous or adenocarcinoma in TCC are different than pure tumor devoid of TCC

6. Morphologic features: Urothelial Carcinoma
Lateral wall
%37
Posterior wall
%18
Trigone
%12
Neck
%11
Ureteric orifice
%10
Dome %8
Anterior wall %4
Multicentrity is common.
They are consequence of intramucosal seeding of a single tumor rather than true multicenteric tumors.

7. 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+

8. Classification of Papillary Urothelial Neoplasms No absolute agreement
WHO 1973 WHO/ISUP Papilloma Papilloma Grade 1 PULMP and low grade Grade 2 low and high grade Grade 3 high grade

9. WHO (2004)/ISUP Classification of Urothelial Tumors
Papillary Urothelial Lesions
Papillary hyperplasia
Urothelial papilloma
Papillary urothelial neoplasm of low malignant potential
Low-grade papillary urothelial carcinoma
High-grade papillary urothelial carcinoma
Flat Urothelial Lesions
Flat uothelial hyperplasia
Reactive (inflammatory) atypia
Urothelial atypia of unknown significance
Dysplasia
Carcinoma in situ

10. 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)

11. 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

12. Squamous neoplasms
Glandular neoplasms
Squamous cell carcinoma
Verrucous squamous cell carcinoma
Adenocarcinoma
Urachal carcinoma
Clear cell adenocarcinoma
In situ adenocarcinoma

13. Neuroendocrine tumors
Mesenchymal and miscellaneous tumors
Rhabdomyosarcoma Leiomyosarcoma Angiosarcoma Osteosarcoma Malignant fibrous histiocytoma Leiomyoma Neurofibroma Haemangioma Malignant melanoma Lymphoma
Small cell carcinoma
Paraganglioma
Carcinoid

14. Urothelial Papilloma 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

16. 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.

17. The diagnosis of PUNLMP should be carefully reconsidered in the presence of stromal invasion because that finding would be highly unusual.

19. 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

22. 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.

24. 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.

26. 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)

27. 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

29. CLINGING TYPE

30. 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
Membranous staining in basal cell layer only

31. Invasion to muscle is of great consequence because of its influence on therapy
Care should be exercised not to misinterpret the inconsistent fascicles of muscularis mucosa (particularly in women) as belong to muscularis properia.
Care should be exercised not to misinterpret the mature adipose tissue that present in lamina propria as perivesical fat
Some times lymphocytic infiltration obscure the epithelial component of urothelial carcinoma (specially squamous ones)

32. Lymphadenectomy Improved survival with number of nodes
sampled nodes suggested as cut point.

33. Immunohistochemical feature
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)
Trombomodeline is very sensitive but positive in most SCC & mesotheliomas
Uroplakin III is very specific but moderately sensitive
CEA, cathepsin B, CA19-9-CD15, CD10,… & TTF1
P53 in high proportion of UC (particularly high grade ones) and correlates well with prognosis.

34. High grade UC vs Prostatic carcinoma
UC+: Ck34 β E 12, ck7, P53
Prostatic carcinoma+: PSA, PSAP, leu7

35. UC versus inverted papilloma
ki67, p53 & ck20 (all of them positive in urothelial carcinoma)

36. Staging of bladder cancer
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.

38. 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.

39. 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.

40. 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).

41. Stages of bladder cancer
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)

42. Configuration (papillary or solid) Depth of penetration
The pathology report of a bladder biopsy should include the following informations:
Grade
Configuration (papillary or solid)
Depth of penetration
Presence of muscle
Lymphatic invasion
Blood vessel invasion
Margins and TNM staging in cystectomy specimens