1. Pathology 430/827 Bladder cancer Etiology, classification, and diversity
David M. Berman, MD, PhD
Pathology and Molecular Medicine
Queen’s Cancer Research Institute
bermanlab.org

2. Objectives
Recognize who gets bladder cancer and why

3. Objectives Recognize who gets bladder cancer and why
Recognize different types of bladder cancers
Two genomic pathways cause bladder cancer
Bladder cancers can change (“progress”) over time
Grade
Stage

4. Objectives Recognize who gets bladder cancer and why
Recognize different types of bladder cancers
Two genomic pathways cause bladder cancer
Bladder cancers can change (“progress”) over time
Grade
Stage
Understand concept of epithelial differentiation and how it produces different types of bladder cancer cells

5. Epidemiology 4th most common cancer in men,
Affecting ~3% of men in Western countries
3x less frequent in women
Peak age 75yrs

6. Epidemiology
In 2013 in US & Canada,
~80,000 new cases
~16,000 deaths

7. Recurrence Up to 70% of cases recur.
Estimated $3 billion annually U.S.,
Biggest expense = surveillance (cystoscopies).

8. Urinary bladder: A urine storage system
Lumen
(optional)

9. Epithelial architecture
Intermediate Cell
(basal)
(niche?) 9

10. Uroplakins form permeability barrier
The 3D structure of the 16 nm mouse uroplakin particle at 10 Å resolution. (A) The top view of the 3D density map of a mouse 16 nm uroplakin particle that is contoured at the 1.5σ level. The boundary of a `subunit' consisting of an inner and an outer subdomain is outlined in blue. (B) The particles as seen in a hexagonal crystalline array with one unit cell illustrated. (C) The side view of the 16 nm particle showing, from top to bottom, the joint (J), trunk region (TK), transmembrane domain (TM) and cytoplasmic domain (C). (D) One of the six inverted U-shaped subunits of the 16 nm particle, consisting of an inner subdomain (left) connected to an outer (right) subdomain via a (top) horizontal joint (j; outlined in blue). This inverted U-shaped subunit presumably represents a fundamental building block of the 16 nm particle (Staehelin et al., 1972; Hicks et al., 1974). (E) The inner subdomains of two neighboring subunits are connected via a minimal contact between them (double arrowhead). In A, the stellate-shaped particle has a maximal diameter of 17.5 nm and has a large lipid-filled, central hole (∼6 nm in diameter); in C the particle is about 12 nm tall with a 6.5 nm extracellular and a 0.5 nm cytoplasmic region [from atomic force microscopy data (Min et al., 2002)]. All panels except B are to the same scale; bar (in A) 2 nm. The unit cell in B is 16.5 nm in length.
Min G et al. J Cell Sci 2003;116:
©2003 by The Company of Biologists Ltd

11. Three cell layers of benign urothelium
Differentiation in urothelial carcinoma
Uroplakins
Basal cells
repopulate
Intermediate
cells mature
Superficial
cells protect
He X et al., 2009 Stem Cells, 27:1487 11

12. Epidemiology
Older male
336,000 cases/yr
~3,000 cases/yr *

13. Presentation
Jemal A et al. Cancer statistics, CA Cancer J Clin. 2007 *

14. 5-year survival
Jemal A et al. Cancer statistics, CA Cancer J Clin. 2007 *

15. Recurrence
$$$$$$$$$ *

16. Symptoms
>
Hematuria (>75%)
Dysuria (~10%) *

17. RISK Smoking Strong (~50%) Occupation Strong (~25%)
similar to lung cancer in environmental risk factor. Rarely familial. Even
Smoking Strong (~50%)
Occupation
Strong (~25%) *

18. RISK Iatrogenic Schistosomes
similar to lung cancer in environmental risk factor. Rarely familial. Even *

19. RISK Arsenic Muir Torre Syndrome Family History
similar to lung cancer in environmental risk factor. Rarely familial. Even *

20. Common (75%) Recur (50%) Local treatment
urologist jargon vs. pathologist *

21. Uncommon (25%)
Usually progress
urologist jargon vs. pathologist *

22. urologist jargon vs. pathologist
Local treatment
Radical treatment *

23. Progression and classification of urothelial carcinoma
Grade Low or High High
85%
Grade High High

24. Bladder Cancer Staging
STAGE
Primary tumour (T)
Regional Lymph Nodes (N)
Distant Metastasis (M)
Ta or Tis I T1 II T2
III
T3 or T4a IV
T4b
AND/OR N1-N3
AND/OR M1

25. Survival rates by stage
Relative 5-year  Survival Rate
98% I
88% II
63%
III
46% IV
15%

26. Non-invasive papillary urothelial carcinoma

27. Papillary urothelial neoplasia
Fibrovascular cores
Urothelium

28. Low grade non-invasive papillary urothelial carcinoma

29. High grade non-invasive papillary urothelial carcinoma

30. Invasive urothelial carcinoma

31. Flat/invasive urothelial carcinoma
Benign
Carcinoma
in situ (CIS)

32. Invasive urothelial carcinoma

33. H-RAS/FGFR3 Activation Urothelial Hyperplasia
Two Pathways
H-RAS/FGFR3 Activation
Papillary/Noninvasive
PUNLMP
LG Papillary UrCa
Urothelial Hyperplasia
Loss of CDKN2A
Normal
Urothelium
P53/RB Inactivation
Flat/Invasive
Flat CIS
Superficial inv.
Muscle inv. UrCa

34. HRAS/FGFR3+
P53/RB-
urologist jargon vs. pathologist *

35. Studies describing molecular subtypes
Sweden (Lund)
Texas (MD Anderson
TCGA (U.S.)
Bladder cancer has had a terrific explosion of important research since 2013.

36. Molecular Subtypes Non-invasive Invasive
Urobasal A (Lund) ~ Luminal (Texas) ~ Group B (TCGA)
Urobasal B (Sweden)
Squamous-like (Sweden) , Basal (Texas)

37. Different cell types within a bladder cancer

38. Hypothetical link between injury and cancer

39. Activation of Sox9 by bladder injury
Ling et al., 2009 Cancer Research

40. Autocrine loop linking injury to bladder cancer
Ling et al., 2009 Cancer Research

41. Epithelial differentiation in cancer
Epigenetic changes
Intermediate Cell
Epigenetic changes
(Basal cell) 41

42. Urothelial differentiation in Urothelial Carcinoma Xenografts
Benign
Urothelium
SW780
Cell Line
Xenograft 42

43. 67 Kd Laminin Receptor: Surface marker of tumor “basal cells”
Ki67!!!!!!!!
But not in vitro
He X et al., 2009 Stem Cells, 27:1487 43

44. 67LR expression in vivo identifies basal-like bladder cancer cells
CK17
FACS
SW780 Human Bladder cancer xenograft
Single cell digest
67LR- (87%)
67LR+ (13%)
Inject 10 sites, 2-20k cells each
He X et al., 2009 Stem Cells, 27:1487 44

45. “Basal” cells form tumors. More differentiated cells do not
67 LR bright (Basal)
Unfractionated
67 LR dim (Differentiated)
He X et al., 2009 Stem Cells, 27:1487 45

46. Gene Expression Programs in Basal-like Urothelial Cancer Cells
Migration
Angiogenesis
Apoptosis
Proliferation
67LR+
67LR_
CK17
Signaling pathways
Jak-STAT
Notch
FAK
mTOR
EGFR
Wnt
TGF beta
He X et al., 2009 Stem Cells, 27:1487 46

47. Conclusions Two pathways of bladder cancer
Genomic differences between cancers
Epithelial injury is a risk factor
Molecular links exist between injury repair and cancer
Bladder cancers differentiate in a manner similar to benign urothelium
Genomic differences within cancers