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

Objectives 1.Recognize who gets bladder cancer and why

Objectives 1.Recognize who gets bladder cancer and why 2.Recognize different types of bladder cancers A.Two genomic pathways cause bladder cancer B.Bladder cancers can change (“progress”) over time I.Grade II.Stage

Objectives 1.Recognize who gets bladder cancer and why 2.Recognize different types of bladder cancers A.Two genomic pathways cause bladder cancer B.Bladder cancers can change (“progress”) over time I.Grade II.Stage 3.Understand concept of epithelial differentiation and how it produces different types of bladder cancer cells

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

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

RISK Smoking Strong (~50%) Occupation Strong (~25%)

IatrogenicSchistosomes RISK

Family History Muir Torre Syndrome Arsenic

Symptoms > Hematuria (>75%)Dysuria (~10%)

Urinary bladder: A urine storage system Lumen (optional)

Common (75%) Recur (50%) Local treatment

Uncommon (25%) Usually progress

Radical treatment Local treatment

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

Bladder Cancer Staging STAGEPrimary tumour (T)Regional Lymph Nodes (N)Distant Metastasis (M) 0Ta or Tis00 IT100 IIT200 IIIT3 or T4a00 IVT4bAND/OR N1-N3AND/OR M1

Survival rates by stage StageRelative 5- year Survival Rate 098% I88% II63% III46% IV15%

Non-invasive papillary urothelial carcinoma

Papillary urothelial neoplasia Fibrovascular cores Urothelium

Low grade non-invasive papillary urothelial carcinoma

High grade non-invasive papillary urothelial carcinoma

Invasive urothelial carcinoma

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

Invasive urothelial carcinoma

Sweden (Lund) North Carolina (UNC) Texas (MD Anderson TCGA (U.S.) Studies describing molecular subtypes

Non-invasiveInvasive Urobasal A (Lund) ~ Luminal (Texas, NC) ~ Group B (TCGA) Urobasal B (Sweden) Squamous-like (Sweden), Basal (Texas, NC) Molecular Subtypes

Different cell types within a bladder cancer

(niche?) Epithelial architecture (basal) Intermediate Cell

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

Differentiation programs in cancer REYA ET AL. NATURE (2001) 414:105 Stem cells Intermediate cells Fully differentiated cells

Cancer Stem Cells Minority tumor cell subpopulation Resistant to standard “killing” therapies –Chemotherapy –Radiation  Responsible for recurrence and therapy resistance

Stem cells Intermediate cells Fully differentiated cells Growth rate Slow Fast N/A

Targeting Cancer Stem Cells

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

Urothelial differentiation in Urothelial Carcinoma Benign Urothelium Bladder Cancer

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

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

“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

Gene Expression Programs in Basal-like Urothelial Cancer Cells Migration Angiogenesis Apoptosis Proliferation Poor prognosis 67LR + 67LR _ CK17 He X et al., 2009 Stem Cells, 27:1487

Sweden (Lund) Texas (MD Anderson TCGA (U.S.) Studies describing molecular subtypes

Basal differentiation = shorter survival

Tailored therapy?

Conclusions Two pathways of bladder cancer – Genomic differences between cancers Bladder cancers differentiate in a manner similar to benign urothelium Genomic subtypes correspond to different cell types in benign urothelium Treatment strategies need to be adapted to new subtypes