Pathology 430/827

Bladder cancerEtiology, classification, and diversity

David M. Berman, MD, PhDPathology and Molecular MedicineQueen’s Cancer Research Institutebermand@queensu.cabermanlab.org

Objectives

1. Recognize who gets bladder cancer and why

Objectives

1. Recognize who gets bladder cancer and why2. Recognize different types of bladder cancers

A. Two genomic pathways cause bladder cancerB. Bladder cancers can change (“progress”) over

timeI. GradeII. Stage

Objectives

1. Recognize who gets bladder cancer and why2. Recognize different types of bladder cancers

A. Two genomic pathways cause bladder cancerB. Bladder cancers can change (“progress”) over time

I. GradeII. Stage

3. Understand concept of epithelial differentiation and how it produces different types of bladder cancer cells

Epidemiology

• 4th 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

Recurrence

• Up to 70% of cases recur.• Estimated $3 billion annually U.S.,

– Biggest expense = surveillance (cystoscopies).

Urinary bladder:A urine storage system

Lumen

(optional)

(niche?)

Epithelial architecture

(basal)

Intermediate Cell

Uroplakins form permeability barrier

Min G et al. J Cell Sci 2003;116:4087-4094

©2003 by The Company of Biologists Ltd

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

Epidemiology

336,000 cases/yr ~3,000 cases/yrOlder male

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

Presentation

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

5-year survival

Recurrence

$$$$$$$$$

Symptoms

>

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

RISK

SmokingStrong (~50%)

OccupationStrong (~25%)

Iatrogenic Schistosomes

RISK

RISK

FamilyHistory

Muir Torre Syndrome

Arsenic

• Common (75%)

• Recur (50%)

• Local treatment

• Uncommon (25%)

• Usually progress

Radical treatmentLocal treatment

Progression and classification of urothelial carcinoma

Grade Low or High High

Grade High High

85%

Bladder Cancer Staging

STAGE Primary tumour (T) Regional Lymph Nodes (N) Distant Metastasis (M)

0 Ta or Tis 0 0

I T1 0 0

II T2 0 0

III T3 or T4a 0 0

IV T4b AND/OR N1-N3 AND/OR M1

Survival rates by stage

Stage Relative 5-year Survival Rate

0 98%I 88%II 63%III 46%IV 15%

Non-invasive papillary urothelial carcinoma

Papillary urothelial neoplasia

Fibrovascular cores

Urothelium

Low grade non-invasivepapillary urothelial carcinoma

High grade non-invasivepapillary urothelial carcinoma

Invasive urothelial carcinoma

Flat/invasive urothelial carcinoma

Benign

Carcinomain situ (CIS)

Invasive urothelial carcinoma

Two Pathways

Urothelial Hyperplasia

Flat CIS

PUNLMPLG Papillary UrCa

Superficial inv. Muscle inv. UrCa

H-RAS/FGFR3 Activation

P53/RB Inactivation

Normal Urothelium

Papillary/Noninvasive

Flat/Invasive

Loss of CDKN2A

HRAS/FGFR3+

P53/RB-

• Sweden (Lund) • Texas (MD Anderson • TCGA (U.S.)

Studies describing molecular subtypes

Non-invasive Invasive

•Urobasal A (Lund) ~ Luminal (Texas) ~ Group B (TCGA)

• Urobasal B (Sweden)

• Squamous-like (Sweden) , Basal (Texas)

Molecular Subtypes

Different cell types within a bladder cancer

Hypothetical link between injury and cancer

Activation of Sox9 by bladder injury

Ling et al., 2009 Cancer Research

Autocrine loop linking injury to bladder cancer

Ling et al., 2009 Cancer Research

Epithelial differentiation in cancer

Epigenetic changes

Epigenetic changes

(Basal cell)

Intermediate Cell

Urothelial differentiation inUrothelial Carcinoma Xenografts

BenignUrothelium

SW780 Cell LineXenograft

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

CK1767LR- (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

Signaling pathways•Jak-STAT•Notch•FAK•mTOR •EGFR•Wnt •TGF beta

67LR+

67LR_

CK17

CK17

He X et al., 2009 Stem Cells, 27:1487

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