Transcript Transitional Cell Carcinoma (TCC)

Tumors of Urinary system
Hao Zeng, M.D.
Department of Urology
West China Hospital
Types of tumors in urinary system
Urothelial cancer of Bladder
 Renal cancer
 Prostate cancer
 Testicular cancer
 Penile cancer

Estimated new malignant cases in North America(2013)
Estimated mortality of malignant cases in North America(2013)
Prevalence of urological tumors in
developing countries (China)

Urothelial cancer of Bladder

Renal cancer

Prostate cancer
Urothelial Carcinoma
(Transitional cell carcinoma)
Definition of Urothelial Carcinoma

The epithelium of urinary tract is referred as
urothelium or transitional epithelium.

The pelvis of the kidney, ureters, bladder, and
urethra are lined by this kind of epithelium

Therefore, the same type of cancers seen in
either one of the above organ can also occur in
the other sites. (Multi-locus origination)
Location

Urothelial Carcinoma of the Bladder
Compromises 90+% of all bladder cancers
 Other urothelial malignancies of the
bladder include:

 adenocarcinoma
 squamous
carcinoma
 urachal carcinoma
Non-Urothelial Tumors in the Bladder






Small cell carcinoma
Sarcomas (typically leiomyosarcoma)
Lymphomas
Pheochromocytoma
Carcinosarcoma
Metastatic tumors
Incidence





68,810 new cases diagnosed in 2010 in USA
The 4th most common cancer in men
The 11th most common cancer in women
260,000 new cases diagnosed annually
worldwide
120,000 deaths worldwide each year
Demographics

Gender:
Male to Female ratio = 3.5:1

Age:
Rates in those aged 70 years and older
are approximately 2 to 3 times higher
than those aged 55-69 years,
 about 15 to 20 times higher than those
aged 30-54 years

Risk Factors for Bladder TCC

Age (peak in 7th decade)


Incidence in those 70 years and older are
approximately two to three times higher than those
aged 55-69 years, and about 15 to 20 times higher
than those aged 30-54 years
Occupational exposures


Amines and aniline dyes
Dye workers, rubber workers, leather workers,
truck drivers, painters, and aluminum workers
Risk Factors for Bladder TCC

Cigarette Smoking

50% of these cancers in men and 30% in women
are due to smoking

Phenacetin abuse

Cyclophosphamide treatment


transplant immunosuppressant
Arsenic, Coffee and Artificial sweeteners
Prevention of Urothelial carcinoma

The greatest prevention strategy is
reduction of cigarette smoking

Cigarette use increases one's risk for
bladder cancer by 2 to 6 times

When cigarette smokers quit, their risk
declines in two to four years
Pathology - Gross
Pathology- Microscopic
Bladder Anatomy

Four layers. Important for staging


the cancer.
Epithelium: Urothelial mucosa
Lamina propria: a layer of connective tissue
and blood vessels under the epithelium.
Within the lamina propria, there is a thin and often
discontinuous layer of smooth muscle called the
muscularis mucosae.
 This superficial layer of smooth muscle is not to be
confused with the true muscular layer of the bladder
called the muscularis propria or detrusor muscle.

Bladder Anatomy

Muscularis propria (Detrusor muscle):

For purposes of staging bladder cancer, the
muscularis propria has been divided into:
Superficial muscularis propria (inner half)
Deep muscularis propria (outer half).

Perivesical soft tissue:

This outermost layer consists of fat, fibrous tissue
and blood vessels.

When the tumor reaches this layer, it is considered
out of the bladder
Classification of Urothelial carcinoma of bladder
Non-invasive: Ta, T1, Tis
Invasive: T2-T4
Bladder urothelial carcinoma Stage

Non-invasive

Ta
confined to mucosa

T1
Invasion into lamina propria

TIS
Intraepithelial CIS
Non-invasive urothelial carcinoma

At initial diagnosis,
70% of patients with
bladder cancers
have non-invasive
disease

70-80% will relapse

4-30% will progress
to invasive disease
Bladder urothelial carcinoma Stage

Invasive

T2a

T2b

T3a

T3b

T4
Invasion into
superficial muscularis propria
Invasion into
deep muscularis propria
Invasion through muscle into
perivesical fat in microscope
Invasion through muscle into
perivesical fat in macroscope
Invasion into
adjacent organs
Invasive Bladder urothelial carcinoma

30% of urothelial
carcinomas invade the
detrusor muscle (T2-T4)
at presentation

Highly aggressive

May spread by the
lymph and blood
systems to bone, liver,
and lungs
Signs and Symptoms

Hematuria


Flank Pain


Gross, Painless, Whole range, Intermittent
due to obstruction, pelvic mass, or metastatic
disease
Irritative voiding symptoms (5-10%)

Frequency, urgency, dysuria
Diagnosis and Evaluation of
Bladder urothelial carcinoma

Cystoscopy with

Biopsy/Resection






send for pathology
KUB+IVP
CT of abdomen and pelvis - assess lymph
nodes
Bimanual exam under anesthesia
Cytology
FISH(Chrom3,7,9,17 mut)
Cytoscopy and Biopsy
Description of
bladder mass:
 Location
 Size
 Shape
 Base
 Amount
IVP
Ultrasonography
CT
MRI
Cytology

Normal urothelial cells
uniform appearance
abundant cytoplasm
small nuclei

High grade cancer cell
Bladder cancer cells are
enlarged, with large and
dark nuclei
P16(红)位点,17染色体着丝粒(绿)
3(绿),7(红)染色体着丝粒
正常人
P16(红)缺失,17染色体多体
3,7染色体多体
患者
Treatment

Non-invasive disease

Transurethral resection (TUR-Bt)

Immediate instillation (within 24h after resection)

Routine instillation (every week for 6-8w)

Maintenance instillation (every month till 1y)

Radical cystectomy is seldom

Regular surveillance with cystoscopy (every 3m)
Treatment

Postoperative intervention drugs

Chemotherapy
Mitomycin C (most effective)
 Others include Doxorubicin and thiotepa


Intravesical immunotherapy
BCG (bacille Calmette- Guerin)
 improved response with addition of alphainterferon if failed with BCG alone

Treatment

Invasive disease (Stage T2 or greater)

Radical Cystectomy



patients will require urinary diversion
50% of patients with muscle invasive TCC
will have metastatic disease at diagnosis
Cystectomy not curative and additional
therapy needed with metastases
Neo-adjuvant chemotherapy
 Adjuvant chemotherapy

Treatment

Muscle invasive TCC


Select patients (Stage T2) may be treated
with transurethral resection
Partial cystectomy may be an option in select
patients with unifocal disease away from the
ureteral orifices and bladder floor in whom 2
cm margins are attainable
Treatment

The role of Chemotherapy

Neo-adjuvant chemotherapy




Neo-adjuvant chemotherapy showed survival benefit in the
treatment of invasive bladder cancer, especially in pts with
T2-T3 stage
Neo-adjuvant chemotherapy could reduce 16% of death risk
in pts with bladder cancer
Meta-analysis: improvement of 5-year OS and PFS is 5%
and 9%, respectively.
Adjuvant chemotherapy

The clinical value of adjuvant chemotherapy after surgery is
still controversial, due to lack of large scale prospective
RCTs.
Metastases with Invasive TCC

Lymphatic


pelvic lymph nodes
Hematogenous metastases

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liver
lung
bone
adrenal gland
bowel
Metastatic or Unresectable Tumors

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

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Platinum-based chemotherapy
GC used most commonly
MVAC (classic regimen)
Radiation therapy
Interventional therapy
Bio-therapy
Enrolled into Clinical Trial
Survival

Non-invasive (Ta, Tis, T1)


70% at 5 years with TURBt
80% at 5 years with cystectomy
Recurrence
 66% at 5 years overall
 88% at 15 years despite resection


15% with muscle invasive disease
BCG decreases recurrence to 17-55%
with one 6 week course

best for CIS
Survival

Invasive (T2, T3, T4)

Radical cystectomy
T2
 T3


45-70% at 5 years
35-60% at 5 years
Radiation Therapy
T1, T2
 T3, T4



40% at 5 years
20% at 5 years
N1,N2 (nodal metastases) 7% at 5 years
50-70% recurrence rate
Progression

TCC is a progressive disease




Grade 1
Grade 2
Grade 3
10-20%
20-35%
35-65%
Surveillance is key



Cystoscopy
Urinalysis + B ultrasound + cytology
Newer approaches in research
Renal Cell Carcinoma
Epidemiology

Responsible for 80-85% of primary renal neoplasms

54,390 newly cases in USA in 2010

The 7th and 9th common malignancies in men and
female, respectively

Incidence increased gradually over past 30 yrs (23% per year)

Approximately 12,000 deaths/year
Incidental Findings

Incidential Finding:




A large number of RCCs now are discovered as an
incidental finding due to abdominal CT or ultrasound
performed for abdominal pain, trauma, or in the workup for other medical problems
In a 1971 review, hematuria, abdominal
mass, pain, and weight loss most common
presentation.
Only 10% were discovered incidentally in
the 1970’s, compared to 61% in 1998.
25% metastases at diagnosis
Risk factors

Risk factors

Smoking (2 fold):The longer a person smokes, the
higher the risk. Decreased for those who quit.

Occupational exposure: Possibly asbestos, cadmium
or gasoline exposure (1.4–2 fold)

Acquired cystic disease of the kidney (30 fold)


ACKD occurs in 35-50% of chronic dialysis (usu after 8-10
yrs of dialysis)
Phenacetin: ? No longer sold in the United States
Other risk factors - genetic

Von Hippel-Lindau disease (1/3 get RCC)



Hereditary papillary RCC


Autosomal dominant
Abnormalities in chromosome 3p
Mutated c-met oncogene (chromosome 7p)
Tuberous sclerosis (<5%)


Autosomal dominant
2 loci have been identified


chromosome 9 (TSC1)
chromosome 16p (TSC2), near the gene for the most
common form of autosomal dominant polycystic kidney
disease (PKD1)
Pathology


85% of renal cell cancers are
adenocarcinomas, 90% of which are of
proximal convoluted tubular origin

Clear Cell Carcinoma (70-80%)

Papillary (10-15%) - slower growing

Chromophobe, Sarcomatoid
Transitional cell carcinomas - renal pelvis
Gross specimen of RCC
Description of
Renal mass:
 Location
 Size
 Shape
 Texture, color
 Multiple
 Adjacent
Presenting Symptoms


Classical Triad symptoms

1. Hematuria: Gross or Microscopic

2. Mass: A lump or mass in the kidney area

3. Pain
It is uncommon, only present in 10% of patients
with RCC

If present, strongly suggests metastatic disease
Systemic or paraneoplastic symptoms

Less common symptoms:







Fatigue
Loss of appetite
Weight loss
Recurrent fevers
Lethargy
Hypertension
Anemia
Endocrine abnormalities

Erythrocytosis (1-5%)




Mutate VHL protein – impaired 02 sensing
Excess erythropoietin production
Excess parathyroid hormone related
protein (PTHrP)
Hypercalcemia (15%)

PTHrP, lytic bone lesions, or excess
production of IL-6 can all contribute
Presenting signs and symptoms

Scrotal varicocele (mostly L sided) – 11%


Obstruction of gonadal vein where it enters the renal vein
Vena caval / atrial involvement (5-10%)

can produce ascites, hepatic dysfunction, et al.

Local extension (liver, pancreas, colon)

S/Sx of metastatic disease

lung, lymph nodes, bone, and liver

Brain, ipsilateral adrenal, contralat kidney
Evaluation/Workup



History
Physical Exam
Lab Studies


urinalysis
Radiological Evaluation



B-ultrasound, Doppler’s ultrasound
KUB + IVP (intravenous pyelogram)
CT, MRI
History







Flank Pain (41%)
Hematuria (36%)
Weight loss (36%)
Flank Mass (24%)
HTN (20%)
Hypercalcemia (6%)
Erythrocytosis (3%)
Past Medical History


Smoking History
Environmental Exposures





Asbestos, Cadmium, dyes, benzene
Family History
ESRD and Hemodialysis
Von Hippel Lindau
Tuberous Schlerosis
Physical Exam





Abdominal mass
Flank pain
Bruit sign
Varicocele
Hypertension
Laboratory Studies




Urinalysis
Urine culture with sensitivities
CBC (anemia)
BMP (Cr and Ca++)
Radiological Studies





Ultrasound
KUB + IVP
CT scan, MRI
RPG (retrograde pyelogram)
Angiography
Ultrasound
can differentiate simple cysts from other lesions
with >95% accuracy. If not clearly a cyst  CT.
D/Dx mainly RCC, hamartoma, xanthogran pyelo

IVP
CT scan
Plain scan
Enhanced scan
CT scan
CT scan: 91% accurate for staging (as
compared to stage after surgery)


98% sens, 96% spec for renal vein invasion

83% sens, 88% spec for metastatic LAD

46% sens, 98% spec for perinephric invasion

100% spec for adjacent organ invasion
MRI
MRI is useful if IVC or atrial involvement
suspected and to identify extent of IVC
involvement.

Retrograde Pyelogram
Angiography
Renal arteriography- D/Dx

Useful if nephron sparing approach planned
Metastatic Work-up


Chest X-ray
CT



Abdomen and Pelvis: lymphadenopathy or
elevated liver function tests
Head/Chest (mental status changes, lung
lesions)
Bone scan – esp if >T3a or if nodes
with bone pain
 PET scan may be more sens for bony mets

Metastatic Work-up

Laboratory Tests



Liver Function Tests (LFTs)
Serum Calcium
Sites of metastases include:

Lung (69%) Bone (43%) Liver (34%) Lymph
Nodes (22%) Adrenal gland(s) (19%)
Brain (7%)
TNM classification of RCC(2004)
TNM classification of RCC(2010)
Treatment







Radical Nephrectomy
Partial Nephrectomy (nephron sparing)
Laparoscopic Nephrectomy
Target molecule therapy
Immunologic Therapy
Radiation
Chemotherapy
Surgical management

Stage
I
(<7cm)
or
Stage
II
(>7cm
but
NSS has been a golden standard for
limited to kidney, no nodes or mets)
the management of small renal mass

 partial or radical nephrectomy

Partial if
Principle:
 Bilateral tumors
 Patients with solitary kidney
Adequate
cancer control with
 Chronic Renal Insufficient
maximal
preservation
of renal function
 Small
(4cm) or tumor at pole

Laparo nephrectomy possible if mass <10cm

Less operative morbidity and shorter hosp stays
Laparoscopic Nephrectomy
Stolzenburg et al. Comparative Assessment of Laparoscopic Single-Site Surgery Instruments
to Conventional
Laparoscopic
Laboratory
Setting. J of Endou.
2010;24,
Number
2,1–7.
RCT for
comparison
of LESSin with
Laparoscopic
surgery
is now
ongoing!
White WM, et al. Single-port urological surgery: single-center experience with the first 100
cases. Urology. 2009;74(4):801–4.
Surgical management

Stage III






invasion into adrenal or perinephric region
Not beyond Gerota’s fascia
Enlarged nodes in abdomen (often inflammatory and
not malignant)
Renal vein or Inferior Vena Cava invasion
 Radical nephrectomy
If IVC involvement above hepatic veins, technically
difficult surgery (often requires C-P bypass)
Surgical management

Stage IV disease




Dissection of regional nodes can provide
important prognostic info


Extension beyond Gerota’s fascia
More than one regional node group
Frank metastasis
If microscopic node involvement, 50% 5yr OS
Cytoreductive nephrectomy should be
achieved in patient with stage Ⅳ disease.
Adjuvant management of metastatic disease





Target molecule therapy
Immunotherapy
Chemotherapy
Radiation therapy
Supportive/palliative care
Molecular mechanism of RCC
Normal condition
Carcinogenesis
70-80% RCC occur mutation of VHL gene
Shuin, et al. Jpn J Clin Oncol 2006
Mechanism of Target molecule therapy
Garcia JA, et al. 2007
Types of target molecules

Receptor tyrosine kinase inhibitor


mTOR inhibitor


Sunitinib, Sorafenib, Axitinib, Panzopanib
Tersirolimus, Everolimus
VEGF antibody:

Bevacizumab
Efficacy evaluation of target molecules as first-line
therapy in treatment of metastatic RCC
Trial (ref.)
N
Exp.
arm
Control
arm
Median
PFS
Median
OS
Motzer et al.
2007
750
Sunitinib
IFN
11 vs.
5 mo
28 vs.
14 mo
Escudier et al.
2007
905
Sorafenib
Placebo
5.5 vs.
2.8mo
19.3 vs.
15.9 mo
Escudier et al.
2006
189
Sorafenib
IFN
5.7 vs.
5.6 mo
NA
Yang et al.
2003
116
Bevacizumab
Placebo
4.8 vs.
2.5 mo
NA
Hudes et al.
2007
626
Temsirolimus
IFN
3.7 vs.
1.9 mo
10.9 vs.
7.3 mo
Escudier et al.
2007
649
Bevacizumab
plus IFN
IFN
10.2 vs.
5.4 mo
NA
2010 EAU guideline for advanced RCC
1ST LINE THERAPY
Grade A
Grade B
Sunitinib
Temsirolimus
For good and intermediate risk pts
For poor-risk pts
IL-2/IFN
Only use in selected pts with a good risk and clear cell histology
2ND LINE THERAPY
Grade A
Sorafenib
2010 NCCN guideline for advanced RCC
Clinical trial
Subsequent Therapy
Options:
Bevacizumab+IFN(1)
And after TKI(2A)
Pazopanib(1)
Sunitinib after cytokine(1)
High-dose IL-2 for selected pts
And after TKI(2A)
Sorafenib for selected pts
Temsirolimus after cytokine
And Best supportive care
Clinical trial (preferred)
(2A) and after TKI(2B)
Temsirolimus(1 for poor-risk, and
High-dose IL-2(2B)
First-line Therapy Options:
Predominant
clear cell
histology
Relapse or stageⅣ
and medically or
surgically
unresectable disease
Sunitinib (Category 1) Progression Clinical trial (preferred)
Temsirolimus for poor risk(1)
Sorafenib after cytokine(1)
2A for other risk groups)
Non-clear cell
histology
IFN(2B)
Low-dose IL-2+IFN(2B)
Sorafenib/Sunitinib(2A)
Bevacizumab(2B)
Pazopanib(3)
And best supportive care
Chemotherapy(3):
Gemcitabine or capecitabine or
5-FU or floxuridne or doxorubicin(in
Sarcomatoid only)
And best supportive care
NCCN version1, 2008
Systemic Therapy – Sunitinib(Case1)
Papillary renal cell carcinoma
Baseline
After 4months
Systemic Therapy – Sunitinib(Case2)
Baseline
After 4months
Systemic Therapy – Sunitinib(Case3)
Baseline
After 4months
Immunotherapy-IFN

Interferon alpha





Approx 15% resp rate
Median time to response 4 mo
Often short-lived and/or partial responses
CR rate less than 1%
Largest study to eval long-term outcome (Motzer et al,
JCO 2002)



Retrospective review of 463 pts on 6 trials
Median OS 13 mo
14% 2yr PFS
Immunotherapy – IL-2

High-dose IL-2





1992: FDA approval based on 7 phase II trials (255
pts)
600,000 – 720,000 IU/kg q8h up to 14 doses. Repeat
q 12 weeks, up to 3 cycles
Severe toxicities
Need ICU monitoring
Selected patients could have good and long response



Pathological type: CCRCC
Without liver metastasis
CAIX overexpression
Immunotherapy – IL-2

Selected patients with good and long response
 Pathological type: CCRCC
 Without liver metastasis
 CAIX overexpression
 14-20% response rate, 7% CR
 23 mo median duration of response
 4% toxic death
Systemic chemotherapy

Single agent



Vinblastine: 2.5 – 25% resp rate
Floxuridine: 10-20% resp rates in small
studies
Review of 72 diff regimens (mainly single
agent), found resp rate of 5.6%

Mostly limited responses, rare to see increased
survival
Chemotherapy

Combination chemoRx

Gemcitabine / 5FU (Rini et al, JCO 2000)
17% resp rate
 PFS 29 weeks
 Unclear if superior to single agent Rx


Overall, RCC is considered chemoRx
resistant, and no regimen can be
considered standard of care at this time.
Reasons for chemo resistance of RCC




Proximal tubule cells (source of most RCC),
have high expression of P-glycoprotein (Multi
Drug Resistant, MDR) mRNA
In one study 6/8 RCCs and 4/4 RCC cell lines
overexpressed MDR
Another study: if 1% or > cells (+) for MDR, PFS
4mo vs 27 mo
Attempts to use MDR modifiers like CsA or PSC
833 have so far been unrewarding
Palliative / supportive care

Pain, bleeding




Analgesic medications
XRT to sites of painful mets (esp bone mets)
XRT for cord compression
Angioinfarction (renal art embolization)


“Clot colic”



No survival benefit but can relieve Sx
Ureteral stents
hydration
HyperCa, fatigue, fever, decr appetite

NSAIDs, bisphosphonates, hydration, appetite
stimulants
Prognostic factors(localized)







Size of tumor>7cm
Fuhrman grading ≥3
Lymph node(+)
With hemorrhage or necrosis within tumor
Non-clear cell type
Invasion into caval wall
Tumor thrombus extending above diaphragm
Prognostic factors (Metastatic)
 MSKCC score






<1 year interval from diagnosis to systemic
therapy
Karnofsky performance status <70
LDH 1.5-fold higher than upper limit of normal
HGB less than lower limit of normal
Corrected serum Ca2+>10mg/dl
More than 2 sites of metastasis
Poor-prognosis patients are defined as those
with≥3 predictors of short survival
Survival

5 year survival according to stage at nephrectomy
 Stage 1
65-93%
 Stage 2
47-68%
 Stage 3
34-51%
 Stage 4
2-20%

Spontaneous regression in <1% of RCC
UCLA integrated staging system (UISS)
2-y CSS(%):99
93
82
69
37
7
5-y CSS(%):97
81
63
39
17
7
Survival

Metastatic disease



30% with metastatic RCC at time of diagnosis
20-30% relapse within pts with high risk RCC
Average survival of 10.2 months
Cytokine-era
Target-era
Favorable-risk:
20months
 Intermediate-risk: 10months
 Poor-risk:
4months

not reached
27months
8.8months
谢 THANK YOU 谢