Clinical Aspects of Cancer Staging and PathologyStaging and Pathology

Simon J Hall MDChairman Department of UrologyChairman, Department of Urology Director, Deane Prostate Health & Research CenterMount Sinai School of MedicineMount Sinai School of MedicineNew York, New York

Wh t i C n r?What is Cancer?

Local Behavior Local Behavior Lack of contact inhibition Invade surrounding organsg g

Metastasis The ability to grow outside home environment So called “seed and soil phenomenon”

Lymphatic spread Hematogenous spread

Stage & Grade TerminologyStage & Grade Terminology

Staging: Clinical Measure of Disease Physical Exam Radiographic Imaging Pathology: depth of invasion –metastases

Pathologic Grading: Marker of Behavior Based on pathologist Based on pathologist Novel molecular markers

R di r phi St inRadiographic Staging

44M with obesity and type II DM referred 44M with obesity and type II DM referred for incidentally found left renal mass.

PMHx: DM, Dyslipidemia, ys p de a SurgHx: Hydrocelectomy Medications: Glipizide Medications: Glipizide Allergies: NKDA Social: 1-2 PPD x 20 years Social: 1 2 PPD x 20 years

12/21/07L i R di l NLaparoscopic Radical Nx Clear cell RCC, grade 2. Clear cell RCC, grade 2. 6.0cm in greatest dimension. Invasion of the Renal Vein Invasion of the Renal Vein. Negative surgical margins.

pT3NxM0 Excellent correlation of Clinical and Excellent correlation of Clinical and

Pathological staging

MS-05-08360 3/3/05P il L iPenile Lesion

62 year old male presents with a penile lesion of 6 months duration. No pain.PMH & PSH i PMH & PSH negative

Medication: None PE: uncircumsized with some tightness;

2cm red raised lesion on glans of penis.

P il S C ll C rPenile Squamous Cell Cancer Pathology: Squamous cell carcinoma in Pathology: Squamous cell carcinoma in

situ (Bowen’s disease) with foci of invasive squamous well differentiated SCC.

Clinical Dx: SCC – unable to stageg Pathological Dx: Stage T1 SCC

U l i P th l P t t DiUrologic Pathology: Prostate Disease

Pathologic Upstaging: Prostate DiseaseI li ti f P iti M iImplications of Positive Margins

Types of Positive ypmargins True extracapsular

extensionextension Iatrogenic – surgeon

cut into prostate Focal vs broad Focal vs broad

Natural History of Positive margins PSA recurrence

30-50% by 5 years 30 50% by 5 years

Urologic Pathology: Prostate Disease T t t f P iti M iTreatment of Positive Margins

Surveillance Surveillance Radiation Therapy

60-64 Gy to prostate bed 60 64 Gy to prostate bed

EORTC 22911 SWOG8794 EORTC 22911 SWOG8794 74% vs 52% 73 vs 44% (PSA progression free)

Ganswindt et al EUR Urol 2008

U l i P th l R l MUrologic Pathology: Renal Masses

Incidental Renal Masses

Urologic Pathology: Renal Masses

Pathology of Small Incidental Masses (2cm) Pathology of Small Incidental Masses (2cm) 25% Oncocytoma 20% Chromophobe RCCsp

Treatment Options Surveillance Cryotherapy Partial nephrectomy

Urologic Pathology: Renal MassesE l i P diEvolving Paradigm

Indications for Biopsy Indications for Biopsy History other cancer

Esp. if other ? Mets seen

Enlarged Lymph Nodes Unclear if Resectable

Treatment OptionsS i t Surgery mainstay

Observation vs MIS Need for pathologic diagnosis. Need for pathologic diagnosis.

Urologic Pathology: Renal MassesC Bi S ffiCan a Biopsy Suffice

C r M h i f I d tiCancer: Mechanism s of Induction Genetics Genetics

Knudsen’s 2 hit theory Inherited disorders vs sporadicp

Risk factors: Smoking Chronic inflammation UV radiation

C P i F il S dCase Presentation: Family Syndromes Pt is a 33 y.o male who presented to the Pt is a 33 y.o male who presented to the

ER 10/28 with c/o headache and dizziness for two months.

Difficulty walking, “feeling unsteady” No nausea or vomitingg No change in vision or hearing.

Br i T r C r b llBrain Tumor: Cerebellum Patient with large foramen Patient with large foramen

magnum/cerebellar tumor with obstruction of the ventricular outflow foramen and hydrocephalus.

Enhancing lesions at C5 and C6 Large syringomyelia type cystic cavity at

C1 and C2 and a second larger l dsyringomyelia type cystic cavity extending

from C5 to thoracic spinal cord.

Abd i l S r i f r VHLAbdominal Screening for VHL

Abd i l S r i f r VHLAbdominal Screening for VHL

Abd i l S r i f r VHLAbdominal Screening for VHL

Abd i l S r i f r VHLAbdominal Screening for VHL

Abd i l S r i f r VHLAbdominal Screening for VHL

I i R ltImaging Results Enhancing 2 x 2 cm right lateral upper Enhancing 2 x 2 cm right lateral upper

pole renal mass. 3 cm medial enhancing rt mid pole mass3 c ed a e a c g t d po e ass 2 cm complex cyst left upper pole w/

enhancing mural nodule and septal g penhancment.

Multiple bil renal cysts Multiple cystic pancreatic lesions Normal Adrenals

P ti t Hi t rPatient History 10/31 –Given the large extent of CNS 10/31 Given the large extent of CNS

disease, Neurosurgery placed a VP shunt with no plans for surgical excision of the tumors.

2/2/06 – Pt seen by genetics Heterozygous for a T to C mutation at

nucleotide 479 if the VHL gene.

VHL Ur l i l W rk pVHL Urological Work up referred for bilateral renal masses and referred for bilateral renal masses and

diagnosis of VHL Patient reports no more HA, dizziness.at e t epo ts o o e , d ess Family history – sister with similar cysts in

pancreas and kidney “being followed in p y gNJ”

V Hipp l Li d S drVon Hippel Lindau Syndrome Genetic Disorder Genetic Disorder

Brain Tumors: cerebellum Brain Tumors: cerebellum Cystic lesions: liver, pancreas, kidney Pheochromocytomas Pheochromocytomas Renal Cell Cancers Cystadenomas of epididymis Cystadenomas of epididymis

PT CHPT CH Pt is a 74 Y Female with a long history of Pt is a 74 Y Female with a long history of

gross hematuria. Pt ignored symptoms for 1-2 years.t g o ed sy pto s o yea s Pt has no definite risk PMHx significant for arthritis and macular PMHx significant for arthritis and macular

degeneration. Pt reported to Elmhurst ER for evaluation Pt reported to Elmhurst ER for evaluation

during an episode of gross hematuria.

Pt CHPt CH Pt was hemodynamicly stable.y y Abd: soft. No CVAT Gyn: palpable but mobile mass appreciated

anterior to vaginal wall with out evidence of anterior to vaginal wall with out evidence of cervical disease

Creatinine 1.4 Hct 29.5 UA: blood Ucx: no significant growth Ucx: no significant growth CT obtained

TURBTTURBT Given CT findings pt was brought for TURBT after g p g

cardiac clearence. Extensive tumor was found that:

Obscured the UOs and trigone Obscured the UOs and trigone Involved the left and right lateral bladder wall Circumferential bladder neck involvement Involvement of the proximal urethra Involvement of the proximal urethra

Partial resection was performed for tissue diagnosisl dd k d h d Bladder neck and urethra were not resected to

preserve sphincter.

Papillary – Low magnificaiton

Invasion into lamina propria

Atypical Nuclei

St i F r Bl dd r C rStaging For Bladder Cancer T0: No evidence of primary tumor Ta: Noninvasive papillary Ta: Noninvasive papillary

carcinoma Tis: Carcinoma in situ (i.e., flat

tumor) T1: Tumor invades laminar propria T1: Tumor invades laminar propria T2: Tumor invades muscle T3: Tumor invades perivesical

tissueT4 T i d f th T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall

T4a: Tumor invades the prostate T4a: Tumor invades the prostate, uterus, vagina

T4b: Tumor invades the pelvic wall, abdominal wall

N I i Bl dd r C rNon-Invasive Bladder Cancer Approximately 70-80 % of bladder cancer pp y

present as superficial cancer About 10-20 % of superficial cancers progress to

l i i l imuscle invasive lesions Grade and stage influence recurrence and

progressionprogression Low grade Ta: 50-70 % recur, 5 % progress High grade T1: 80 % recur, 50 % progress (3y)

CIS 50% develop muscle invasive disease (5y) CIS- 50% develop muscle invasive disease (5y)

I iti l M tInitial Management Most patients with localized disease undergo a p g

TUR for diagnosis and staging The efficiency of the TUR may be less than

ll dgenerally presumed Residual disease may be seen in up to 40-70% of cases

if repeat TUR is done with weeks

T1 tumors may show worsening prognosis in up to 25 % on repeat TUR, and repeat TUR should be done if no muscle is identified on initial be done if no muscle is identified on initial pathology

FAFA 21 M presents to ER with cc of abdominal 21 M presents to ER with cc of abdominal

pain HPI:

vague abdominal pain x 3 weeks (dull, worsening)

Mild R flank pain, no fever, no N/V, possible 5 lb weight loss last month

slowly growing L testicular mass x 2 months slowly growing L testicular mass x 2 months. No other c/o

FAFA PMHx: No cryptoorchidism PSurgHx: none FHx: N/C Meds: tylenol for pain Meds: tylenol for pain

PEGeneral: no cachexia, thin, NADGeneral: no cachexia, thin, NADPulm: slight expiratory wheeze b/lAbd: mass R lateral/superior to umbilicus. NT/ND,

+BS. Minimal + R flank

FAFA GU:

normal DRE L testicle superior pole/ epididymal mass – well

circumscribed, indurated, not mobile. No masses b/l testes, small transilluminating area inferior

R testes

Labs: WBC, chem WNL. Crea 0.7 UA: nitrate neg, LE neg, blood neg LFT’s: wnl

ER CT scan obtained

CT bdCT abd

CTCT

CTCT

FAFA CT: CT:

multiple b/l lung masses massive necrotic retroperitoneal p

lymphadenopathy causing R renal obstrxn Massive hypodense liver lesions

GUGU Tumor markers Tumor markers

BhCG: >200,000 LDH: 648 AFP: 3

Possible L inguinal orchiectomy pending U/S

U/SU/S

U/SU/S No discrete testicular mass No discrete testicular mass R-sided microlithiasis b/l hydroceles R>L b/l hydroceles R>L Small varicoceles b/l

FAFA Surgery cancelled on presumptive Dx of Surgery cancelled on presumptive Dx of

extragonadal GST CT-guided biopsy:C gu ded b opsy

Choriocarcinoma

JJ stent on R Pt started on chemotherapy

T ti l r MTesticular Mass 24 yo male graduate student noted a 24 yo male graduate student noted a

painless mass in right testis. No increase in size since noted; no h/o trauma

or STDs

PE: firm nodule on lower pole of testis USG: tumor in lower pole of Testis Markers: AFP, HCG and LDH negative

Fi l Di iFinal Diagnosis Sertoli cell tumor Sertoli cell tumor

• 0.6 cm cm circumscribed• Limited to the testis• No vascular or lymphatic invasion• Resection margin negative for tumor• Adjacent testicular tissue with reduced spermatogenesis

Methods of Disease ScreeningMethods of Disease ScreeningA Two Part ProcessA Two Part Process

Di ti T t Diagnostic Test Picks up disease before clinically apparent

Treatment Intervention Prolongs Survivalg Impacts on Pain and Suffering

Prostate Cancer ScreeningProstate Cancer ScreeningDiagnostic test: PSADiagnostic test: PSA

Intervention: RRP or Radiation Therapy

If cure is possible is it necessary?If cure is possible, is it necessary? - if cure necessary, is it possible?

Willet Whitmore 1988

PSA & Prostate CancerPSA & Prostate Cancer Levels of PSA Levels of PSA

Catalona WJ et al, JAMA, 1998

Specificity & Sensitivity (ROC) of PSA f D t ti P t t CPSA for Detecting Prostate Cancer

ROCs comparing percent free prostate-specific antigen (PSA) to total PSA in reflex range subset of 4.1 to 10.0 ng/mL. Areas under the receiver operating characteristic curves for percent free PSA and total PSA are 0.71 and 0.52, respectively (P<0.05).

Vashi et al Urology 1997

Cancer Detection in PCPT R dl f PSARegardless of PSA

15% PSA <4.0 had cancer24% PSA 2.1-3.027% PSA 3.1-4.0 Thompson et al NEJM 2004

PSA Screening: Threat of Over DiagnosisThreat of Over Diagnosis Definition of Over Diagnosis Definition of Over Diagnosis

Disease which will not yield symptoms before death

Disease in those who die prior to clinical diagnosis

Over diagnosis in 18-44%

Draisma G et al JNCI, 2003Yao & Yao, JNCI, 2003

Has Use of PSA Affected Mortality?Has Use of PSA Affected Mortality?

Chu KC et al, Cancer, 2003

White males: 27% decrease A A males: 17% decrease

Underlying Cause of Lower Mortality in PSA EraMortality in PSA Era

D d M t lit M t t ti DiDecreased Mortality - Metastatic DiseaseLinked to

Decreased Incidence not Survival of Patients with Metastatic Disease

Chu KC, Cancer, 2003

Does Treatment of Localized P t t C P l S i l?Prostate Cancer Prolong Survival?

18% 35% 35% RR reductions

695 patients75% T275% T2Mean PSA 12F/u 10.8 yrs

Major effects lost after 10 years

Bill-Axelson et al JNCI 2008

Wh f T1 ?What to expect for T1c cancers?

C # 1Case # 1 54 yo man with PSA 5.8 (16% free) 54 yo man with PSA 5.8 (16% free)

Last year it was 3.5 Has IPSS 18 Normal DRE

TRUS + PNB 52cc gland Gleason 3+3 - <5% one core

L Ri k T1Low Risk T1c Expectant Management Expectant Management Radical Prostatectomy Seed Implant Seed Implant External Beam Radiation Therapy

Repeat Biopsy: 2 months later <5% Gleason’s 3+3 <5% Gleason s 3+3

S d Opi iSecond Opinion

Expectant Management + Uroxatral (afluzosin)

7/03 8/03 5/04 8/04 11/04 3/05 6/05 9/05 1/06 4/06 7/06 11/06 1/07

PSA 5.9 4.1 4.39 5.9 3.6 5.7 5.7 5.4 5.29 5.25 4.36

%Free 16% 25% 19% 19

Biopsy 3+3 <5%

3+3 <5%

BPHBPH

More Conservative AS CriterionM nt Sin i E p ri nMount Sinai Experience

More Conservative Biopsy Criterion 50 patients: 60+/-7.4

yrs’ PSA 5 8 47 T1c

Confirmatory Biopsy Results (n=50)

2225

yrs PSA 5.8, 47 T1c 44 had 1 core involved;

6 had 2 cores 40 <5% 8 5 10% 1

17

15

20

40 <5%, 8 5-10%, 1 15%, 1 20%

All re-biopsied before moving to AS

64

0

5

10

moving to AS 0No CancerSampled

No Change orvolume

decrease

VolumeIncrease

GradeIncrease

Active SurveillanceTh M t Si i E p riTheMount Sinai Experience

1st Surveillance Biopsy Results (n=22)Table 3.Review of Outcomes

50%

36%

30%

40%

50%

60% # of Patients % Treated

F/U (mont

hs)

Mount Sinai 36 8 24

9% 9%

0%

10%

20%

No CancerSampled

No Change orvolume

decrease

VolumeIncrease

GradeIncrease

UCSF 321 21 24

Klotz et al. 299 34 64

Warlick et al. 320 31 23

Hardie 2005 80 14 42decrease

25

30

12

14

0.3

0.35

Predictors of Treatment

Patel 2004 88 35 44

10

15

20

Perc

ent F

ree

PSA

(%)

19.618.1

4

6

8

10

PSA

(ng/

ml)

5.9

4.6

0.1

0.15

0.2

0.25

PSA

Den

sity

(ng/

ml/c

c)

0.12

0.15

Predictors of Treatment

0

5

No Treatment Treatment0

2

No Treatment Treatment 0

0.05

P

TreatmentNo Treatment