Diseases of the prostate - 2009ERSPC 2009 and PLCO •!ERSPC - >160,000 men – 20% risk...

Diseases of the Prostate

Dr Jon Oxley

Southmead Hospital, Bristol

13th May 2009

Topics

•!Background and screening

•!Normal histology

•!Benign conditions mimicking cancer

•!Multidisciplinary team meeting

•!Small volume disease

•!High Grade PIN

•!Gleason grading

•!Radical prostatectomy

•!Slide seminar

Incidence of prostate cancer

Trends in Prostate Cancer Incidence and Mortality in England and Wales, 92-04

European age-standardised rates Source: ONS (Office for National Statistics) and WCISU (Wales Cancer Intelligence and Surveillance Unit)

Age related incidence

Crude Incidence Rates 2002

Source: ONS, WCISU

Why has incidence increased?

•!PSA testing

•!Better reporting

•!Biopsy rate increasing

•!Greater patient awareness

PSA

•!First described in 1979

•!Sensitive but lacks specificity

•!Age dependent normal ranges

•!6th decade <2.5ng/ml

•!8th decade <6 ng/ml

•!Affected by UTI, prostate size, iatrogenic

Transrectal ultrasound

•!US abnormalities associated with cancer uncommon

•!Hypoechoic areas may be benign

•!Increased numbers of biopsies from 4 to 10 in recent years to overcome these problems

Treatment options

Radical prostatectomy (open,laparoscopic,robotic)

Radiotherapy – including brachiotherapy +/- HDR boost

Active monitoring

Hormones

HIFU

Cryotherapy

Screening for prostate cancer

General Principles of Screening

•!The condition should be a significant health problem

•!The natural history should be understood

•!There should be an early or latent stage

•!Treatment at an early stage should be of more benefit than started at a later stage

•!There should be a suitable test

•!Test should be acceptable to the population

•!Screening should be repeated at intervals

•!Facilities available for diagnosis & treatment

•!Chance of harm should be less than chance of benefit

•!Cost effective

ERSPC 2009 and PLCO

•!ERSPC - >160,000 men – 20% risk reduction in deaths from prostate cancer in screened group. N Engl J Med. 2009 Mar 26;360(13):1320-8

•!PLCO – USA – 76693 men – no risk reduction if screened. N Engl J Med. 2009 Mar 26;360(13):1310-9.

•!48 men treated for prostate cancer for every life saved

ProtecT Study flowchart up to April 2009

226,716

Invitations

111,091 (49%)

Prostate check clinic attenders

10,274 (11.1%)

Raised PSA

2,618 (82%) Localised

324 (10%) Advanced

232 (7%) Excluded

3,174 (31%) Total cancer

ProtecT randomisation

2618

Eligible cases

1651 (63%)

Randomised

967(37%)

Preference

540

A Monitoring

546 Surgery

541 Radiotherapy

Annual follow-up

263

Surgery

506

A Monitoring

130

Radiotherapy

& 57 Brachy

Prostatectomies by Age Band and Year

Includes radical prostatectomies (OPCS Codes M611-619) England only Source: HES 6

Pathology

Look at a prostate for normal histology Anterior

Posterior

Right Left

A

B

Area A

Area B

Ejaculatory ducts

Ejaculatory ducts

Seminal vesicle

Benign mimicking cancer

1.! Seminal / ejaculatory duct epithelium

2.! Basal cell hyperplasia

3.! Clear cell adenosis (variants)

4.! Atrophy

Seminal vesicle / ejaculatory duct

•!Lipofuscin granules

•!Nuclear pleomorphism

•!Tufting of cytoplasm

Basal cell hyperplasia •!Dark staining

cytoplasm

•!Antler shaped glands with little cytoplasm

•!High molecular weight keratin positive

Clear cell adenosis •!Various

entities described

•!Clear cytoplasm with small nuclei

•!Crowded glands

•!Report as atypical but not HG PIN

Clear cell adenosis – 34Beta

Atrophy

•!Pale cytoplasm

•!Dilated glands

•!Occasional small nucleoli

•!Loss of basal layer

Atrophy contd.

Small nucleoli

Atrophy – 34Beta

Multidisciplinary team meeting

Patient A

•! 48 year man, asymptomatic. No comorbidity

•!PSA 4.1 ng/ml

•!TRUSS guided biopsies

- 4/8 biopsies show high grade

intraepithelial neoplasia

•!Significance?

High grade prostatic intraepithelial neoplasia (HG PIN)

HG PIN

HG PIN

•! 55yr old, asymptomatic. No comorbidity

•!PSA 7.5 ng/ml

•!TRUSS guided biopsies

- 1/8 biopsies show a few acini with

well differentiated cancer

•!Significance?

•!What next?

Patient B

Small volume on core

High molecular weight cytokeratin (34BetaE12)

34BetaE12

Interpreting immunohistochemistry

•!At the periphery of benign nodules loose staining

•!Attenuated in PIN and benign nodules

•!Negative gland surrounded by strongly positive glands is very suspicious

•! Reference: Cytokeratin 34BetaE-12 immunoreactivity in benign

prostatic acini. Goldstein et al, Am J Clin Pathol 1999;112:69-74

Patient C

•! 59 year old, asymptomatic. No comorbidity

•!PSA 7.1 ng/ml

•!TRUSS guided biopsies

- Gleason 7 adenocarcinoma

in 3/8 biopsies, all on right side

•!Management?

Gleason Score

•!Based on architecture

•!Nomogram devised by Gleason in 1975

•!Two grades

•!First number is predominant pattern

•!Second number is next commonest

Gleason score

grade 3 + grade 4

= GLEASON SCORE 7

Tips to grading 1 – Jelly bean grading

•!Grade 1 – Jelly bean crosssection

– NEVER in core

•!Grade 2 – Jelly bean – rarely in core

•!Grade 3 – Bent jelly bean – commonest

•!Grade 4 – Melted jelly bean (gland fusion)

•!Grade 5 – Blended jelly bean (single cells)

or small cell (often PSA -ve)

Tips to grading 2

•!Start at Gleason grade 3 and go up or down

•!If only one pattern – double it

•!If any high grade area put in score

•!NEVER GRADE IN HORMONE TREATED

•!If a score of 4 or below is reported needs review (only acceptable in TURPs)

Major pitfalls

•!Cribriform Gleason grade 3 versus glandular fusion in grade 4

Reference: Current diagnostic pathology

Minimum dataset RIGHT (+ RIGHT APEX)* Cores:

Number of cores involved: (Apex is positive / negative)*

Total percentage of tumour:

Adenocarcinoma Gleason score=……+……=

! Perineural invasion yes no

Extraprostatic invasion yes no not assessable

Seminal vesicle invasion yes no not assessable

Vascular invasion yes no

!

LEFT (+ LEFT APEX)* Cores: [as above]

CONCLUSION

! Prostatic adenocarcinoma

! Type of tumour : microacinar other(state)

!OVERALL GLEASON SCORE: ………+………=………

Volume in cores

•!Shown to reflect stage in radical prostatectomy (ref: Grossklaus J Urol 2002)

•!Large volume in core = more advanced stage

•!BUT converse is not true.

•!Several methods

•!Number of cores involved

•!Length in mm

•!% of each core

•!% of total cores

Extracapsular invasion

•!Tumour in fat

•!Tumour in Ganglion

•! 58 year old, asymptomatic. No comorbidity

•!PSA 8.2 ng/ml

•!TRUSS guided biopsies

- 3/6 show Gleason 7 adenocarcinoma

•!Underwent radical prostatectomy

•!Lymph nodes clear. Capsular penetration

at base on right. Perineural infiltration

•!Further management?

Patient D

Radical prostatectomy cut up

Apex and Base

•!Shave or perpendicular?

Seminal vesicles

•!Various techniques

•!Vertical cut

•!Embed in total

Whole mounts

•!Advantages

•!Orientation

•!Less blocks / slides

•!Easier to demonstrate

•!Disadvantages

•!Technically difficult (esp. immuno)

•!Storage

Whole mount

Extracapsular extension

Ganglion with perineural invasion

Surgical margins

•!Intracapsular positive – the surgical margin is inside the prostate and tumour is present at this margin.

•!Extracapsular positive – the surgical margin is outside the prostate but tumour has breached the capsule and extends to this margin.

•!Apex positive – tumour is present at the apical margin

•!Base positive - tumour is present at the base margin

Surgical margins Base

Apex

Circumferential

(intra or extraprostatic)

Intraprostatic positive (pT2+)

Volume calculation - estimate

Volume calculation

•!Width x Length x thickness of block

•!…ml = ….cm x ….cm x 0.5cm

Maximum length

•! Either width or length

Minimum dataset PSA (if known) :

Weight (g) :

Tumour present (Yes/No) :

Urothelium (Normal/Other) :

Type of tumour (microacinar, ductal, other) :

Number of Foci (1,2,3,4+) :

SITE of TUMOUR – Largest :

2nd :

MAXIMUM LENGTH (mm) :

TOTAL VOLUME (ml) :

High Grade PIN (Yes/No) :

PERINEURAL INVASION (Yes/No) :

VASCULAR INVASION (Yes/No) :

CAPSULAR BREACH (Yes/No) :

EXTRAPROSTATIC SURGICAL MARGIN : Positive Negative

INTRAPROSTATIC SURGICAL MARGIN : Positive Negative

APEX MARGIN : Positive Negative

BASE MARGIN : Positive Negative

SEMINAL VESICLES : Positive(R) Positive(L) Negative

Lymph Nodes : Yes (R) (L) None

OVERALL GLEASON SCORE : + =

STAGE : pT N

Stage

Stages (2002 – TNM):

pT2 confined

pT2a one lobe

pT2b more than half one lobe

pT2c both lobes

pT2+ +ve intraprostatic margin

pT3 extracapsular

pT3a extracapsular,

pT3b seminal vesicle

Stage

Takehome message

•!Never Gleason score below 5

•!Recognise Grade 4 fusion as clinically affects management

•!Spot extracapsular invasion on cores

•!Use 34BetaE12 with a low threshold

References •! Cytokeratin 34BetaE-12 immunoreactivity in benign prostatic acini. Goldstein et

al, Am J Clin Pathol 1999;112:69-74

•! Percent of cancer in the biopsy set predicts pathological findings after prostatectomy. Grossklaus et al, J Urol 2002;167:2032-2036

•! Gleason scores of prostate biopsy and radical prostatectomy specimens over

the past 10 years. Smith et al, Cancer 2002;94:2282-7

•! The pathological interpretation and significance prostate needle biopsy findings: implications and current controversies. Epstein & Potter, J Urol 2001;166:402-410

•! Problems in grading and staging prostatic carcinoma. McWilliam et al, Curr Diag Path 2002;8:65-75

•! The 2005 International Society of Urological disease (ISUP) Consensus

conference on Gleason grading of prostatic carcinoma. Epstein et al. Am J Surg Pathol 2005 29:1228-1242

•! What’s new in prostate cancer disease assessment in 2006? J Epstein Curr Opin

Urol 16:146-151

•! Andriole GL, Crawford ED, Grubb RL III, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-1319.

•! Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320-1328.

Slide seminar •!Study the pictures and complete the answer

sheet.

•!We will examine the interobserver variation when we review the answers – so please complete on your own.

•!Useful reference:

Problems in grading and staging prostatic carcinoma.

McWilliam et al, Curr Diag Path 2002;8:65-75

Case 1 Gleason grading

•!Gleason grade this area

PSA

Case 2 •!Gleason grade this area

Case 3 •!Gleason grade this area

Case 4 •!Gleason grade this area

Case 5 •!Gleason grade this area

Case 6 •!Gleason grade this area

Case 7 •!What feature should you comment on?

Case 8

•!Benign or malignant?

Case 8 contd.

Case 9 •!Estimate the volume (%core)

Case 9 – contd. •!Measure or field?

Case 10 •!Estimate the volume (% of core)

Case 11

•!What feature should you comment on?

Case 12

•!Gleason grade this area?

LP34

Case 13 •!Benign or malignant?

Case 14

•!Benign or malignant?

Note mitosis

Case 14 – 34beta immuno

Case 15

•!Benign or malignant?

Case 15 – 34beta immuno

Case 16 •!Benign or malignant?

Case 17 •!Benign or malignant?

Case 17 – 34beta immuno

Case 18 •!Benign or malignant?

Case 18 – 34beta immuno

Case 19

•!Benign or malignant?

Case 19 – 34beta immuno

Case 20 – Bonus case!! •!Large renal clear cell carcinoma Fuhrman

grade 4 with renal vein invasion.

•!Adrenal gland- ?diagnosis

Case 20 contd

Vimentin

Synaptophysin

Answer sheet

1 Gl. grade 5 11 Extracapsular

2 Gl. grade 3 12 Gl. grade 2

3 Cribriform

Gl.grade 3

13 Gl. grade 2

4 Gl. grade 2 or 3 14 Basal hyperplasia

5 Gl. grade 3 15 Suspicious/HG PIN

6 Gl. Grade 4 16 Malignant

7 Perineural 17 Gl. grade 2 or 3

8 HG PIN 18 Suspicious

9 33% 19 Basal hyperplasia

10 66% 20 Normal adrenal

The End

•!www.jonoxley.com

•!Email: jon.oxley@bristol.ac.uk