Pathology of Prostatic Enlargement. Introduction Anatomy – 5 lobes. Simplified: 3 lobes ; right,...

Pathology of Pathology of Prostatic EnlargementProstatic Enlargement

IntroductionIntroduction

Anatomy – 5 lobes. Simplified: 3 lobes ; right, left, middle 3 zones : base, middle, apex Median/Posterior – (BPH/Cancer) Function ? Hormone response – Estrogen like Enlargement – Inflammation / growth Neoplastic / Non neoplastic growth. BPH / Cancer.

Male Male Urogenital Urogenital SystemSystem

Enlargement of Prostate:Enlargement of Prostate:

BPH – Benign Prostatic HyperplasiaInflammations – infectionsNeoplasms – Carcinoma.

IntroductionIntroduction

Common non-neoplastic lesion.Involves peri urethral zone.BPH is common as men age.75% among men aged 70-80yearsOver 90% in people aged over 90yRare before the age of 40y.? Physiological …

BPH-Pathophysiology:BPH-Pathophysiology:

Excess hormones – estrogen like. Nodular hyperplasia of glands & stroma.From normal 20 to 30 50 to 100 gm.Press upon the prostatic urethra.Obstruction - difficulty on urination Dysuria, retention, dribbling, nocturiaInfections, hydronephrosis, renal failure. Not a premalignant condition*

BPH - MechanismBPH - Mechanism

Hormonal imbalance with ageing.Estrogen sensitive peri-urethral glands.Accumulation of dihydrotestosterone in

the prostate and its growth-promoting androgenic effect

Some Drugs (Finasteride) inhibit dihydrotestosterone and diminishes prostatic enlargement.

BPH-MorphologyBPH-Morphology

Microscopically, nodular prostatic hyperplasia consists of nodules of glands and intervening stroma. (Mostly glands)

The glands variably sized, with larger glands have more prominent papillary infoldings.

Nodular hyperplasia is NOT a precursor to carcinoma.

BPH-mechanism of obstruction:BPH-mechanism of obstruction:Median lobe (3rd lobe) Ball valve mechanism

BPH-Complications:BPH-Complications:

1. Urethral compression2. Ball valve mechanism3. Bladder hypertrophy4. Trabeculation5. Diverticula formation6. Hydroureter – bilateral7. Hydronephrosis

BPH-Bladder Gross – Identify Cues?BPH-Bladder Gross – Identify Cues?

Trabeculations Hypertrophy of wall Stone - urolithiasis Inflammation Median lobe- ball valve. Enlarged prostate.

BPH-Bladder morphology:BPH-Bladder morphology:

Hypertrophy Trabeculation Median lobe

protrusion.

Benign Prostatic Hyperplasia:Benign Prostatic Hyperplasia:

Normal Prostate:Normal Prostate:

Nodular BPH:Nodular BPH:

BPH - MorphologyBPH - Morphology

Adenocarcinoma Prostate:Adenocarcinoma Prostate:

Adenocarcinoma of the prostate is common in elderly men.

It is rare before the age of 50, but seen in over half of men 80 years old.

Many of these carcinomas are small and clinically insignificant.

Is second only to lung carcinoma as a cause for tumor-related deaths among males.

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Adenocarcinoma of ProstateAdenocarcinoma of Prostate The most common form of cancer in menThe most common form of cancer in men the 2nd leading cause of deaththe 2nd leading cause of death Incidence of clinical cancer in US:Incidence of clinical cancer in US:

50-70 / 100,00050-70 / 100,000– Less common in AsiansLess common in Asians– More common in blacks More common in blacks

Higher incidence of “latent” cancerHigher incidence of “latent” cancer– From 20% in fifties to 70% in seventiesFrom 20% in fifties to 70% in seventies

Etiologic factors:Etiologic factors:– Familial (genetic) predispositionFamilial (genetic) predisposition– Environmental factorsEnvironmental factors– Androgen receptor sensitivityAndrogen receptor sensitivity– etc.etc.

Cancer Statistics – 2002 USACancer Statistics – 2002 USA

Adeno-Ca ProstateAdeno-Ca Prostate?

?

?

Adeno-Carcinoma + BPHAdeno-Carcinoma + BPH

BPH with Adenocarcinoma:BPH with Adenocarcinoma:

Adenocarcinoma Prostate: (HP)Adenocarcinoma Prostate: (HP)

Diagnosis:Diagnosis:

Digital examination – hard, gritty, fixed.Ultrasonography (trans-rectal) Tumor Marker – PSA Biopsy - TURPNone of these methods can reliably detect

small cancers.Occult cancer is more common than

clinical ca.

Prognosis of Adenocarcinoma:Prognosis of Adenocarcinoma:

Grade & Stage Prognosis. Urinary obstruction, metastasize to

lymph nodes and bones.Bladder, kidney damage.Hematuria.Spread to Lungs or liver – rare.

TURP-Bits (Diagnosis + Treat )TURP-Bits (Diagnosis + Treat )

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Main Diagnostic ToolsMain Diagnostic Tools

Digital Rectal Examination (DRE)Digital Rectal Examination (DRE)

Serum PSASerum PSA

Trans-Rectal Ultra-sonography (TRUS)Trans-Rectal Ultra-sonography (TRUS)

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Serum PSA: Serum PSA: changing viewschanging views Former PSA Thresholds:Former PSA Thresholds:

0 – 3.99 0 – 3.99 ng/mLng/mL NormalNormal4 – 9.99 4 – 9.99 ng/mLng/mL SuspiciousSuspicious > 10 > 10 ng/mLng/mL Probable tumor >>> BiopsyProbable tumor >>> Biopsy

PSA Cut-off point for Biopsy:PSA Cut-off point for Biopsy:– From 4 to 2.5From 4 to 2.5 ng/mLng/mL Gilbert SM, Cavallo CB, Kahane H, Lowe FC. Gilbert SM, Cavallo CB, Kahane H, Lowe FC.

Evidence for prompting prostate biopsy: review of Evidence for prompting prostate biopsy: review of 36,316 biopsies36,316 biopsies. . UrologyUrology, 2005; , 2005; 65:549-55365:549-553

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Modifications in PSAModifications in PSA

Suspicious cases:Suspicious cases:– PSA Density: PSA Density: > 0.15 > 0.15

– PSA Velocity: PSA Velocity: Annual rate of PSA rise >0.75Annual rate of PSA rise >0.75 ng/ml/year is Highly suggestive of Cancerng/ml/year is Highly suggestive of Cancer

– Percent Free PSAPercent Free PSA::• Calculated as %fPSACalculated as %fPSA (fPSA X 100 / PSA) (fPSA X 100 / PSA)

• LOWLOW %fPSA (<6-10%) %fPSA (<6-10%) favors cancerfavors cancer

• HIGH HIGH %fPSA (>23%) %fPSA (>23%) favors BPHfavors BPH

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Prostate Biopsy EvolutionProstate Biopsy Evolution

11 - - 22 cores (Finger-guided)cores (Finger-guided)

Sextant biopsy (TRUS-guided)Sextant biopsy (TRUS-guided)

Extended 5-region biopsy Extended 5-region biopsy (10-18 cores)(10-18 cores)

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TRUS guided BiopsyTRUS guided Biopsy

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Sextant BiopsySextant Biopsy

BASE

MIDDLE

APEX

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Extended 5-Extended 5-Region BiopsyRegion Biopsy

(> 10 cores)(> 10 cores)

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Agenda:Agenda:

Overview of prostatic adenocarcinomaOverview of prostatic adenocarcinoma Diagnostic tools: changing attitudesDiagnostic tools: changing attitudes Cancer diagnosis: Cancer diagnosis: minimal pathologic criteriaminimal pathologic criteria Difficult diagnoses: IHC and other solutionsDifficult diagnoses: IHC and other solutions Gleason grading: 2005 ISUP consensusGleason grading: 2005 ISUP consensus Staging: AJCC/UICC TNMStaging: AJCC/UICC TNM Cancer Reporting checklist (CAP approved)Cancer Reporting checklist (CAP approved) Future outlookFuture outlook

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Minimal Pathologic Criteria for Ca.Minimal Pathologic Criteria for Ca.

1-1- Infiltrating aciniInfiltrating acini

2- Enlarged hyperchromatic nuclei 2- Enlarged hyperchromatic nuclei

3- Prominent ( > 2-3 3- Prominent ( > 2-3 m) nucleolim) nucleoli

4- CLOSE BACK TO BACK ACINI4- CLOSE BACK TO BACK ACINI

5- LOSS OF BASAL LAYER5- LOSS OF BASAL LAYER

6- MONOLAYERING6- MONOLAYERING

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Cancer CytologyCancer Cytology

Normal

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Agenda:Agenda:

Overview of prostatic adenocarcinomaOverview of prostatic adenocarcinoma Diagnostic tools: changing attitudesDiagnostic tools: changing attitudes Cancer diagnosis: minimal pathologic criteriaCancer diagnosis: minimal pathologic criteria Difficult diagnoses: Difficult diagnoses: IHC and other solutionsIHC and other solutions Gleason grading: 2005 ISUP consensusGleason grading: 2005 ISUP consensus Staging: AJCC/UICC TNMStaging: AJCC/UICC TNM Cancer Reporting checklist (CAP approved)Cancer Reporting checklist (CAP approved) Future outlookFuture outlook

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Difficult DiagnosesDifficult Diagnoses

Adenocarcinoma (Gleason pattern 1-2)

Adenosis (benign)

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Main Differential DiagnosesMain Differential Diagnoses

1-1- Structural mimic of cancer:Structural mimic of cancer: Atypical Small Acinar Proliferation Atypical Small Acinar Proliferation

(ASAP)(ASAP)

2- Cytologic mimic of cancer:2- Cytologic mimic of cancer: High-Grade Intraepithelial Neoplasm High-Grade Intraepithelial Neoplasm

(HGPIN)(HGPIN)

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1- ASAP1- ASAP

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ASAPASAP

Qualitative limitation

Quantitative limitation

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Atypical Small Acinar Proliferation (ASAP)Atypical Small Acinar Proliferation (ASAP)

NOT a distinct entityNOT a distinct entity

Indicates suspicion BUT NOT PROOF of Ca.Indicates suspicion BUT NOT PROOF of Ca.

Next step:Next step:– Aditional sections (resolving 10%)Aditional sections (resolving 10%)– IHC staining (34IHC staining (34E12)E12)– Rebiopsy 3-9 months later Rebiopsy 3-9 months later (from the entire gland)(from the entire gland)

• PPV: 37% PPV: 37%

1977

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2- HGPIN2- HGPIN

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High Grade Prostatic Intraepithelial High Grade Prostatic Intraepithelial Neoplasm (HGPIN)Neoplasm (HGPIN)

A medium-sized acinus with stratified (flat, A medium-sized acinus with stratified (flat, tufting, micropapillary or cribriform) atypical tufting, micropapillary or cribriform) atypical nuclei & prominent nucleoli nuclei & prominent nucleoli

Patchy basal cell immunostainingPatchy basal cell immunostaining Rebiopsy (3-6 months interval for 2 years):Rebiopsy (3-6 months interval for 2 years):

– PPV 23%PPV 23% May be isolated May be isolated (Not accompanied by cancer):(Not accompanied by cancer):

– No rise of PSANo rise of PSA Combined HGPIN / ASAP: Combined HGPIN / ASAP:

– PPV 44%PPV 44%

1986

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IHC in prostate CancerIHC in prostate Cancer

Indications:Indications:1- Distinction of Benign from Malignant1- Distinction of Benign from Malignant

• High molecular weight cytokeratin (34High molecular weight cytokeratin (34E12, CK5/6)E12, CK5/6)

– Negative cytoplasmic marker (in basal cells)Negative cytoplasmic marker (in basal cells)• P63P63

– Negative nuclear stain (in basal cells)Negative nuclear stain (in basal cells)• AMACR (P504S)AMACR (P504S)

– Positive cytoplasmic marker (in tumor cells)Positive cytoplasmic marker (in tumor cells)– Also positive in HGPIN, 31% of Bladder Ca. & Also positive in HGPIN, 31% of Bladder Ca. &

70% of Colorectal Ca.70% of Colorectal Ca.

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HMW-CK (34HMW-CK (34E12)E12)

Normal Glands

Negative in Carcinoma

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AMACR AMACR (P504S) stain (P504S) stain in Carcinomain Carcinoma

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P63P63 / / AMACR AMACR

cocktailcocktail

Incresing IHC resolution:

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3434E12 / P63 / AMACR E12 / P63 / AMACR 2-chromogen cocktail2-chromogen cocktail

Incresing IHC resolution:

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IHC in prostate Cancer IHC in prostate Cancer (Cont.)(Cont.)

Indications:Indications:2- Differential Dx from urothelial carcinoma:2- Differential Dx from urothelial carcinoma:

PSA PSAP 34PSA PSAP 34E12 Leu7E12 Leu7

Prostate Ca + + – + Prostate Ca + + – +

Urothelial CaUrothelial Ca – – –– + + – –

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IHC in prostate Cancer IHC in prostate Cancer (Cont.)(Cont.)

Indications:Indications:3- Differential Dx in metastatic carcinoma:3- Differential Dx in metastatic carcinoma:

Bone Tumor:

PSA stain

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Agenda:Agenda:

Overview of prostatic adenocarcinomaOverview of prostatic adenocarcinoma Diagnostic tools: changing attitudesDiagnostic tools: changing attitudes Cancer diagnosis: minimal pathologic criteriaCancer diagnosis: minimal pathologic criteria Difficult diagnoses: IHC and other solutionsDifficult diagnoses: IHC and other solutions Gleason grading: Gleason grading: 2005 ISUP consensus2005 ISUP consensus Staging: AJCC/UICC TNMStaging: AJCC/UICC TNM Cancer Reporting checklist (CAP approved)Cancer Reporting checklist (CAP approved) Future outlookFuture outlook

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Gleason Grading Gleason Grading (Donald F Gleason (Donald F Gleason 1966)1966)

– Glandular architecture (NOT Glandular architecture (NOT cytology)cytology)

– Low magnification(Low magnification(40 ;40 ;100)100)– Five grades (1-5)Five grades (1-5)– Combined Score:Combined Score:

11grade (pattern) + 2grade (pattern) + 2 grade (pattern) grade (pattern)

Scores 2-4: Scores 2-4: Low grade (Well-diff,)Low grade (Well-diff,)Scores 5-7: Scores 5-7: Intermed grade (Mod.-diff.)Intermed grade (Mod.-diff.)Scores >7: Scores >7: High grade (Poorly-diff.)High grade (Poorly-diff.)

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20052005 ISUP ISUP Consensus Consensus

GradingGrading

50 uropathologists50 uropathologistsAgreement > 2/3Agreement > 2/3

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CONSENSUS:CONSENSUS: In needle Biopsy:In needle Biopsy:

– Combined score 2+1 or 2+2 are exceptionalCombined score 2+1 or 2+2 are exceptional

– Add the most common grade + the highest Add the most common grade + the highest grade (even if limited)grade (even if limited)• e.g., report e.g., report 33 + + 44 + small focus of + small focus of 55 as: as: 3 + 53 + 5

– Disregard grade 2 if two higher grades are presentDisregard grade 2 if two higher grades are present

– Assign individual scores to separate cores Assign individual scores to separate cores only ifonly if submitted separately submitted separately

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CONSENSUS:CONSENSUS: In radical prostatectomy:In radical prostatectomy:

– Report limited higher grade as tertiary Report limited higher grade as tertiary patternpattern• e.g., score: e.g., score: 4 + 34 + 3 and tertiary pattern: and tertiary pattern: 55

– Assign separate scores to discrete nodulesAssign separate scores to discrete nodules• e.g., a peripheral e.g., a peripheral 4 + 44 + 4 nodule and a central nodule and a central

2 + 22 + 2 nodule nodule

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Cribriform Pattern: grade 3Cribriform Pattern: grade 3

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Ductal Adenocarcinoma: 4+4Ductal Adenocarcinoma: 4+4

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Colloid (Mucinous) Ca: 4+4Colloid (Mucinous) Ca: 4+4

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Small Cell Ca. (No grading)Small Cell Ca. (No grading)

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Pseudohyperplastic Ca. : 3+3Pseudohyperplastic Ca. : 3+3

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Glomeruloid Pattern: 3 or 4Glomeruloid Pattern: 3 or 4

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Agenda:Agenda:

Overview of prostatic adenocarcinomaOverview of prostatic adenocarcinoma Diagnostic tools: changing attitudesDiagnostic tools: changing attitudes Cancer diagnosis: minimal pathologic criteriaCancer diagnosis: minimal pathologic criteria Difficult diagnoses: IHC and other solutionsDifficult diagnoses: IHC and other solutions Gleason grading: 2005 ISUP consensusGleason grading: 2005 ISUP consensus Staging: Staging: AJCC/UICC TNMAJCC/UICC TNM Cancer Reporting checklist (CAP approved)Cancer Reporting checklist (CAP approved) Future outlookFuture outlook

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Old Staging System (A-D)Old Staging System (A-D)

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Current Staging of Prostatic CaCurrent Staging of Prostatic Ca

TNM classification (AJCC / UICC):TNM classification (AJCC / UICC):

– Clinical TNM (cTNM)Clinical TNM (cTNM)

– Pathological TNM (pTNM)Pathological TNM (pTNM)

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Primary Tumor (T) - ClinicalPrimary Tumor (T) - Clinical

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Primary Tumor (pT) - PathologicalPrimary Tumor (pT) - Pathological

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Agenda:Agenda:

Overview of prostatic adenocarcinomaOverview of prostatic adenocarcinoma Diagnostic tools: changing attitudesDiagnostic tools: changing attitudes Cancer diagnosis: minimal pathologic criteriaCancer diagnosis: minimal pathologic criteria Difficult diagnoses: IHC and other solutionsDifficult diagnoses: IHC and other solutions Gleason grading: 2005 ISUP consensusGleason grading: 2005 ISUP consensus Staging: AJCC/UICC TNMStaging: AJCC/UICC TNM Cancer Reporting checklist (CAP approved)Cancer Reporting checklist (CAP approved) Future outlookFuture outlook

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Reporting checklist for prostatic Ca. Reporting checklist for prostatic Ca. (based on AJCC/UICC TNM, 6th (based on AJCC/UICC TNM, 6th edition 2005 - CAP approved)edition 2005 - CAP approved)

Specimen type & Specimen type & macromacro description: description:1- Needle biopsy1- Needle biopsy

– Size & No. of coresSize & No. of cores– Notify if < 5mm in aggregateNotify if < 5mm in aggregate

2- TUR2- TUR– size & weight of specimensize & weight of specimen– Describe suspicious areasDescribe suspicious areas

3- Enucleation3- Enucleation– As aboveAs above

4- Radical prostatectomy4- Radical prostatectomy– Structures included (seminal vesicles LN etc.)Structures included (seminal vesicles LN etc.)– As aboveAs above

Optional

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Histologic type of tumorHistologic type of tumor Histologic Grade (Gleason score)Histologic Grade (Gleason score)

– Primary & secondary patternsPrimary & secondary patterns– Tertiary pattern only for radical prostatectomyTertiary pattern only for radical prostatectomy– Isolated scoring for isolated tumor nodulesIsolated scoring for isolated tumor nodules

Tumor quantitationTumor quantitation– Needle biopsy:Needle biopsy:

• % of tissue involved by tumor% of tissue involved by tumor• Total linear mm. Of Ca. / Total length of coresTotal linear mm. Of Ca. / Total length of cores• No. of positive cores / total No. of coresNo. of positive cores / total No. of cores

– TUR:TUR:• % of tissue involved by tumor% of tissue involved by tumor• No. of positive chips / total No. of chipsNo. of positive chips / total No. of chips

Reporting checklist for prostatic Ca. Reporting checklist for prostatic Ca. (based on AJCC/UICC TNM, (based on AJCC/UICC TNM, 6th edition 2005 - CAP approved)6th edition 2005 - CAP approved)

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Tumor quantitationTumor quantitation (Cont.)(Cont.)– Enucleation & Radical prostatectomyEnucleation & Radical prostatectomy

• % of tissue involved by tumor% of tissue involved by tumor• Tumor size (dominant nodule / nodules)Tumor size (dominant nodule / nodules)

Pathologic staging (pTNM) only for radicalPathologic staging (pTNM) only for radical Surgical margins only for radicalSurgical margins only for radical Perineural invasionPerineural invasion Periprostatic fat & seminal vesicle invasionPeriprostatic fat & seminal vesicle invasion Lymphatic (small vessel) invasionLymphatic (small vessel) invasion Venous (large vessel) invasionVenous (large vessel) invasion Additional pathologic findings Additional pathologic findings (e.g., HGPIN - (e.g., HGPIN -

BPH - therapy related changes)BPH - therapy related changes)

Reporting checklist for prostatic Ca. Reporting checklist for prostatic Ca. (based on AJCC/UICC TNM, 6th (based on AJCC/UICC TNM, 6th edition 2005 - CAP approved)edition 2005 - CAP approved)

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Agenda:Agenda:

Overview of prostatic adenocarcinomaOverview of prostatic adenocarcinoma Diagnostic tools: changing attitudesDiagnostic tools: changing attitudes Cancer diagnosis: minimal pathologic criteriaCancer diagnosis: minimal pathologic criteria Difficult diagnoses: IHC and other solutionsDifficult diagnoses: IHC and other solutions Gleason grading: 2005 ISUP consensusGleason grading: 2005 ISUP consensus Staging: AJCC/UICC TNMStaging: AJCC/UICC TNM Cancer Reporting checklist (CAP approved)Cancer Reporting checklist (CAP approved) Future outlookFuture outlook

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Future Outlook: Future Outlook: Molecular pathologyMolecular pathology

1- Carcinogenesis:1- Carcinogenesis:– Overexpression of some genes Overexpression of some genes (DNA microarray)(DNA microarray)

• Hepsin: a trans-membrane serine protease Hepsin: a trans-membrane serine protease -Methyl Acyl coA racemase (AMACR-p504s)-Methyl Acyl coA racemase (AMACR-p504s)

– Underexpression (turn-off) of some genesUnderexpression (turn-off) of some genes• Cancer suppressor genes (e.g., PTEN, KAI-1)Cancer suppressor genes (e.g., PTEN, KAI-1)• Glutathione S-transferase gene promoter (GSTP1)Glutathione S-transferase gene promoter (GSTP1)

2- Early tumor detection and Prognosis:2- Early tumor detection and Prognosis:– P53 mutation in more advanced casesP53 mutation in more advanced cases– DNA ploidy correlating tumor grade & stageDNA ploidy correlating tumor grade & stage– smad-4 protein (TGF-smad-4 protein (TGF- related) overexpression related) overexpression

in advanced Cancerin advanced Cancer– EZH2: transcription factor overexpressed in EZH2: transcription factor overexpressed in

aggressive & metastatic diseaseaggressive & metastatic disease

Presenting sympton

A 74 year old man presented with a three month history of weakness and tiredness

For the past month he was also seen to have haematuria.

He was admitted to a district hospital and after two weeks was found to be in urinary retention

He was treated with a catheter, but transferred when his urinary output fell and he became increasingly breathless.

Past history.

2 prostate operations in the past ? For what reason

On examination

Blocked catheter noted – irrigated and developed haematuria.

Patient unable to move legs (on further questioning he has been paraplegic for 1 month)

Pallor noted

Rectal exam – hard lumpy prostate.

Clinical diagnosis

1. Prostate Ca.

2. Spinal cord compression secondary to bony metastases

3. Anemia secondary to ? Renal failure and haematuria

4. CCF secondary to fluid overload and anemia.

Investigations

Creatiine 4.7

Hb 5.7

X-rays to follow

X-rays of pelvis and spine

Multiple lytic lesions

Destruction of disc and ? vertebral collapse

Treatment

He was booked for trans-urethral resection of the prostate and bilateral orchidectomy.

Samples of prostatic tissue and testicular tissue were sent for pathology

TURP-Prostate Biopsy

Tumor tissue

Normal Prostatic glands

Stroma

TURP-Prostatic Carcinoma

High power view showing

Tumor tissue

Forming glands

TURP-Prostatic Carcinoma

Tumor embolism in a dilated lymphatic vessel.

Orchidectomy - Testes biopsy

Inflammatory tissue

Atrophic semineferous tubules

Pathology of Prostatic Enlargement. Introduction Anatomy – 5 lobes. Simplified: 3 lobes ; right,...

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