PROSTATE PATHOLOGY

NORMAL

Anatomy

Weight: 30-40g

Basal portion located beneath bladder neck

Apex above urogenital diaphragm

Skeletal muscle at apex extends into prostateà glands admixed with skeletal muscles does not mean neoplastic or extraprostatic extension

Rectum and prostate separated by thin fascia

3 cell types

Secretory: PSA, PAP

Basal: HMK (cytoplasmic), p16 (nuclear)

NE:

IHC markers:

HMK (34βe12): basal cells

P63: basal cells

PSA: prostatic specific Ag

PAP: prostatic acid phosphatase

AMA CoA racemase (alpha methyl acyl)

AMACR+ conditions

Cancer

HGPIN

Foci of adenosis

Whats are zones?

Transition zone: central periurethral, containing proximal urethra

Central zone: back of transition zone, toward back of prostate, contains ejaculatory ducts

Peripheral zone: cup-shaped, supports TZ and CZ

 

 

PROSTATITIS

Name types*

Acute bacterial

Chronic bacterial

Chronic abacterial

Granulomatous

Compare acute and chronic bacterial prostatitis

Acute bact	Chronic bact	Chronic abact (no1)
Fever, dysuria, tender prostate	Asymptomatic or vague discomfort with dysuria	Same as chronic bacterial
KEEPS  Retrograde, lymphatics, BV, catheterization, surgeries	KEEPS  Recurrent UTI (cystitis, urethritis)* by same bug	No history of recurrent UTI*
Clinical features and urine culture	Leucocytes and positive cultures in expressed prostatic secretions	>10 leukocytes/HPF in expressed prostatic secretions but negative culture
Edema  Sheets of PMN in parenchyma and lumens Abscess Necrosis	Must have lymphoid aggregates, numerous plasma cells, macrophages and PMN*  Also requires clinical symptoms of chronic prostatitis*[1]

Don’t sign out acute or chronic prostatitis; just call acute or chronic inflammation

 

GRANULOMATOUS INFLAMMATION

Ddx of granulomatous inflammation

Nonspecific granulomatous prostatitis

Post-biopsy granuloma

Post-BCG therapy (no1): can be necrotizing, bug morphology indistinguishable as TB. Rare cases of dissemination reported

TB

Allergic granulomatous prostatitis

6. Mycotic prostatitis: nearly all in immunocompromised. Blastomycosis, coccidiomycosis, Cryptococcus,…

7. Sarcoidosis

NONSPECIFIC GRANULOMATOUS PROSTATITIS

Etio? Infectious?

Ruptured acinus results in FB reaction to prostatic secretions and contents

Not infectious

Micro

Lobular infiltrate of foamy macrophages, lymphocytes, plasma cells, granulomas with giants (next to ruptured acini)

Differentiate epithelioid histiocytes from cancer

Prostatitis	Adenocarcinoma
Plasma cells, eosinophils, PMN	No
CD68	CK+

 

POST-BIOPSY GRANULOMA

Micro

Large central fibrinoid necrosis surrounded by palisading epithelioid histiocytes

ALLERGIC GRANULOMATOUS PROSTATITIS

Micro

Necrobiotic granulomas surrounded by many eosinophils

 

OTHER THINGS TO WATCH OUT FOR

Malakoplakia

Amyloidosis: corpora amylacea also stains for Congo Red?

Calculi: from calcification of corpora amylacea

Cysts

Melanocytic lesions such as melanosis and blue nevi

Mucous gland metaplasia: goblet cells with tiny basal nuclei, in small nests up to 10 cells

BPH

Reliable

Poor clinicopathologic correlation. Only 50% of histology have large prostate. Only 50% of large prostate have ssx.

Mechanism

5a-reductase type 2à DHT (dihydrotestosterone)à prostate growthà obstruction

Alpha1-adrenoreceptor in prostatic stromaà SM contractionà obstruction

 

Locations of BPH nodules

Periurethral (transitional zone)

Slit-like urethral orifice

What’s earliest change?

Early: stromal hyperplasia (SM with fibrous tissue)

Mixture of glands and fibromuscular stromal components

Cystic dilation, papillary infolding

2 layers: columnar secretory + cuboidal basal

Infarcts, squamous metaplasiaà reactive change in proximity can mimic cancer

How to diagnose on needle biopsy?

You should not diagnose BPH but rather benign prostatic tissue because limited sampling and needle does not reach transition zone.

Differentiate reactive changes secondary to infarction from cancer

Reactive: localized, next to infarct

 

PIN

Define***

Benign architecture but malignant cytology

LGPIN vs HGPIN

LGPIN	HGPIN
Normal architecture  Papillae Undulating luminal surfaces
No	Nucleoli visible at 20x (not required if significant pleomorphism)
Micro  Slightly enlarged nuclei Stratification	Micro  Large nuclei Dark (sometimes vesicular) Overlapping nuclei Amphophilic cytoplasm Epithelial HP High N/C Lower nuclear grade as getting toward center (grading based on cells immediately against BM) Stratification
	Basal layer fragmented but present
	Variants  Tufting (no1) Micropapillary Cribriform

Incidence of HGPIN in needle?

5% (same as ASAP)

Clinical significance of HGPIN on needle biopsy?

Cancer found in 1/3 of subsequent biopsy)à must have repeat biopsy of entire prostate (not directed biopsy as in ASAP) in 12-24 months

What if you find HGPIN on TURP?

Must submit rest of prostatic chips!

Clinical significance unclear. Often no further workup in elderly but not true in younger men

% of HGPIN evolving toward cancer?

Unknown (unlike in cervix). Therefore, HGPIN can’t not be called premalignant until we know its natural history

HGPIN vs cancer

HGPIN	Cancer
No	True papillae (FV core)
Normal architecture	Too small or too crowded glands to be benign
Cribriforming without back-to-back glands	Cribriforming with back-to-back glands
	Extensive comedonecrosis
	No basal layer
HGPIN	CCCH
	-Cribriform  -Clear cytoplasm -Nodular or infiltrative patterns
-Atypical nuclei	-Benign nuclei (key)  -Small nucleoli -Very prominent basal layer at periphery
HGPIN	Basal cell HP
Benign architecture (large glands, no crowding)	Small glands
Very rare	Solid nests sometimes
One	Distinct two population (blue and pink)
Perpendicular to BM	Nuclei parallel to BM
HMK-	HMK+

 

TUMORS

PROSTATIC ADENOCARCINOMA

Demo

>50, black>white>Asian

Etiology

Unknown, maybe age, genetic and environmental (diet: fat, lycopenes, vitamins, selenium, soy products)

Familial in 10%à 1q abnormality

Name 5 variants of acinar carcinoma

Atrophic adenocarcinoma

Foamy gland carcinoma

Pseudohyperplastic adenocarcinoma (ddx PIN)

Clear cell adenocarcinoma

Adenocarcinoma with neuroendocrine differentiationà small cell NE carcinoma: typicall PSA-/PAP-, can secrete ACTH or ADH, often mixed with conventional adenocarcinoma

Tumors with squamous differentiation: rare

Signet ring adenocarcinomaà Gleason 5

Cribriform adenocarcinomaà Gleason 4

Sarcomatoid carcinomaà Gleason 5

Other variants

SCC

Mixed

Small cell carcinoma

Mucinous adenocarcinoma*: ³25% extracellular mucin, aggressiveà Gleason 4

Prostatic duct adenocarcinoma: originates from prostatic ducts (vs acini), resembles endometrioid carcinoma, PSA+/PAP+ (what about racemase?)à do not score because considered high-grade already

5 features favoring adenocarcinoma

↑N/C ratio

Large nucleoli

Mitoses

Cytoplasm

No lipofuscin pigment

Flat luminal border

Blue-tinged mucous

Crystalloids

Architecture

Mucinous fibroplasia (collagenous micronodules)

Glomerulations

Perineural invasion (must be circumferential)

Small glands, densely packed, single layer

Gross

Loss of spongy look of normal prostate

Firm and gritty grossly but difficult to discern on microscopy*

Criteria for minimal carcinoma

5% or 1mm

Rules

5% ruleà on the biopsy, drop lower grade if<5%, but keep if it is a higher grade

eg. 1) 98% 4+4, 2% 3

then = 4+4

eg. 2) 98% 4+4, 2% 5

then = 4+5

Assign a separate Gleason score to each dominant tumour nodule

Treatment decisions

Watchful waiting vs surgery vs radiation

Brachytherapy vs external beam therapy

Nerve-sparing, lymphadenectomy

When surgery is not feasible?

T3 or above but still can use radiation

When nerve-sparing surgery not feasible?

Ipsilateral nerve invasion???

Spread for prostatic cancer

Lymphatic: obsturatorà perivesical, hypogastric, iliac, presacral, para-aorticà cervical LN!

Hematogenous: bone (osteoblastic) (often after LN mets)

Any bony metastatic adenocarcinoma in men should be stained for PSA and PAP

4 pathways of spread to seminal vesicles?

Via periseminal vesicle soft tissue (no1)

Through ejaculatory ducts

Direct extension into seminal vesicle

Lymphovascular metastasis

Define seminal vesicle invasion

Through muscular coat of seminal vesicle

Curative for what stages?

T1-2, equivalent results for surgery and radiation

Radiation also useful for locally advanced tumor (>T2); hormonal therapy also added

Prognostic factors

Gleason*

Staging*

Extraprostatic extension

Margins of resection

4 tissues with cross-reactivity with PSA/PAP

Periurethral glands

Cystitis cystica, cystitis glandularis

Anal glands in men

Urachal remnants (PSA only)

What’s PSA? False elevation in what?

Product of prostatic epithelium, normally found in semen

4ng/mL cutoff between normal and abnormal unreliable

BPH, prostatitis, infarct, instrumentationà organ specific but not cancer specific*

20-40% of T1-2 prostatic cancer have PSA<4

Other modalities?*

PSA density: divided by volume

Age-dependent upper normal limit

PSA velocity

% of free PSA: free PSA/total PSAà lower value in cancer

Value of PSA and other related modalities?*

None can detect early cancer

But great for follow-up

Is prostatic capsule well-defined structure? Where normal glands can extend outside capsule?

No

Base of prostate

Extraprostatic extension. Are perineural invasion outside of prostate considered extraprostatic extension? Where does it occur most commonly?

Fat invasion (nearly 100% accurate)

Ganglionic invasion (about 90% as some ganglions can occur within prostate)

Protruding without capsular breaching (remember it’s a pseudocapsule)

Seminal vesicle invasion

Bladder invasion

No, extraprostatic perineural invasion is not extraprostatic extension (unless it’s large bundle of nerve)

Posterior and posterolateral aspects

Is tumors within “capsule” extraprostatic?

No

Why is it valuable to scan capsule smoothness at low power?

Extraprostatic extension often causes extensive desmoplasiaà irregular surface (good hint)

Is there any distance for calling positive margin?

No, even <1mm benign tissue separating inked margin is still negative margin (unless in colectomy)

When a needle biopsy should be considered unsatisfactory?

Minimal or no prostatic glandular or stromal tissue

Core containing only stroma is still satisfactory

Types of biopsy and risk?

Transrectal needle coreà no tumor seeding reported

Transperineal biopsyà tumor seeding reported

How to process needle cores? Why section thickness important? Why fixative important?

Intervening unstained slides important

Too thick sections result in artificial hyperchromasia and invisible nucleoli

Bouin’s may affect nucleolar prominence?

How to preserve potency? Where does bundle run?

Unilateral neurovascular bundle sparing enough

Posterolateral (surgeon will take as less tissue as possible from this area to spare nerve)

Which margin most commonly positive?

Apex

Any value in doing FS for margins?

Distal margin (apex) is questionable because surgeons often do their possible to take as much as possible

Proximal margin (bladder neck) has value being assessed in FS

To know whether there is any prostatic tissue leftà they scoop out gradually

LN to determine wether radical prostatectomy

Significance of intraductal TCC spread into prostate?

Usually found in TURP

Pagetoid or filling up ducts with central comedonecrosis

Requires radical prostatectomy (cystoprostatectomy) because not reachable by BCG

 

Favoring cancer	Against cancer
Prominent nucleoli  Enlarged nuclei Dark Mitoses	Atrophy (scanty cytoplasm)
Amphophilia (vs pale clear in normal)  Sharp luminal border Lack of lipofuscin	R/O HGPIN  R/O PINATYP R/O adenosis
Blue-tinged mucin  Pink amorphous secretions Crystalloids (pink, geometric)	Inflammation
Mucinous fibroplasia (collagenous micronodule)  Perineural invasion Glomerulations	Corpora amylacea
Crowded small glands (too small or too crowded to be benign) between normal large glandsà important hint but must R/O adenosis  -No basal layer -Haphazard growthà especially useful for very LG tumor

Cut levels

Compare with adjacent normal glands

Do IHC

Second opinion

Minimal carcinoma (<5%) always requires second opinion before signing out

ASAP: How to diagnose? How many glands required? What’s accepted incidence? What to report? What would clinician do? What does a second negative biopsy mean? What to do on resection specimen?

Ask for second opinion or send out for consultation and do IHC (negative basal cell staining in small acini does not confirm malignancy as benign glands can show some heterogeneity in staining) (but presence of basal cell staining probably indicate benign condition)

How many glands??? 3 glands???

Incidence: 5% in needle biopsy

Directed re-biopsy: 3 from ASAP site, 2 from adjacent sites, 1 elsewhere

Negative repeat biopsy does not R/O cancer because false negative rate as high as 25%

Racemase staining pattern???à still can be positive without being cancer because it can be HGPIN

Must sample thoroughly to find tumor

 

 

 

Atrophy	Atrophic cancer
Open lumen  Crowded nuclei High N/C because of scanty cytoplasmà very basophilic at low power Call postatrophic hyperplasia when increased number of crowded atrophic glands (proliferating) Infiltrative
	Macronucleoli
	Presence of adjacent nonatrophic cancer
	Use IHC
Benign	Foamy gland cancer
	Small bland nuclei
	Abundant foamy cyto
	Intraluminal pink secretions
	Use IHC
Benign	Pseudohyperplastic
	Larger glands
	Branching and papillae
	Too closely packed glands for HGPIN
	Nuclear atypia
	Use IHC
SV/ED	Prostatic cancer
Lipofuscine pigments
Degenerating atypia resembling radiation effect	Not as ugly looking
No mitoses	Mitoses
Well-formed glands	Rare to see cytoarchitectural paradox in cancer (truly ugly nuclei in well-formed glands)
Basal cells+	No
PAP- (but PSA unreliable!)	PAP+
TCC	Prostatic cancer
More pleomorphic	-Less pleomorphic even in PD tumors
Glassy cytoplasm	“Softer” foamy clear cytoplasm
Nests	Cords, cribriform glands
More prominent squamous differentiation	Rare
Necrosis	Unusual
Precursors	PIN
Inflamed	Lacks inflammation
PSA-/PAP-	PSA+/PAP+ (careful that PD prostate cancer can lose it)
CK7+/CK20+	Neg
34Be12+  Thrombomodulin+ Uroplakin+	Neg

Adenosis vs prostatic cancer

Adenosis	LG cancer
-Branching, irregular contour, papillae  -Back-to-back -Intraluminal crystalloids -Medium-sized nucleoli -Scattered single cells
Lobular configuration	Haphazard, infiltration at right angle to each other
Graduation transition from small pale glands to larger glands	May be purely small glands
Same appearance as adjacent normal glands	Different
Pale-clear cytoplasm	May be amphophilic
Blue mucin rare	Common
Corpora common	Rare
IHC (patchy basal cells)	Absent
Transition zone	Peripheral zone
Basal cell HP	Cancer
-Possible prominent nucleoli  -Rare mitoses possible -Large nuclei -Individual cell necrosis -Blue mucin
TZ	PZ
Nests or lumens
Peripheral palisading
Well-formed lamellar calcifications	Rare
Intracytoplasmic eosinophilis globules (unique)	No
Prominent stratification	No
HMK+	No

Name benign mimickers of cancer and location

Clear cell cribriform hyperplasia	TURP>needle
Adenosis	TURP>needle
Seminal vesicles and ejaculatory ducts	Needle>TURP
Atrophy	Same
Cowper’s glands	Same
Granulomatous prostatitis	Same
Paraganglia	TURP>needle
Sclerosing adenosis	TURP>needle
Xanthoma	Needle>TURP
Signet ring cell lymphocytes	TURP only
Radiation atypia	Same
Basal cell HP	TURP>needle
Nephrogenic adenoma	TURP>needle
Verumontanum HP	Needle>TURP
Mesonephric HP	TURP only
Colonic mucosa	Needle only

 

PROSTATE STAGING

T1 Clinically inapparent

T1a <5% (TURP)

T1b >5% (TURP)

T1c (Needle biopsy for high PSA)

T2 Confined to prostate

T2a <1/2 of lobe

T2b >1/2 of lobe

T2c Both lobes

T3a Capsule

T3b Seminal vesicle

T4 Bladder/rectum

N0

N1 regional nodes

M0

M1 distant mets

When to upstage?

TURP, needle coreà T1a-c

Clinically apparent and confined to prostateà T2

Sideà T2a-b vs T2c

Capsule invasion (not yet extraprostatic), seminal vesicle invasionà T3a-b

Organsà T4

When is pelvic lymphadenectomy necessary for staging?

Seems that most centers do this… Not sure

Some surgeons do not remove in low-risk patients

In what context do you see pelvic LN? How to process?

FS! If positive, surgery is aborted because non-curative if preoperative Gleason is 8-9. If lower Gleason, surgeons will still resect prostate because metastatic recurrence is quite late.

Submit in toto for FS!

How to stage a large central nodule involving both lobes?

T2c despite solitary nodule

What would surgeon do in cancer diagnosed on TURP (T1a-b)?

Needle biopsy to assess cancer in peripheral zone

Check PSA

Radical prostatectomy if young or positive findings in above

GLEASON GRADING

Pattern 1: WC nodule of uniform, single, separate, closely packed glands

Pattern 2: WC nodule of single, seprate but more loosely arranged and less uniform glandsà still can mentally draw circle around contour of each gland

Pattern 3à most common pattern

-Infiltrating between normal glands, marked variation in size and shape, smaller glands than patterns 1 and 2

-Smoothly circumscribed cribriform nodulesà USCAP 2009 says better upgrade to 4

 

Pattern 4à most important because quite different prognosis from 3

Glands no longer single or separate but form chains, fused acini

Cribriform glands with irregular contours or large cribriform glands

Hyper-nephromatoid pattern

Pattern 5:

No glands at allà single cells, signet rings, cords, sheets, comedonecrosis

What is score associated with WD, MD and PD?

WD: 2-4à never diagnosed on biopsy but ok on TURP

MD: 5-6[2]

PD: 7-10à difference between 3+4 vs 4+3

What to do with 3 grades with highest grade as least common pattern?

Use highest grade as secondary pattern

Example: 3 (70%), 4 (20%), 5 (10%)à 3+5 (not 3+4)

 

What’s tendency in grading in need biopsy?

Under grade

Tumour progression

Associated with ↑serum PSA

Name features in extraprostatic spread

Perineural invasion

Tumour nodule at the surface of the gland

Tumour in periprostatic soft tissue (adipose)

How to report needle biopsy?

-Must give a separate Gleason score to each core

How many cores are taken?

-10

Why shouldn’t one diagnose Gleason 1-2 on need biopsy?

LG tumors tend to be small and to occur in TZ (unreachable by needles)

PROSTATE GROSSING

TURP

If <12g[3]^,[4]à submit everything

For every additional 5g, submit 1 cassette

Cancer present, submit in toto

PROSTATECTOMY

Different inks for each side

Amputate seminal vesicles

Thin shave of base resection margin

Submit vas deferens resection margin

Place probe through urethra

Section prostate perpendicular to urethra

Cut each section into quadrants and submit in separate cassettes

Submit upper, mid and lower levels.

Serial section bladder neck and apical margin and submit on edge

NEEDLE BIOPSY REPORT

Number of positive cores

% of cancer in each core

Gleason for each core

Important to report location

PROSTATECTOMY REPORT

Size: include multicentricity

Histologic grade:

Gleason pattern (primary and secondary and total)

Tumour extent:

Extraprostatic extension

Margins: (eg. left apical posterior)

ureters

urethra

 

AMYLOID

Thioflavin Tà most sensitive for p-component

 

Non-neoplastic causes of high PSA

BPH

Prostatitis

Prostatic infarct

Not in HGPIN

BLADDER RISK FACTORS

Smokers

Aniline dyes

Male

Schistosomiasis (Egypt, SCC)

Analgesics

Cyclophosphamide

Risk factors for SCC

Shisto

EXtrophy

Lithiasis

Indwelling catheter

Cyclophosphamide

 

T1   LPà BCG***

T2   MPà cystectomy***

T2a  Superficial MP (inner half)

T2b  Deep MP (outer half)

T3   Perivesical tissueà still operable???

T4   Nearby organs

N0

N1-3 confined to a single lymph node

N1 <2 cm

N2 2-5 cm

N3 >5 cm

When to upstage?

Detrusorà T2

Perivesicular fatà T3

Organsà T4

Size of tumor in LNà N1-3

 

Lamina propria invasion

Retraction artifact mimics vascular invasion

Minimal desmoplasia

Note: adipose tissue may be present here

Muscularis propria invasion

in b/w large bundles of muscle

Fat in the biopsy

can have fat within the muscularis (ie. do not over diagnose perivesicular invasion)

SECTIONS TO SUBMIT

Tumour (deepest point, deep margin)

Bladder mucosa (ant,post walls and rt, lt lateral walls)

Ureter margins + lesions

Prostate

Urethral margin

Seminal vesicles

Anterior vaginal wall

Lymph nodes

BLADDER SYNOPTIC REPORT

Specimen type

Tumour site

Tumour size

Histologic type (urothelial, adenoca or squamous)

if urothelial (papillary, non-papillary; invasive, non-invasive, microinvasive <0.2cm)

Histologic grade

Extent of invasion

Mult tumours

Vascular/lymphatic invasion

Margins (ureters, urethra, soft tissue)

Regional nodes

Associated epithelial lesions (papilloma, PUNLMP)

Prostate

Vaginal wall

 

TCC with sarcomatoid differentiation

Need to ddx from sarcoma

So, sample some more

Try to identify in situ component

CLASSIFY BLADDER TUMOURS

Primary or Metastatic

Primary

Benign

Urothelial: Papilloma, Inverted papilloma,

Squamous: Squamous papilloma, Condyloma accuminatum (papillary arch, koilocytes, (HPV)

Glandular: Villous adenoma

Mesenchymal tumours:

muscle

Neural (paraganglioma)

Vascular

Other (SFT)

Malignant

Urothelial: CIS, PUNLMP, LGTCC, HGTCC, Invasive TCC

Squamous: SCC

Glandular: Adenocarcinoma, Clear cell adenocarcinoma (ddx of nephroblastic adenoma),

Primary or extension from colorectal

Signet ring

Neuroendocrine:

Small cell carcinoma: (pure or combined with TCC or squamous)

Carcinoid

Large cell NE

Mesenchymal tumours:

Muscle (RMS-embyronal, botryoid subtype in kids)

Neural (paraganglioma)

Vascular

Other (SFT)

Lymphoma

Leukemic infiltrate (Myeloid sarcoma)

Melanoma

 

Remember PSCNà not tumor though

 

 

DIFFERENTIALS

Papillary lesions

Nephrogenic adenoma

Condyloma

Villous adenomaà remember

Adenocarcinoma

Metastasis

Polypoid cystitis

TCC

Malignant mimickers

PSCN

IMT

Nephrogenic adenoma

Giant cell cystitis

Von Brunn nests

Cystitis glandularis

Polypoid cystitis

Spindle cell lesions

Postoperative spindle cell nodule

Inflammatory pseudotumor

Sarcomatoid TCC

Metastatic sarcomatoid carcinoma

Sarcomas

Carcinosarcoma

SFT