Prostate cancer

This article deals with prostate cancer. The vast majority of prostate cancers are carcinomas, i.e. prostatic adenocarcinoma (AKA adenocarcinoma of the prostate, prostatic carcinoma).

General

• Very common.
• Increasing incidence with age - the age in years is an approximation of the percentage of men with prostate cancer.
• Usually an indolent course - most old men die with prostate cancer not from prostate cancer.

Management

The management changes between Gleason 6, 7 & 8; typically, the implications are:

• Gleason 6: watchful waiting or radioactive seeds; surgery if patient wants.
• Gleason 7: do something - often surgery.
• Gleason 8+: bad cancer - do something quickly!

Bottom line:

• You want to be sure when you call something Gleason pattern 4.

Microscopic

Criteria as a list

Major criteria (the ABCs of prostate pathology):

1. Architecture.
   • Increased gland density.
   • Small circular glands.
     • In rare subtypes - large branching glands.
   • "Infiltrative growth" pattern - malignant glands between benign ones.
     • Image: Infiltrative growth pattern (nature.com).
2. Basal cells lacking.
3. Cytological abnormalities:
   • Nuclear enlargement.
   • Nucleoli.

Minor criteria:

1. Nuclear hyperchromasia.
2. Wispy blue mucin.
   • Image: Wispy blue mucin (nature.com) - from Epstein.
3. Pink amorphous secretions.
   • Image: Pink amorphous secretions (nature.com) - from Epstein.
4. Intraluminal crystalloid.
   • Image: Intraluminal crystalloid (nature.com) - from Epstein.
5. Amphophilic cytoplasm.
   • Amphopilic is said to be bluish-red -- though might also be described as blue-grey.
     • Image: Amphophilic cytoplasm is prostate carcinoma.
6. Adjacent HGPIN.
7. Mitoses - quite rare.

Extent/quantity criteria:

• There is no agreed upon minimum number of glands; however, one paper suggests that agreement among experts is low with 5 or less glands.
  • Thus, it has been suggested that six or more glands should be present to diagnose cancer.

Low power features

• Architecture is the key to diagnosing low grade cancer.
  • Back-to-back glands or crowding of glands -- think low grade cancer (Gleason pattern 3).
  • Sharp transition between gland border and lumen.
    • Loss of epithelial folding at the epithelium-gland lumen interface - "punched-out" appearance.
  • Eosinophilic debris within the gland lumen (pink amorphous secretions, intraluminal crystalloid).
  • Blue-tinged acellular material within the gland lumen (mucin) -- uncommon.
  • "Infiltrative": small round/oval (malignant) glands (approx. 5 cells across) interspersed with larger (benign) glands that are 2-3 times larger.

High power features

• Nuclei.
  • Hyperchromatic nuclei (like in HGPIN).
  • Nuclear enlargement.
    • Difficult to appreciate (if cancer isn't side-by-side with normal prostate).
    • Difficult to see if not on high power.
• Nucleoli visible on high power (200x or 100X)
  • May be difficult to see - especially if light intensity is low.
    • One should not use 400x to look for nucleoli (it is a waste of time + you risk overcalling something benign).
  • If I see three good nucleoli in a gland I'm usually confident it is cancer.
• Loss of basal cells - diagnostic feature.
  • Like in breast pathology (where one looks for loss of myoepithelial cells) - this may be difficult to see.

Notes:

• Mitoses are not a common feature - don't waste time looking for them.

Mimics

Mimics of prostate adenocarcinoma:

Entity	Key feature	Detailed microscopic	Other	Image
Adenosis (AKA atypical adenomatous hyperplasia)	gradual transition between normal & small gland (NOT two populations)	many small glands, lack nuclear size variation, basal layer present	nucleoli may be present; may need to do p63 or 34betaE12 to find basal layer	AAH (webpathology.com)
Sclerosing adenosis	gradual transition between normal & small gland (NOT two populations), fibrosis	many small glands, lack nuclear size variation, basal layer present	analogous to sclerosing adenosis of breast (???)	Sclerosing adenosis (webpathology.com)
Atrophy	sharp angulation of gland	nuclear hyperchromasia, scant cytoplasm	may appear right beside non-atrophic tissue	Atrophy (webpathology.com), Partial atrophy (webpathology.com) Sclerotic atrophy (webpathology.com)
Basal cell hyperplasia	two distinct cell populations (in epithelial component)	abundant epithelial cells; nucleoli in pale ('blue') nuclei of basal cells, glandular cell nuclei darker ('purple')	vaguely similar to epithelial hyperplasia of usual type (EHUT) in breast	BCH (webpathology.com)
Bulbourethral gland	no nuclear atypia	clear cytoplasm	apex of prostate	Cowper gland (webpathology.com)
Seminal vesicles / ejaculatory ducts	lipofuscin (yellow granular material in cytoplasm), smudge cells (smeared appearance + hyperchromatic)	fern-like arrangement of epithelium (low power), nucleoli, surrounded by muscle, +/- nuclear inclusions	involvement by cancer changes staging, lipofuscin may be present in prostate, often has marked nuc. size var.; location: usu. base of prostate	SV - high mag. (WC), SV - low mag. (WC)
Radiation effect	marked nuclear size variation	increased stroma (fibrosis), lack nucleoli ???	history of Rx; uniform nuc. size with Hx of Rx should raise susp. of cancer	Radiation changes (webpathology.com), Radiation changes (webpathology.com)
Prostatitis	inflammatory cells (lymphocytes, plasma cells, PMNs)	no nuclear atypia, normal gland arch.	clinical mimic of cancer (elevated PSA); usu. not a problem for the pathologist	Prostatic inflammation (WC)
Vasitis nodosa	sperm within ducts, clinical history (usu. post-vasectomy)	small tubules, nucleoli common, mild atypia, may "invade" vessels, track along nerves	mimics metastatic prostate carcinoma, IHC stains: PSA-, PSAP-	VN (webpathology.com)

Memory device: AAABBRS = atrophy, adenosis, adenosis (sclerosing), basal cell hyperplasia, bulbourethral gland, radiation, seminal vesicles.

Gleason grading system

Overview:

• This system is only one any one talks about.
• Score range: 6-10.
  • Technically 2-10... but almost no one uses 2-5.
• Reported as on biopsy as: (primary pattern) + (secondary pattern or tertiary pattern with the highest grade) = sum.
  • e.g. Gleason score 3+4=7 means: pattern 3 is present and dominant, pattern 4 is the remainder of the tumour - but present in a lesser amount than pattern 3.
• Reported as on prostatectomies as: (primary pattern) + (secondary pattern) = sum, (tertiary pattern)

• Tertiary Gleason pattern - definition: a pattern that is seen in than 5% of the tumour (volume), that is higher grade than the two dominant patterns.
  • The presence of a tertiary patterns adversely affect the prognosis; however, the prognosis is not as bad as when the tertiary pattern is the secondary pattern, i.e. 3+4 tertiary 5 has a better prognosis than 3+5 (with some small amount of pattern 4).

Examples:

• A biopsy has 80% pattern 4, 16% pattern 3 and 4% pattern 5... it would be reported as: 4+5=9.
• A prostatectomy has 80% pattern 4, 16% pattern 3 and 4% pattern 5... it would be reported as: 4+3=7 with tertiary pattern 5.

Testing yourself:

• There is a nice test-yourself quiz from Johns Hopkins: http://162.129.103.34/prostate/.
  • It was studied in a paper by Kronz et al.

Gleason pattern 1 & 2

• Use strongly discouraged by a number of GU pathology experts.

Notes:

• Gleason pattern 1 - probably represents what today would be called adenosis.
  • Should never be used.
• Gleason pattern 2 - used by few GU pathology experts occasionally.
  • Generally, should not be diagnosed on core biopsies.

Gleason pattern 3

• Glands smaller than normal prostate glands + loss of epithelial folding.
• Can draw a line around each gland.
• May have gland branching.
  • Glands have a X, U, V or Y shape.

Notes:

• Gland lumina should be seen.
• All cribriform is now, generally, classified as Gleason pattern 4.

Gleason pattern 4

• Loss of gland lumina.
• Gland fusion.
• Benign looking cords ('hypernephroid pattern').
• Cribriform.
• Glomeruloid pattern - resembles a glomerulus.

Notes:

• One gland is not enough to call Gleason 4.

Images:

• Gleason pattern 4 - cribriform (WC).
• Gleason pattern 4 - small glands & Gleason pattern 5 - single cells (WC).
• Glomeruloid pattern (nature.com).

Gleason pattern 5

• Sheets.
  • Must be differentiated from intraductal growth (which like in the breast are well circumscribed nests).
• Single cells.
  • May be confused with stromal/lymphocytic infiltration.
    • Look for nucleoli, cells should be round (prostatic stroma cells are spindle cells).
• Cords.
• Nests of cells with necrosis at centre.

Image: Gleason pattern 4 - small glands & Gleason pattern 5 - single cells (WC).

Special types

Special types of prostate cancer have set Gleason scores:

Special type	Gleason pattern	Comment
Ductal carcinoma	4	may be graded 3 or 5
Mucinous carcinoma	4
Sarcomatoid carcinoma	5	glands graded separately
Signet ring cell carcinoma	5
Small cell carcinoma	not graded	may be graded 5
Adenosquamous and squamous carcinoma	not graded
Lymphoepithelioma-like carcinoma	not graded
Adenoid cystic carcinoma	not graded
Urothelial carcinoma	not graded
Undifferentiated carcinoma, NOS	not graded

How to remember the ones that aren't graded - think of Ur Lung carcinomas (Urothelial carcinoma, Lymphoepithelioma-like carcinoma):

• Small cell carcinoma.
• Squamous cell carcinoma.
• Adenosquamous carcinoma.
• Adenoid cystic carcinoma.

Staging parameters and margins

Surgical margins

Main article: Surgical margins

• Positive is tumour touching ink.
  • "Close" margins have an increase recurrence risk.

Notes:

• Surgical margin - where the surgeon cut.
  • It is possible to have EPE without a positive margin.
  • It is possible to have a positive margin without EPE.

Rates and implication

Positivity rate varies substantially (13-44%):

• Norway: 26% -- strong dependence on surgeon volume (18% high case load vs. 44% low case load).
• France: 13-17%.

Note:

• There is likely a strong dependence on stage and grade of cancer, i.e. surgeons that operate more on high grade cancers will probably have a higher margin positive rates.

The impact of positive margins:

• Significant modest negative affect on long-term outcome in node negative cancers (pT2-4 pN0).
• Weaker impact than stage and Gleason score.

Extraprostatic extension

Abbreviated EPE.

General:

• Extraprostatic extension (EPE) is difficult to assess (in prostatectomy specimens) as there is no consensus definition.
  • The prostate does NOT have a well defined capsule.
    • Intraobserver agreement for EPE is fair-moderate and lower than for the surgical margin.
• EPE, typically, upstages tumours from T2x to T3a.

Prostatectomy specimens - EPE is present if there is either:

1. A "significant bulge" in the contour of the prostate at low power and no fibromuscular tissue surrounding the malignant cells.
2. Malignant cells directly adjacent to peri-prostatic adipose tissue.

Note:

• The prostate, at the apex, may have some skeletal muscle. Thus, it is difficult to define extention... ergo EPE not called at the apex.

Prostate biopsy - EPE is present if:

• Tumour touches adipose tissue.

Seminal vesicle invasion

General:

• Typically upstages to T3b.

Microscopic:

• Tumour must be in the muscle surrounding the epithelial component; tumour in the adventitia (the loose connective tissue surrounding the seminal vesicles) does not count.

Notes:

• Invasion of the adventitia (only) would quality as EPE; this is, usually, T3a.

IHC

• AMACR +ve.
• AR +ve -- in prostate confined cancer.
  • Usu. -ve in LN +ve disease.
• PSA +ve.
• PSAP +ve.
  • May be positive in hindgut neuroendocrine tumours.
• p63 -ve.
• HMWCK (34betaE12) -ve.

Combination immunostains:

• PIN-4 -- consists of: CK5 + CK14 + p63 + P504S (AMACR).
  • AKA PIN.
  • AKA CAP.
    • Why CAP?
      • A. CAncer of the Prostate.

Molecular changes in prostate cancer

A fusion gene between TMPRSS2 and ERG is described.

• Both genes are on chromosome 21.
• Currently not used diagnostically.
• Fusion gene seen in approximately 50% of prostate cancer.
• A subset of TMPRSS2-ERG known as 2+Edel (seen in ~7% of all prostate cancer cases) predicts poor survival.

Sign out

Prostatectomy specimens

See: CAP checklist.

Biopsy specimens

Important elements - a list:

1. Type of cancer, e.g. "prostatic adenocarcinoma, acinar type".
2. Gleason score including primary and secondary pattern, e.g. "Gleason score 3+4=7".
3. Number of cores and number involved, e.g. "2/3 cores involved by cancer".
4. Percent area involved, i.e. how much of the core is cancer, e.g. "75% of specimen is tumour".
5. Percent area involved that is Gleason pattern 4 or 5, e.g. "25% of the tumour is Gleason pattern 4 or 5".
6. Presence of perineural invasion.
7. Presence of extension into fat (extraprostatic extension).

Notes:

• "Percent area involved" may seem like an odd thing to request 'cause it is sampling dependent, i.e. if the radiologist sticks the biopsy needle deeper into the lesion more of the core is positive, but urologists think it is important -- more important than perineural invasion.

Completely negative

A. PROSTATE, RIGHT LATERAL SUPERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

B. PROSTATE, RIGHT MEDIAL SUPERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

C. PROSTATE, RIGHT LATERAL MIDZONE, BIOPSY:
- BENIGN PROSTATE TISSUE.

D. PROSTATE, RIGHT MEDIAL MIDZONE, BIOPSY:
- BENIGN PROSTATE TISSUE.

E. PROSTATE, RIGHT LATERAL INTERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

F. PROSTATE, RIGHT MEDIAL INFERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

G. PROSTATE, LEFT LATERAL SUPERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

H. PROSTATE, LEFT MEDIAL SUPERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

I. PROSTATE, LEFT LATERAL MIDZONE, BIOPSY:
- BENIGN PROSTATE TISSUE.

J. PROSTATE, LEFT MEDIAL MIDZONE, BIOPSY:
- BENIGN PROSTATE TISSUE.

K. PROSTATE, LEFT LATERAL INTERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

L. PROSTATE, LEFT MEDIAL INFERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE.

No glands

F. PROSTATE, RIGHT MEDIAL MIDZONE, BIOPSY:
- BENIGN FIBROMUSCULAR TISSUE;
- NO PROSTATIC GLANDULAR TISSUE PRESENT.

Inflammation

G. PROSTATE, LEFT LATERAL SUPERIOR, BIOPSY:
- BENIGN PROSTATE TISSUE;
- FOCAL CHRONIC INFLAMMATION. 

F. PROSTATE, RIGHT MEDIAL MIDZONE, BIOPSY:
- BENIGN PROSTATE TISSUE;
- CHRONIC INFLAMMATION. 

F. PROSTATE, RIGHT MEDIAL MIDZONE, BIOPSY:
- BENIGN PROSTATE TISSUE;
- ACUTE AND CHRONIC INFLAMMATION. 

Positive

F. PROSTATE, RIGHT MEDIAL INFERIOR, BIOPSY:
- ADENOCARCINOMA, GLEASON SCORE 6/10 (3+3);
- 1/1 CORE INVOLVED; APPROXIMATELY 5% OF TISSUE INVOLVED.

F. PROSTATE, RIGHT MEDIAL INFERIOR, BIOPSY:
- ADENOCARCINOMA, GLEASON SCORE 6/10 (3+3);
- 1/1 CORE INVOLVED; APPROXIMATELY 25% OF TISSUE INVOLVED;
- PERINEURAL INVASION PRESENT.

G. PROSTATE, LEFT LATERAL SUPERIOR, BIOPSY:
- ADENOCARCINOMA, GLEASON SCORE 7/10 (4+3);
- 1/1 CORE INVOLVED; APPROXIMATELY 5% OF TISSUE INVOLVED;
- PERINEURAL INVASION PRESENT.

H. PROSTATE, LEFT MEDIAL SUPERIOR, BIOPSY:
- ADENOCARCINOMA, GLEASON SCORE 8/10 (4+4);
- 1/1 CORE INVOLVED; APPROXIMATELY 15% OF TISSUE INVOLVED.

H. PROSTATE, LEFT MEDIAL SUPERIOR, BIOPSY:
- ADENOCARCINOMA, GLEASON SCORE 8/10 (4+4);
- 1/1 CORE INVOLVED; APPROXIMATELY 15% OF TISSUE INVOLVED;
- PERINEURAL INVASION PRESENT.

TUMOUR SUMMARY - PROSTATE CORE BIOPSIES:
- HISTOLOGIC TYPE: ADENOCARCINOMA (ACINAR, NOT OTHERWISE SPECIFIED).
- TOTAL GLEASON SCORE: 7.
- PRIMARY PATTERN: 4.
- SECONDARY PATTERN: 3.
- PERCENT OF TUMOUR WITH PATTERN HIGHER THAN GRADE 3: 75%.

- NUMBER OF CORES POSITIVE: 10.
- TOTAL NUMBER OF CORES: 12.
- TOTAL LINEAR MILLIMETERS OF NEEDLE CORE TISSUE: 152 MM.
- PERCENT OF NEEDLE CORE TISSUE THAT IS TUMOUR: 44%.

- PERIPROSTATIC FAT INVASION: NOT IDENTIFIED.
- SEMINAL VESICLE INVASION: SEMINAL VESICLE NOT IDENTIFIED.
- LYMPHOVASCULAR INVASION: NOT IDENTIFIED.
- PERINEURAL INVASION: PRESENT.

- ADDITIONAL FINDINGS: HIGH-GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA, CHRONIC INFLAMMATION (FOCAL).

See also

• Prostate gland.
• Genitourinary pathology