Prostate gland

The prostate adds juice to the sperm. In old men it creates lotsa problems... nodular hyperplasia (commonly called BPH or benign prostatic hypertrophy) and cancer (adenocarcinoma).

Normal

Prostate

• Glands have two cell layers (similar to glands in breast).
  • Second cell layer may be difficult to see (like in breast).
• Epithelium in glands is "folded" or "tufted".
  • Very important - helps on differentiate from Gleason pattern 3.
• Luminal epithelium often clear cytoplasm.
• Single nucleus.

Benign normal:

• Corpora amylacea.
  • Round/ovoid-eosinophilic bodies -- with laminations (layered appearance).
  • In gland lumina.
  • Usually in benign glands - but cannot be used to exclude cancer.
  • Very common.
  • These should be differentiated from eosinophilic proteinaceous debris - which is associated with cancer.

Negatives:

• No nucleoli present (if you see nuclei think: cancer, HGPIN, reactive changes, basal cell hyperplasia).
• No mitoses - these are uncommon... even in high grade prostate cancer.

Notes:

• Tufted epithelium is a strong indicator of benignancy; however two uncommon prostate cancer typically have tufted epithelium:
  • Pseudohyperplastic adenocarcinoma.
  • Foamy gland carcinoma.

IHC of normal prostate

Normal prostate:

• AMACR -ve (mark epithelial cells).
• p63 +ve, HMWCK +ve (mark basal cells).
• PSA +ve, PSAP +ve.

Other accessory glands

Bulbourethral gland

• AKA Cowper's gland.
• Mucinous glands at the apex of the prostate.
  • Resemble (mucinous) salivary glands.

Image: Mucinous/serous salivary gland (duke.edu).

Seminal vesicles

• Leaf-like architecture - epithelial component clustered closely, looks like it connects.
  • Epithelium surrounded by a thick layer of muscle (>10 cells across ~80 microns).
• Lipofuscin (coarse cytoplasmic yellow granules approximately 1-2 micrometers) - key feature.
• Nucleoli - common.
• Nuclear inclusions - common.

Images:

• SV (udel.edu).

Common diagnoses

• Benign.
  • Atrophy - may resemble adenocarcinoma - typically not reported.
  • Adenosis - may resemble adenocarcinoma - typically not reported.
• Prostate adenocarcinoma.
  • Most common Grade is 3+3=6.
• HGPIN (high-grade prostatic intraepithelial neoplasia) - prostate adenocarcinoma precursor lesion.
• ASAP (atypical small acinar proliferation) - used if you have a few abnormal appearing glands... but can't decide between prostate adenocarcinoma & benign.
• Chronic inflammation.
• Acute inflammation - can result in an elevated PSA and may have prompted the biopsy you're looking at.
• Nodular hyperplasia of the prostate; AKA benign prostatic hypertrophy (BPH).
  • Not diagnosed on needle biopsies.
  • BPH is technically incorrect -- the process is a hyperplasia.
    • Hyperplasia = proliferation of cells, hypertrophy = enlargement of cells.
      • How to remember? A. Prostate... hyperPlasia.

Clinical history

• PSA (serum).
  • >10 ng/mL worrisome for prostate cancer.
  • Normal is age dependent - increases with age, usu. cut-off ~ 4 ng/mL.
• HIFU = High Intensity Focused Ultrasound - an ablation procedure for prostate cancer.

Atrophy

General

• Small glands (may mimic Gleason score 3 pattern).

Microscopic

Features:

• Glands often have a jagged edges/prows (in cancer the glands tend to have round edges) - key feature.
  • Prow = forward most part of a ship's bow that cuts through the water.
    • You may have come across prow in the context of breast cancer, i.e. tubular carcinoma.
• Gland density is usually lower than in prostate carcinoma, i.e. glands are not back-to-back - key feature.
• Atrophic glands are often hyperchromatic.
• Scant cytoplasm - usually.

Negatives:

• Nuclei like normal, i.e. nucleoli uncommon.
• Should have two cell layers, i.e. epithelial and myoepithelial (may be difficult to see).

Atrophy vs. cancer

	Atrophy	Cancer
Glandular architecture/ arrangement	angulated glands, may look like they originate from one large duct	round glands, often back-to-back
Nuclear hyperchromasia	marked	moderate
Cytoplasm	scant/minimal	moderate, may be amphophilic
Basal cells	may be visible	absent
Nucleoli	absent	present
Secretions in glands	no	yes - eosinophilic or blue

Basal cell hyperplasia

General

• Atypical appearing glands - typically in transition zone.
• May have nucleoli.

Differentiating between diagnoses

Basal cell hyperplasia vs. cancer[1]

• Low power gland architecture near normal.[2][3]
  • Glands not as small as cancer.
  • Folds in gland lumina.
  • No hyperchromasia.
  • Two cell layers (as in normal prostate glands).

High grade prostatic intraepithelial neoplasia

General

• Abbreviated as HGPIN.
• Thought to be a precursor lesion for prostate adenocarcinoma.

Low-grade PIN:

• Not reported and generally believed to be irrelevant biologically/clinically.
  • PIN not otherwise specified refers to HGPIN.
  • Low-grade PIN has the architecture of HGPIN but lacks the nuclear atypia.

Microscopy

Features:

• Diagnosed on basis of nuclear changes.
  • Hyperchromatic nuclei.
  • Nucleoli present - key feature.
  • Often increased N/C ratio.
• Different architectures (e.g. micropapillary).
• Usually epithelial hyperplasia.

HGPIN architecture

There are several forms:

• Flat - uncommon.
• Tufting - common.
• Micropapillary - common.
• Cribriform - rare.

Note: The architectural pattern is NOT thought to have any prognostic significance -- may, however, be useful for picking it out from benign prostate.

Images:

• HGPIN - low mag. (WC).
• HGPIN - intermed. mag. (WC).
• HGPIN - high mag. (WC).

Differentiating between diagnoses

HGPIN vs. adenocarcinoma:

• Glands with HGPIN have two or more distinct cells layers.

HGPIN vs. normal:

• HPGIN has nuclear changes.

May need IHC (especially for cancer vs. HGPIN).

IHC patterns:

• Cancer: AMACR +ve, p63 -ve, HMWCK -ve.
• HGPIN: AMACR +ve, p63 +ve, HMWCK +ve.
• Normal: AMACR -ve, p63 +ve, HMWCK ve+.

Atypical small acinar proliferation

General

• Abbreviated ASAP.
• It is a waffle diagnosis, i.e. it is not considered an entity with a distinct pathobiology.
  • It is the same as suspicious for carcinoma.
    • ASAP is preferred as it does not contain the word carcinoma and, thus, cannot be misread as carcinoma, i.e. positive for malignancy.
  • Analogous to ASCUS on a pap test.
  • ASAP should be used sparingly.
    • One benchmark is < 3-5% of biopsies.
• Never diagnosed on excision, i.e. prostatectomy specimen.

Histologic characteristics

• Atypical appearing acini.
• Limited extent, e.g. 2-3 glands.
• IHC not contributory.
• Deeper cuts didn't yield anything.

Association with adenocarcinoma

• On subsequent biopsy - chance of finding adenocarcinoma is approximately 40%; this is higher than if there is high-grade prostatic intraepithelial neoplasia (HGPIN).

Management

• ASAP is considered an indication for re-biopsy; in one survey of urologists 41/42 (~98%) of respondents considered it a sufficient reason to re-biopsy.

Common prostate cancer

Criteria as a list

Major criteria (the ABCs of prostate pathology):

1. Architecture - "infiltrative growth" pattern.
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.

IHC

• AMACR +ve, p63 -ve, HMWCK (34betaE12) -ve .
• Usually positive: PSA, PSAP.

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	Image
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 (???)	Image
Atropy	sharp angulation of gland	nuclear hyperchromasia, scant cytoplasm	may appear right beside non-atrophic tissue	Image
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	Image
Bulbourethral gland	no nuclear atypia	clear cytoplasm	apex of prostate	Image
Seminal vesicles	lipofuscin (yellow granular material in cytoplasm)	fern-like arrangement of epithelium, nucleoli, surrounded by muscle	involvement by cancer changes staging	Image
Radiation exposure	marked nuclear size variation	increased stroma (fibrosis), lack nucleoli ???	history of Rx; uniform nuc. size with Hx of Rx should raise susp. of cancer	Image
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	[4]

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

Grading

There is only one grading system that any one talks about...

Gleason grading system

• Score range: 2-10.
• Reported as on biopsy as: (primary pattern) + (secondary pattern or tertiary pattern with the highest grade) = sum.
  • e.g. Gleason grade 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, 15.1% pattern 3 and 4.9% pattern 5... it would be reported as: 4+5=9.
• A prostatectomy has 80% pattern 4, 15.1% pattern 3 and 4.9% pattern 5... it would be reported as: 4+3=7 with tertiary pattern 5.

Gleason pattern 1 & 2

• Academic thing - you can forget about 'em.

Gleason pattern 3

• Glands smaller than normal prostate glands + loss of epithelial folding.
• Can draw a line around each gland.

Notes:

• All cribriform is now classified as Gleason pattern 4.

Gleason pattern 4

• Loss of gland lumina.
• Gland fusion.
• Benign looking cords ('hypernephroid pattern').
• Cribriform.
• One gland is not enough to call Gleason 4.

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.

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..

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.
• Gleason 8+: bad cancer - do something quickly!

Bottom line: You want to be sure when you call something Gleason pattern 4.

Note:

• The usual caveats apply to the above; if the patient is moribund-- nothing is done, if the patient refuses treatment... nothing is done et cetera.

Margins + Extension

Definitions:

• 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.
• 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.

Important:

• EPE cannot be called on a biopsy unless the tumour is next to adipose tissue.

Extraprostatic extension (EPE)

• Prostatectomy specimens: EPE is present if there is a "significant bulge" in the contour of the prostate at low power.
• Prostate biopsy: EPE is present if tumour touches adipose tissue.
  • The prostate, at the apex, may have some skeletal muscle -- it is hard to define the extent... ergo no EPE at apex. (????)

Reporting prostate cancer

Elements of a prostate biopsy report with cancer

Important elements:

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.

Prostatectomy specimens

See: CAP checklist.

Unusual forms of prostate cancer

Ductal adenocarcinoma

Features:

• Crowded columnar (or cigar-shaped) nuclei.
  • Vaguely resembles colonic adenocarcinoma.
• Usually seen in association with conventional (acinar) prostate adenocarcinoma.

Foamy gland carcinoma

Features:

• Tufted glandular border.
• Abundant eosinophilic (or hyperchromatic) cytoplasm - key feature.
• Gland size larger than "typical" prostate cancer.

Pseudohyperplastic prostatic adenocarcinoma

Features:

• Usually associated with conventional (acinar) prostate adenocarcinoma.
• Pale (normal) cytoplasm).
• Pseudopapillary infolding - key feature.
• Large size glands.

See also

• Urothelium.
• Genitourinary pathology.

External links

• CAP prostate check list - cap.org.
• CAP prostate protocol - cap.org.
• Gleason score quiz - Johns Hopkins Prostate Center.