Last updated: 9/22/2020 Prepared by Kurt Schaberg MD

Prostate Tumors
Acinar Adenocarcinoma (The most common/default type of “Prostate Cancer”)

An invasive adenocarcinoma consisting of neoplastic prostatic epithelial cells with secretory

differentiation arranged in a variety of patterns, typically without basal cells.
Most common cancer in men and second leading cause of cancer death in the U.S.A.

Prevalence is strongly correlated with age (older = higher prevalence)

Majority are multifocal, often with 2-3 separate tumors in each prostate.
Most commonly located in posterior/posterolateral peripheral gland.
Early tumors are often asymptomatic. Locally advanced prostate cancer mimics BPH with urinary
symptoms. Bone very common site of metastasis → bone pain and pathologic fractures

Morphology: Always use multiple features (there is no single feature to Dx!)

Nuclear Features:
Benign
• Prominent nucleoli
• Nuclear enlargement
• Nuclear hyperchromasia
• Mitotic figures
• Apoptotic bodies
Cytoplasmic features:
• Amphophilic cytoplasm
• Sharp luminal borders
Luminal contents:
• Blue-tinged mucin
• Pink amorphous secretions
• Crystalloids
Benign
Architecture:
• Crowded small glands
• Linear row of atypical glands spanning the width of a core
• Small glands on both sides of a benign gland
• Haphazard, infiltrative pattern

Absent basal cell layer (can highlight with IHC, as fibroblasts may mimic basal cells)
Usually lack desmoplastic stroma. When present, often associated with high-grade carcinoma.

Findings more common in benign glands:

• Atrophic cytoplasm
• Merging with benign glands
• Corpora amylacea
• Inflammation
• Lipofuscin
Cancer
 Features Specific To Malignancy Mucinous Fibroplasia
(collagenous micronodules)
Glomerulations Perineural Invasion
Dense nodules of collagen (hyalinized
Cribriform formations To Dx malignancy, tumor must
mucin) surrounded and encased by
attached only to one edge completely encircle nerve. (Benign
epithelium
of the surrounding gland glands may abut, but not encircle)

Specific Variants (Same prognosis, unless

otherwise mentioned)
Atrophic variant
Cytoplasmic volume loss (like atrophy), Often absent
nuclear enlargement and nucleoli→ mimicking benign
atrophy!
Luckily, conventional carcinoma often present nearby.
Can be sporadic or after therapy.
Often Gleason pattern 3 (small infiltrative glands)

Pseudohyperplastic variant
Simulates luminal cell hyperplasia→ papillary
infoldings, luminal undulations, and branching.
Round nuclei, not pseudo stratified, with prominent
nucleoli.
Often relatively pure and well-circumscribed.

Foamy gland variant

Abundant foamy/xanthomatous cytoplasm
and small, pyknotic nuceli
Usually combined with usual type (rare to be
pure)
 Rare Variants (continued)

Microcystic variant
Large, dilated round glands with flattened luminal
cells→ mimic benign atrophy.

Mucinous (colloid) variant

≥25% of tumor has extracellular mucin pools
Can only be Dx’d on prostatectomy (on Bx say
“mucinous features”)
Mentally subtract mucin for grading.

Signet ring-like variant

≥25% of tumor is composed of infiltrative single
cells with large vacuoles (that do not actually
contain mucin). Gleason pattern 5.
Poor prognosis. Must consider GI metastasis.
Notably, vacuoles can be seen in any grade
prostatic cancer (vacuoles ≠ Signet ring-like)!

Sarcomatoid variant (Carcinosarcoma)

Biphasic with both epithelial and mesenchymal
differentiation. Poor prognosis.
Can see various heterologous elements.

Hypernephroid variant (vanishing variant)

Sheets of cells with abundant clear cytoplasm.
Gleason pattern 4

Pleomorphic giant cell variant (not pictured)

Giant bizarre anaplastic cells with pleomorphic
nuclei and without a spindle cell component.
Poor prognosis.
Gleason Grading Based on architecture at low power (using 4x or 10x objective).

Circumscribed nodule of closely packed but

separate, uniform, rounded to oval, medium-

1
sized acini

Should not be diagnosed regardless of the type

of specimen, with extremely rare exceptions

Fairly circumscribed, yet at the edge of the

tumor nodule there may be minimal infiltration

2
Do not diagnose on biopsy, rarely diagnosed
regardless of specimen.
Glands are more loosely arranged and not quite
as uniform as Gleason pattern 1

Well-formed glands (with lumina)

3
Separate, discrete, Non-fused

Infiltration

Ill-defined, poorly formed glands

Gland fusion

4
ALL cribriform glands
Hypernephromatoid
Glomerulations
Ductal Adenocarcinoma (without necrosis)

Often Disqualifies from Active Surveillance

Essentially no glandular differentiation:

• Solid sheets

5 • Cords
• Single cells
• Linear arrays
Comedocarcinoma with central necrosis

Notes: Given the importance of distinguishing between patterns 3 and 4 for active surveillance, getting
levels can be helpful to differentiate tangential sectioning of small well-formed glands (pattern 3) from
poorly-formed glands (pattern 4).
Gleason Scoring
Biopsies:
Most common pattern + Second most common pattern = Score
• If the tumor has only one pattern, then add the same pattern twice.
• No tertiary pattern assigned.
• In the setting of high-grade cancer one should ignore lower-grade patterns if they occupy less
than 5% of the area of the tumor. (e.g., 98% pattern 4 and 2% pattern 3 → 4+4=8)
• High-grade tumor of any quantity, as long as it was identified at low to medium magnification
should be included. (e.g., 98% pattern 3 and 2% pattern 4 → 3+4=7)
• On needle biopsies with patterns 3, 4, and 5, both the primary pattern and the highest grade
should be recorded. Consequently, tumors with Gleason score 3 + 4 and a tertiary pattern 5
would be recorded as Gleason score 3 + 5 = 8.

Prostatectomies:
Most common + Second most common = Score, with tertiary pattern if present
• In the setting of high-grade cancer one should ignore lower-grade patterns if they occupy less
than 5% of the area of the tumor.

Grade Groups
Grade Group Gleason Score
1 ≤6 Only individual discrete well-formed glands

2 3+4=7 Predominantly well-formed glands with a lesser

component of poorly formed/fused/cribriform
glands
3 4+3=7 Predominantly poorly formed/fused/cribriform
glands with a lesser component of well-formed
glands

4 8 - Only poorly formed/fused/cribriform glands

- Predominantly well-formed gland and lesser
component lacking glands
- Predominantly lacking glands and lesser
component of well-formed glands
5 9-10 Lack gland formation (or with necrosis) with or
without poorly formed/fused/cribriform glands

For cases with >95% poorly formed/fused/cribriform glands or lack of glands on a core or at radical
prostatectomy, the component of <5% well-formed glands is not factored into the grade.
 Immunohistochemical Stains
Markers of Prostatic Origin
Prostate Specific Antigen (PSA), Prostatic Acid Phosphatase (PSAP), NKX3.1, Prostein
Each marker ~95% sensitive. NKX3.1 is the most specific.
PSA & PSAP can decrease after androgen deprivation therapy and are less specific (e.g., also get some
salivary gland tumors).
Markers of limited utility due to poor sensitivity or specificity: ERG, AR, AMACR.

Cancer vs Benign Glands Most useful for the confirmation of a small quantity of tumor.
Basal cells are absent in invasive prostatic adenocarcinoma (usually).
Stains for basal cells
Cytoplasm: High-molecular weight cytokeratins (HMWCK) (e.g., 34βE12, CK5/6)
Nuclear: p63, p40
AMACR (aka P504S or Racemase): frequently overexpressed in glandular neoplasia of the prostate
(~90%) with granular cytoplasmic staining. Needs to be done in combination with basal markers as
HGPIN is often positive.
ERG: expression is highly specific for neoplastic prostate glands, but has a low sensitivity (~50%), so
doesn’t have much value over AMACR.

Notable Pitfalls:
Loss of basal cells is not specific for cancer and
may be observed in benign mimics like atrophy,
partial atrophy, and adenosis.
Rare cases of adenocarcinoma can stain for
basal markers (even though they don’t have
basal cells) in a non-basal distribution.
AMACR expression can be seen in benign
mimics such as atrophy, adenosis, and
nephrogenic adenoma.

Common triple stain:

HMWCK + p63 → Brown cytoplasmic and
nuclear, respectively, staining of basal cells in
benign glands

AMACR → Red cytoplasmic staining in

neoplastic glands (that in this case are also
lacking basal cells, supporting the diagnosis of
cancer)
 Diagnosing Limited Cancer
Major Criteria for diagnosing prostate cancer (no single criteria is diagnostic):
1) Infiltrative growth
2) Absence of basal cells
3) Nuclear atypia (nuclear enlargement with prominent nucleoli)

How many glands do you need?

There is no absolute number, but many urologic
pathologists like to see at least 3 glands with
cytologic/architectural features of cancer.

Atypical Small Acinar Proliferation (“ASAP”)

A descriptive term (not an entity) designed to be
used when you have a collection of small glands
suspicious for cancer but lack definitive diagnostic
features or are too small to be certain that they do
not represent the edge of a benign lesion.
IHC in ASAP: Basal cells may be missing in benign
small glands, so, immunohistochemistry is primarily
useful to disprove cancer, not to prove cancer.
Detection of even rare basal cells in any of the
glands of the suspicious population essentially
excludes carcinoma for the entire population.
Clinical follow-up for ASAP: Repeat biopsy

What to do with these 4 glands?

This is potentially a borderline case. If this is all
you had, it’d probably safest to go “ASAP” given
how limited they are and the absence of
prominent nucleoli, but some might call it 3+3

Benign Glands Prostatic Adenocarcinoma

Big, regularly spaced glands Small, infiltrative glands with haphazard and
variable spacing
Papillary infoldings Sharp luminal contours
Small nuclei without nucleoli Large nuclei with prominent nucleoli and
frequent hyperchromasia
Abundant pale, clear apical cytoplasm Amphophilic cytoplasm
Corpora amylacea Eosinophilic or blue mucin secretions
 Biopsy Reporting
For each biopsy specimen/location report:
• Gleason Score and Grade Group
• Number of cores with cancer ( or for TURPs the number of positive chips and total number of chips)
• Linear extent of cancer in each core (percentage and/or length)
• Perineural invasion or extraprostatic extension (if present)
• Percentage of pattern 4 should be recorded in cases with a Gleason score 7 (with very limited
pattern 4, the patient may still be eligible for active surveillance)

PROSTATE, LEFT MEDIAL TRANSITION ZONE, BIOPSY

- Prostatic adenocarcinoma, Gleason Score 3+4=7 (Grade Group 2), 10% Pattern 4, Involving 1 of
1 cores, 5% of tissue

Discontinuous Cancer
5% Additive Total = 10% 5%
Controversial! Several studies have shown that
the linear total (“end to end”) method
correlates better with prostatectomy findings
as they often represent portions of the same
tumor. However, there is no consensus so Linear Total = 95%
consider reporting both for now.

Extraprostatic Extension
Presence of tumor beyond the confines of the
prostate gland. Including:
• Invading fat
• Involving loose connective tissue beyond the plane of the
prostate (does not need to be directly touching adipocytes)
• Involving perineural spaces in the neurovascular bundles
• In the apex and base, EPE is determined when the tumor
extends beyond the confines of the normal glandular
prostate (can be hard to clearly define)
Invasion of the urinary bladder neck: neoplastic glands involve the thick intersecting smooth muscle
bundles characteristic of the bladder neck region in the absence of associated benign prostate tissue.
Seminal vesicle involvement: invasion of the muscular wall of seminal vesicle (must be Extraprostatic)

Genetics
Recurrent mutations in the ETS family of transcription factors: most commonly TMPRSS2-ERG fusion
Other frequent mutations: TP53, PTEN
Prostate cancer is one of the most heritable cancer types, driven by numerous common mutations
(and some rare germline mutations). This risk is mostly associated with many SNPs with each having
relatively low risk/penetrance (but the effect can be multiplicative).
BRACA2→ significantly increased risk of prostate cancer
 Treatment effect
Can show minimal or extensive changes in both benign and
malignant glands. Use stains liberally.
Do not grade if significant treatment effect (behave better
than grade would suggest). Benign Gland with
Radiation atypia
Radiation therapy:
Benign glands: atrophic, basal cell immunophenotype, may
show marked radiation atypia.
Adenocarcinoma: often inconspicuous with vacuolated
cytoplasm and inconspicuous nuclei/nucleoli

Hormonal therapy:
Tumor with
Benign glands: diffuse atrophy with prominent basal cells
Treatment
Adenocarcinoma: atrophic with vacuolated cytoplasm and
effect
small inconspicuous nuclei/nucleoli

Active Surveillance
Management strategy where patients diagnosed with prostate cancer undergo regular follow-up with
serum PSA tests and repeat biopsies (looking for progression), rather than receiving immediate
definitive treatment with curative intent. Focus on low and very low risk patients

NCCN Inclusion Criteria:

Absolute (Low risk):
• Gleason Score ≤6
• PSA <10 ng/mL
• Clinical stage <T2a (Tumor involves one-half of one lobe or less)
Especially if (Very low risk):
• Fewer than 3 prostate biopsy cores positive, all ≤50%
• PSA density <0.15 ng/mL/g
PNI allowed

NCCN Progression Criteria: (initiates transition to curative therapy)

• Gleason grade 4 or 5 on repeat biopsy
• Prostate cancer found in a greater number of biopsies or greater extent of biopsies

Excluded if: any variant other than acinar adenocarcinoma (e.g., ductal, sarcomatoid, small cell),
intraductal carcinoma

Active Surveillance Protocol: Serum PSA monitoring, Digital rectal exam, repeat prostate biopsies (6-12
months after initial) yearly for up to 10 years.
 Intraductal Tumors Non-invasive tumors growing within ducts

High-grade Prostatic Intraepithelial Neoplasia (“HGPIN”)

Pre-invasive neoplastic proliferation.
Often multifocal.
Cytologic changes resembling cancer:
• Nuclear enlargement
• Prominent nucleoli
• Hyperchromasia
• Clumped chromatin

Although non-invasive, basal cells may

be patchy (so be careful interpreting
IHC!)
Four main architectures: tufting,
micropapillary, cribriform, and flat
Often cytoplasmic AMACR staining
Clinical importance: associated with subsequent detection of cancer (more HGHPIN→ higher risk)

Intraductal Carcinoma
Diagnostic requirement:
Malignant epithelial cells filling large acini and
prostatic ducts, with preservation of basal cells
with either:
- Solid or dense cribriform pattern, or
- A loose cribriform or micropapillary pattern
with either:
- Marked nuclear atypia (nuclei 6x
normal or larger)
- Comedonecrosis Comedonecrosis
Can be seen in two scenarios:
1) Intraductal spread of a high-grade invasive
cancer (majority of cases)
2) Distinct precursor lesion (separate from
HGPIN) with high risk of progression to cancer

IHC often required for diagnosis to demonstrate

basal cells. Can show loss of PTEN (rarely seen in
HGPIN)

If seen on biopsy→ often treat with radical prostatectomy as highly associated with cancer and multiple
adverse factors (high Gleason grade, high tumor volume, etc..). Sometimes repeat biopsy immediately.
If a lumen-spanning atypical lesion morphologically falls short of Intraductal Carcinoma, best to call
“Atypical Intraductal Proliferation” and recommend immediate repeat biopsy.
 Other Tumors
Ductal Adenocarcinoma
Subtype of prostatic adenocarcinoma with
tall, columnar, pseudostratified epithelium
Cytoplasm is usually amphophilic.
Often elongate nuclei with more cytologic
atypia that acinar type.
Prominent nucleoli, coarse chromatin, and
lots of mitotic figures.
Frequent necrosis.
Combination of papillary and cribriform
architecture in dilated glands
Old name: “endometrioid” (looks like
endometrioid adenocarcinoma of uterus)
Typically periurethral location
Similar IHC to acinar type: no basal cells,
AMACR positive.
More aggressive than average acinar
adenocarcinoma.
Grade as pattern 4, but if necrosis as 5

Basal Cell Carcinoma

Malignant neoplasm composed of basal cells

Most cases show various proportions of:

• adenoid cystic/cribriform pattern with
inspissated secretions, and a
• basaloid pattern with small solid nests of
basal cells

Desmoplastic stroma. Can have hyaline rim.

IHC: basal cell markers usually label

outermost layers (sparing luminal cells),
while luminal cells stain with CK7.
HER2/neu overexpressed.
Some cases with Adenoid cystic morphology
have MYB-rearrangements (like elsewhere)
Normal PSA

Can be aggressive.
 Urothelial Carcinoma
Most often secondarily involving the prostate
from the bladder and/or prostatic urethra.
Note: Determining which site the urothelial
carcinoma is coming from is very important for
staging!! Bladder→ Prostate stroma =T4, while
Prostatic urethra→ Prostate stroma = T2

Morphology similar to urothelial carcinoma of

bladder (often pleomorphic epithelioid cells
with frequent squamous differentiation).

Frequent spread of CIS or pagetoid spread into

ducts. Invasion elicits desmoplastic stroma.

IHC: p63, HMWCK, GATA-3 (+), NKX3.1 & PSA (-)

Pagetoid Spread of CIS

Squamous Neoplasms
Very Rare. Arise through either divergent differentiation of basal cells or transdifferentiation of usual
adenocarcinoma following hormone therapy.
Squamous Cell Carcinoma: Pure squamous morphology. Similar morphology/IHC to SCC elsewhere. Must
be distinguished from secondary involvement of a bladder/urethral SCC or TCC.
Adenosquamous Carcinoma: Both glandular (acinar) and squamous morphology.

Neuroendocrine Tumors
Adenocarcinoma with neuroendocrine cells
Neuroendocrine cells can be seen on IHC in
many usual prostate cancers, does not seem
to be clinically significant, so no need to stain
routinely
Some cases show “Paneth cell-like
neuroendocrine differentiation” with
eosinophilic granules. Can see similar changes
in benign glands.

Well-differentiated Neuroendocrine Tumor

Very rare. Must exclude adenocarcinoma with
neuroendocrine differentiation (with more
typical areas).

Small Cell Neuroendocrine Carcinoma. Morphologically identical to in the lung (small cells with scan
cytoplasm and stippled, hyperchromatic nuclei). May be admixed with acinar adenocarcinoma or
pure. Do not Gleason grade. Stains with at least 1 neuroendocrine marker usually. May be TTF-1
positive. Ki67 near 100%. Very aggressive.
 Mesenchymal Tumors
Stromal Tumor of Uncertain Malignant Potential (“STUMP”)
Tumor of specialized prostatic stroma.
Often present with urinary symptoms.
Several growth patterns:
• Hypercellular stroma with scattered degenerative-
appearing cells admixed with benign glands.
• Phyllodes subtype with leaf-like branching
• Also: myxoid, epithelioid, hypercellular bland stroma
IHC: Express CD34 and PR
Usually good prognosis. My recur or progress

Stromal Sarcoma
Malignant tumor of specialized prostatic stroma.
Phyllodes-like growth pattern with malignant,
pleomorphic stroma or fascicular growth similar to a
leiomyosarcoma
IHC: Express CD34 and PR
Can behave aggressively.

Other Tumors Synovial Sarcoma

Leiomyoma Inflammatory Myofibroblastic Tumor (IMT)
Leiomyosarcoma Solitary Fibrous tumor (SFT)
Rhabdomyosarcoma Hemangioma
Angiosarcoma Granular cell tumor

Immunohistochemistry of Mesenchymal Lesions:

STUMP Stromal Sarcoma Leiomyosarcoma Rhabdomyosarcoma IMT SFT GIST

CD34 + + - - - + +
SMA +/- - + + + - -
Desmin +/- - + + -/+ - -
Myogenin - - - + - - -
CD117 - - - - -/+ - +
ALK1 - - - - +/- - -
PR + + +/- - - +/- -
Modified from: Epstein and Netto. Biopsy Interpretation of the Prostate. 5th Edition
 Seminal Vesicle
Normal Anatomy
Complex papillary folds lined with pseudostratified tall
columnar epithelium with microvesicular lipid-filled
cytoplasm and prominent lipofuscin pigment (golden-
brown and refractile granules, which help distinguish it
from prostate).
Moderate to severe cytologic atypia with large irregular
hyperchromatic nuclei with coarse chromatin and
prominent nucleoli. Likely degenerative.
Stains with GATA-3

Amyloidosis
Linear or massive nodular subepithelial deposits of
amorphous eosinophilic fibrillar material.
Relatively common benign incidental finding. Not
associated with systemic amyloidosis.
Highlighted with Congo Red with “Apple-green”
birefringence

Adenocarcinoma
Always first consider secondary involvement, most
commonly by prostatic acinar adenocarcinoma.
Primary adenocarcinoma is RARE. It has a variety of
patterns. Most often a papillary clear cell tumor,
but can be hobnail, etc..
IHC: CK7(+), CK20(+/-), Prostate maker (-).
Often poor prognosis.

Mixed Epithelial and Stromal Tumors (“MEST”)

Biphasic tumors with stromal and benign
epithelial components. Cystic to solid masses.
Cystadenoma→ Lobular pattern. Branching
lumens and cysts of various sizes.
Fibroadenoma→ Spindle cell component is more
pronounced.
Adenosarcoma→ Stroma is densely cellular and
condenses around distorted gland spaces (like
Phyllodes tumors or adenosarcoma of uterus)
 Mimics of Cancer
Basal Cell Hyperplasia
Proliferation of basal cells piling up and filling
tubules/glands→ may form solid nests
Appear very blue due to crowded nuclei with scant
cytoplasm.
Retains lobular architecture and smooth borders.
Nuclei are very bland with very small nucleoli
Basal cell markers very strongly positive.

Central Zone Sampling

Anatomic zone with characteristic complex architecture.
Stratified eosinophilic cytoplasm and prominent basal
cell layer.
Intra-luminal bridges ("Roman arches")
Can mimic HG-PIN, so in biopsies from the mid-base,
have higher threshold for HGPIN & r/o normal anatomy!

Verumontanum mucosal gland hyperplasia

Crowded glands near verumontanum. Often nearby
urothelium. Corpora amylacea often present

Adenosis
(aka Atypical Adenomatous Hyperplasia)
Well-circumscribed tightly packed, largely
uniform glands. Lobular architecture. Pale to
clear cytoplasm. Admixture of small and larger
glands.
Occurs in the transition zone (mostly seen in
TURPs and Prostatectomies)
Some features suggestive of carcinoma may be
seen such as prominent nucleoli and
crystalloids/mucin, but often merge with
benign glands.
Principal differential diagnosis is Gleason grade
2 carcinoma. This distinction requires IHC for
basal cells:
• Basal cells may be decreased in Adenosis
• Demonstration of any basal cells indicates
adenosis in this context
• Carcinoma must lack basal cells completely
 Atrophy
“Simple” Atrophy
Basophilic glands with scant cytoplasm (both
apically and laterally).
Normal caliber glands with normal spacing.

Postatrophic Hyperplasia (“PAH”)

Tightly packed very small cytologically bland
glands. Very blue at low-power.
Usually clustered around a larger dilated “feeder”
duct (Think: TDLU of breast)
Bland nuclei without prominent nucleoli
Basal cells present
Stroma often sclerotic

Partial Atrophy
Retain moderately abundant pale/clear cytoplasm
lateral to the nuclei (with reduced apical
cytoplasm), which may produce pale glands that
lack the blue appearance of atrophy.
Frequently merges with nearby atrophy.
Bland nucleoli without prominent nucleoli.
No infiltrative growth.
Undulating luminal surfaces.
Retained (but possibly decreased) basal cell
markers.

Cowper’s Glands
Periurethral, near apex
Lobular architecture with central duct
Abundant mucin-filled cytoplasm (PASd+)
No nuclear atypia or prominent nucleoli.
Basal cells markers positive, frequently muscle-
specific actin positive (unlike in prostate)
IHC: PSAP negative (PSA may be positive)
 Clear Cell Hyperplasia
Big nodules of clear cells with cribriform pattern.
Smooth gland borders and lobular pattern.
Uniform bland nuclei without prominent nucleoli
Intact basal cell markers.
Most often seen in central zone on TURP in setting
of BPH.

Sclerosing Adenosis
Dense spindled stroma with compressed and
distorted epithelial elements
Entrapped epithelium ranges from small acini to
cords and single cells. No cytologic atypia.
Can have surrounding hyaline sheath
Basal cells present with unique immunologic profile
Usual markers positive (p63, HMWCK)
Also express myoepithelial markers (smooth muscle
actin, S100)

Other Mimics
Nephrogenic adenoma
Malakoplakia
Seminal Vesicle
Mesonephric hyperplasia
Colonic mucosa
Urothelial metaplasia
Granulomatous prostatitis
Signet-ring lymphocytes
Paraganglia