Madeleine Moussa

Madeleine Moussa, MD FRCPC
Conflict of Interest Disclosures
Madeleine Moussa

I have no financial interest, arrangement or affiliation
with one or more organizations that could be perceived
as a direct or indirect conflict of interest in the content of
this presentation.
Objectives: to recognize “Benign Mimickers of Prostate Cancer”
in prostate needle core biopsy:
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Seminal vesicles
Cowper’s glands
Verumontanum mucosal hyperplasia
Central zone glands
Paraganglion
Adenosis
Atrophy
Basal cell hyperplasia
Post radiation atypia
Reactive glands
Clear cell hyperplasia
Sclerosing adenosis
Non-specific granulomatous prostatitis
Xanthoma
Malakoplakia
High grade PIN
Most common benign mimickers on needle biopsy tissue:
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Atrophy (10%) / partial (36%)
Atypical adenomatous hyperplasia (AAH) (4%)
Radiation atypia (6%)
Inflammatory atypia (5%)
Basal cell hyperplasia (3%)
High grade PIN (5%)
Seminal vesicles/ ejaculatory ducts
Cowper’s gland
Nephrogenic adenoma
Pattern Based Approach:
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Recognize benign entities that mimics:
 Small gland pattern
○ Gleason score 4-6 carcinoma
 Large gland/ cribriform pattern
○ Gleason 7-8 carcinoma
 Fused gland / solid pattern
○ Gleason score 8-10 carcinoma
Small Gland Pattern
* Normal anatomic structures
 Seminal vesicle/ejaculatory ducts
 Cowper’s gland
 Verumontanum mucosal gland hyperplasia
* Benign process:
 AAH / Adenosis
 Atrophy
 Basal cell hyperplasia
 Post radiation atypia
 Nephrogenic adenoma
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Prostate biopsy?
Pca Gleason 2+2 = 4/10
 AAH ( adenosis)
 ASAP
 Seminal vesicles
 Atrophy
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Seminal Vesicles/Ejaculatory Duct:
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4-5% in needle core biopsies /
3% TURP
• Architecture
• Central lumen with surrounding clusters of
smaller glands ( adenotic SV)
• Convoluted glands, cuboidal/columnar cells
• Papillary folds
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Cytology
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Golden-brown lipofuscin pigment
Monster nuclei (atypia) smudge cells
Nuclear pseudo-inclusions
No mitosis
Immunohistochemistry
• PSA (-), PAP (-)
• (+) CK34BE12 basal cells in SV
Lipofuscin pigment may be
seen with cancer (rare)/PIN
Pigment in HGPIN:
Cowper’s Gland
(Bulbourethral glands)- rare in Bx:
* Periurethral glands located below the
prostatic apex in urogenital diaphragm
* Architecture:
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Lobular pattern ( small, compact tubuloalveolar glands)
Dimorphic appearance: central duct with surrounding
round acini
Intermixed with skeletal muscle
* Cytology:
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Small hyperchromatic nuclei pushed to periphery by
abundant, mucinous cytoplasm with narrowing of
lumen, no cellular atypia
* Immunohistochemistry/Stains:
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PAS-D, Mucicarmine (+)
PSA variable, PAP (-)
** DDX: Foamy gland PCa
Foamy gland Pca:
Architecture:
Crowded and/or infiltrative glands
with foamy cytoplasm, low N:C
ratio, pink acellular secretions
Cytology:
Can look bland, often lack
prominent nucleoli
Nuclei look round rather than oval
as in benign glands
Empty vacuoles in cytoplasm
Immunohistochemistry:
Basal markers - (most helpful)
AMACR + (68-70%)
Verumontanum Mucosal Gland Hyperplasia (Rare in Bx)
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Situated beneath the posterior urethral mucosa (point at which the
utricle and ejaculatory ducts merge with the prostatic urethra)
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Architecture and Cytology:
 Packed small acini with orange-brown (rust colored) dense
luminal corpora amylacea
 Adjacent to urothelium
 Basal layer present Basal cell markers (+)
 Lack prominent nucleoli
Adenosis (Atypical Adenomatous Hyperplasia)
(AAH):
Proliferative lesion (represents extreme end
of BPH)
 Frequent in transition zone
 Not common needle biopsies (1%) /
TURP (2-20%)
 Overall significance remains uncertain
Architecture & Cytology:
 Lobular pattern, small crowded glands
admixed with large glands,
 basal cells usually present at least focally
/ AMACR (+)
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Minimally infiltrating growth: 13%
Crystalloids: 24%
 Prominent nucleoli: 13% (No macronucleoli)
 Mitosis: 3%
 Intraluminal wispy blue mucin: 3%
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DDX of AAH:
Pca Gleason grade ( 2 or 3)
 Pseudohyperplastic Pca
 Benign hyperplasia
 Sclerosing adenosis
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AAH vs Pca Gleason score
(2+2)=4/10
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Diagnosis not made ever on needle biopsy
*Favor Pca:
* Nuclear atypia
* Large nucleoli, variable nuclear size
* Diffuse basal cell absence
Favor AAH:
*Continuity with complex glands with
hyperplastic architecture
Basal cell marker +
Sclerosing Adenosis:
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Architecture:
Nodular compact arrangement of small acini
with spindle cell (myoepithelial) component
 Infiltrative pattern but overall
circumscribed
 Hyaline sheath structure around some
glands
 Cytology:
 uncommon to have atypical features:
prominent nucleoli, mitoses, crystalloids
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Immunohistochemistry:
 Basal markers + (most glands,
SMA
as well as single cells and cords)
 Myoepithelial differentiation
(muscle specific actin+, S100+)
S100
Atrophy:
Common
 Variants:
• Simple atrophy with or without cystic
change
• Sclerotic atrophy
• Post atrophic hyperplasia
* Proliferative inflammatory atrophy
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Am J Surg Pathol 30:1281-1291, 2006
Atrophy:
Simple Atrophy:
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Architecture:
 At least partially lobular pattern
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Cytology:
 Uniform, small, shrunken, dark blue cells,
scant cytoplasm, may have mild to
moderate nucleolar enlargement but not
prominent
Immunohistochemistry:
*Basal cells markers (+) but often
patchy or even absent in some
glands,
*May express AMACR
Post-Atrophic Hyperplasia:
•Architecture:
• Combination of atrophic glands and hyperplastic glands
• At least partially lobular pattern
•Cytology:
• Within a gland, there can be a mixture of atrophic and non
atrophic cytoplasm (leads to irregular gland shapes e.g. stellate)
• May have clear or amphophilic cytoplasm
• Nuclear enlargement may be present
 May have mild to moderate nucleolar enlargement but not
prominent
Uncommon ( 2-3%)
DDX: Atrophic Prostate adenocarcinoma
Rare / unless history of hormone therapy
 Architecture: infiltrative
 More atypia: prominent nucleoli/ more cytoplasm than
in benign atrophic glands
 Immunohistochemistry:
- Basal cell markers (-)
- AMACR (+) – lower sensitivity
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Pca
Basal Cell Hyperplasia:
Often seen with atrophy, BPH, post hormonal therapy
 (Needle bx: 10%)
 Fetalization of prostate
 Architecture:
 Nodular expansion of uniform round glands with stratified nuclei
(other patterns: solid, cribriform, acinar)
 Dark blue, ovoid to coffee bean nuclei with vesicular chromatin,
scant cytoplasm , sometimes prominent nucleoli (atypical 2%)
 Lined by 2 or more layers of basal cells (p63, HMWCK (+)
 May have intraluminal calcifications
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DDX: adenoid basal cell tumor
Radiation Therapy Effects:
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External beam radiation
Brachytherapy (radioactive seed implantation)
Architecture:
 Lobular pattern or random individual glands with
irregular angulated contours within abundant stroma
Cytology:
 Marked degenerative nuclear atypia (smudgy),
cytoplasmic vacuolization, prominent nucleoli
common
Basal cell markers +
Therapy Related Changes:
 LHRH analogs and anti-androgens:
○ Benign glands:
 Glandular atrophy
 Stromal predominance
 Diffuse basal cell hyperplasia
 Squamous and transitional cell metaplasia
Case?
AMACR / CK7 / PSA
AMACR
CK7
PSA
Nephrogenic adenoma (metaplasia):
Tubules, cords and signet ring like tubules
 Prominent nucleoli
 Blue-tinged mucinous secretion (32%)
 Focal (PSA 36%) and (PAP 50%) (-/+)
 Negative HMW CK34BE12 (-/+)
 Positive AMACR (35-58%)
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ASAP?
Histological Features Resulting in ASAP:
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Limited number of glands
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Crowded glands with no or minimal cytological atypia
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Adjacent to HGPIN (outpouching / tangential HGPIN)
Inflamed glands
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Artifact:
 Crush artifact obscuring histology
 Atypical glands at the tip or edge of biopsy core
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Immunohistochemistry??
Large Gland/ Cribriform Pattern
Large Gland/Cribiform Pattern
DDX: Pca Gleason grade 4/ intraductal ca
 Normal anatomic structures
 Central zone glands
 Benign process:
 Reactive glands/ inflammation
 Clear cell cribriform hyperplasia
** HGPIN
Central Zone Glands (rare in Bx)
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Often mistaken for HGPIN, Cribriform Carcinoma
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Architecture:
 Complex architecture with roman bridges
 cribriform pattern
 Prominent basal layer
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Cytology:
 May have cytologic atypia
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Immunohistochemistry:
 Basal markers (+)
Reactive Glands:
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Architecture:
 Associated with inflammatory infiltrate
 Basal layer present
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Cytology:
 Basophilic nuclei, occasional prominent
nucleoli
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Immunohistochemistry:
 Basal markers (+)
Clear Cell Cribriform Hyperplasia
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Form of BPH, mistaken for HGPIN, cribriform carcinoma
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Architecture:
 Crowded cribriform glands with clear cytoplasm
 Some glands have a basal cell layer
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Cytology:
 No cytological atypia
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Immunohistochemistry:
 Basal cell marker (patchy), same as HGPIN
Clear cell cribriform hyperplasia more common in TZ,
PIN more common in peripheral zone
Cribriform pattern: Differential Diagnosis:
*Clear cell cribriform hyperplasia
* Pseudohyperplastic PCa
*Cribriform HGPIN
*Cribriform Carcinoma / IDCa / Ductal Ca
Pseudohyperplastic Pca:
Architecture:
Closely packed large glands with
branching and papillary enfolding
Cytology:
Typical features of malignant glands
(especially prominent nucleoli)
Immunohistochemistry:
Basal cell markers (–)
AMACR + (lower sensitivity)
Complex cribriform?
INTRADUCTAL CA / HIGH GRADE PIN
IDC-P
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Contour or branching
architecture of prostate duct
Micropapillary tuft lacking
fibrovascular cores
Rounded, circumscribed
borders
Markedly enlarged nuclei (X6)
marked nuclear pleomorphism
Mitotic figures
Frequent comedonecrosis
DDX: Gleason grade 5 Pca
Basal cells present ( +)
Modern Pathology 2006 (19) 1528-1535
HG-PIN
Lack solid or dense
cribriform patterns
 Enlarged nuclei ( X3)
 More uniform atypia
 Rare mitosis
 Rare focal necrosis
 Basal cells present (+)
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High grade PIN:
Intraducal carcinoma:
Ductal Pca:
Case?
Fused Gland/Solid Pattern
(Pca grade 4/5/ Pca with post therapy effects):
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Normal anatomic structures
 Paraganglion
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Benign process:
 Sclerosing adenosis
 Non-specific granulomatous prostatitis
 Xanthoma
 Malakoplakia
Paraganglion
Chromogranin
Case?
PSA
Non-Specific Granulomatous Prostatitis:
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Simulates cancer clinically and microscopically
 Elevated PSA
 Prostate firm or hard on DRE
Architecture:
 Mixed inflammatory infiltrate containing:
histiocytes, lymphocytes, neutrophils,
eosinophils, plasma cells, giant cells
 PSA-, PAP-, CK-, CD68+
Malakoplakia (rare)
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Variant of granulomatous prostatitis associated with
defective intracellular lysosomal digestion of bacteria
(usually gram negative)
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Architecture:
 Sheets of large epitheliod histiocytes, lymphocytes and
plasma cells with occasional basophilic inclusions
(Michaelis-Gutmann bodies)
(represent precipitation of calcium or iron on bacterial debris)
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Immunohistochemistry:
 CD68+, CK-, PSA-, PAP Von Kossa stain and Perl’s Prussian blue
(Michaelis-Gutmann bodies)
Xanthoma
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Architecture:
 Circumscribed solid nodular pattern, can form cords
and/or individual cells with stromal infiltration
 ( lipid-laden macrophages)
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Cytology:
 Benign nuclei, inconspicuous nucleoli, abundant
vacuolated foamy cytoplasm
 No mitoses
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Immunohistochemistry:
 CD68+, PSA, PAP, CAM5.2 (-)
 DDX: hormone therapy effect on Pca
 Foamy carcinoma ( grade 4)
Prostate Bx (post therapy Pca):
Post Hormonal Therapy Pca
Post hormone therapy PCa:
Basal marker
PSA
Summary:
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Normal anatomic structures:
 Small: seminal vesicles/ejaculatory ducts,
Cowper’s glands, verumontanum mucosal
hyperplasia
 Large: central zone glands
 Fused/Solid: paraganglion
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Pathophysiological conditions:
 Small: Adenosis, Atrophy, Basal cell Hyperplasia, Post
Radiation Atypia
 Large: Reactive glands, Clear cell hyperplasia, HGPIN
 Fused/Solid: Sclerosing adenosis, Non-Specific
Granulomatous Prostatitis, Xanthoma, Malakoplakia
Summary:
Wide range of mimickers of prostate adenocarcinoma
 Recognition of the unique histologic features to
prevent over diagnosis of prostate cancer
 In all cases, the presence of conventional
adenocarcinoma will help facilitate the diagnosis
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QUESTIONS?
THANK YOU