Prostate Cancer Diagnosis:

Pitfalls and Mimickers

George J. Netto, M.D.

Professor and Chair of Pathology
University of Alabama at Birmingham
 Disclosures

J. Epstein and G.J. Netto

Differential Diagnosis in Genitourinary System
 Overview

• Introduction
• Mimickers of PCa
• Mimickers of Low Grade Pca
• Mimickers of High Grade PCa
 Prostate Carcinoma
Implications of Accurate Diagnosis

• Prostate needle biopsy REMAINS the gold standard

Diagnosis
Management
Prognostication

• MRI Guided Biopsy

• Recognizing a “limited focus of carcinoma” on a needle biopsy prevents

from false negative reading

• Equally important is the recognition of morphologic mimickers of cancer

that lead to false positive interpretation

• Medico-legal implications of false positive diagnosis

 Morphologic Clues of PCA
Archictectural
• Crowded glands with round (annular) architecture (GG1)
• Straight inner borders
• Poorly formed glands/cribriform/solid nests/individual cells (GG2-5)
• Infiltration between benign glands (cancer mobility)
Cytological
• Nuclear enlargement/hyperchromasia
• Amphophilic cytoplasm
• Prominent nucleoli
Content
• Wispy blue mucinous/ Eosinophilic proteinaceous secretions
• Crystalloids (Cancer Crystals)
Others
• PNI
• Extravasated mucin/ Mucinous fibroplasia
• Glomeruloid structures
 Prostate Carcinoma
Potential Diagnostic Mimickers

• Very helpful to categorize mimickers of PCa into two groups,

based on the grade of PCa that they could be confused with:

Benign Mimickers of Low Grade Carcinoma

(Gleason Score 6 / Grade Group 1)

Benign Mimickers of High Grade Carcinoma

(Gleason Score 7-10 / Grade Groups 2-5)
 Mimickers of Low Grade PCa (GS6/GG1)

•Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
 Mimickers of Low Grade PCa (GS6/GG1)

• Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
Adenosis of the Prostate: Histologic Features in
Needle Biopsy Specimens
Gaudin PB, Epstein JI
Am J Surg Pathol 1995; 19:737-747.

Adenosis of the Prostate: Histologic Features in

TUR Specimens
Gaudin PB, Epstein JI
Am J Surg Pathol 1995
 Adenosis
(Atypical Adenomatous Hyperplasia)

Incidence

• TURP - 1.6%
- Multifocal – average 3 foci per specimen
- Occasionally over 5% involvement

• Needle - 0.8%
 Diagnostic Criteria of Adenosis

• Lobular/nodular architecture
• Pale-clear cytoplasm
• Small glands share cytoplasmic nuclear features with larger glands
• Medium sized nucleoli
• Blue mucinous secretions and eosinophilic crystals are rare
• Corpora amylacea common
• Basal cells present (crescents)
 Features Shared in Adenosis and Cancer

• Crowded glands
• Crystalloids
• Medium sized nucleoli
• Scattered poorly formed glands and single cells
• Minimal infiltration at periphery
 Adenosis
Needle Biopsy

• 16% with more than 1 focus

• One of the more difficult diagnoses on biopsy

• Nodular/lobular architecture may not be appreciated

• IHC: Can be AMACR positive with only patchy basal cell

staining (p63, HMWCK)
PCa Gleason Grade 6
PCa Gleason Grade 6
 Adenosis
(Atypical Adenomatous Hyperplasia)

• To avoid misinterpretation constellation of features in a given

lesion should outweigh the significance of any one diagnostic
feature

• On Needle Bx: a category of atypical glands suspicious for PCa

can not rule out adenosis is acceptable in difficult cases, with a
recommendation to repeat biopsy
 Mimickers of Low Grade PCa (GS6/GG1)

• Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
 Atrophy
Post Atrophic Hyperplasia
Partial Atrophy (PTAT)

Simple Atrophy

- Acini distributed in lobular configuration

- Typical basophilic appearance due to relative lack of cytoplasm

- Cystic dilated glands can be encountered in simple atrophy

- Should not pose diagnostic difficulties

Post atrophic hyperplasia (PAH)

- Rarely enter DDx of Pca

- Retained lobular architecture: closely packed “hyperplastic”

small acini surrounding “feeding” duct
- Associated sclerotic collagen
PCa Gleason 6/GG1

Atrophy
PCa with ATROPHIC FEATURE
PCa with ATROPHIC FEATURE
PCa with ATROPHIC FEATURE
 Partial Atrophy (PTAT)

• Feature Mimicking PCa

- Occasionally lacks lobular organization
- Pale cytoplasm
- Slight nuclear enlargement and occasional nucleoli

• IHC
PTAT can express AMACR
PTAT can be patchy or negative for p63/HMWCK

• DDX: Atrophic PCa vs PTAT

Adherence to strict criteria for diagnosing “atrophic” PCa

Oppenheimer JR, Epstein JI Am J Surg Pathol, 1998

 Mimickers of Low Grade PCa (GS6/GG1)

• Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
 Mesonephric Remnants Hyperplasia

Florid Hyperplasia of Mesonephric Remnants Involving Prostate and

Periprostatic Tissue: Possible Confusion with Adenocarcinoma
Gikas PW, Del Buono EA, Epstein JI. Am J Surg Pathol 1993; 17:454-460

Mesonephric remnant hyperplasia involving prostate and periprostatic tissue:

findings at radical prostatectomy.
Chen YB, Fine SW, Epstein JI. Am J Surg Pathol. 2011 Jul;35(7):1054-61
 IHC

PAX 8 Positive
PSA Negative

HMWCK?
AMACAR?
P63?
 Mimickers of Low Grade PCa (GS6/GG1)

• Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
 Radiation Change in the Prostate

• RT effect on Benign Prostate

DDX: Prostate Cancer

• RT results – effect on PCa Prognosis

• Bx Negative for cancer
• Bx Positive for cancer (with treatment affect)
• Bx Positive for cancer (w/o treatment affect)
Post-radiotherapy Prostate Biopsies: What Do They Really Mean?
Results for 498 Patients

Crook J, Malone S, Perry G, et al.

Int J Rad Onc Biology Physics 2000;48:355-67
 Radiation Biopsy Results: Positive

• Histologically, ordinary prostate cancer is seen, which

resembles non-radiated cancer
(assign Gleason Grade)

• Do not grade radiated cancer with treatment effect

• If biopsy performed too soon (<12 months), can not tell if the
cancer is resistant or has not had enough time to be
destroyed by the treatment
Atypia in Non-neoplastic Prostate Glands after Radiotherapy for
Prostate Cancer: Duration of Atypia and Relation to Type of
Radiotherapy

Magi-Galluzi C, Sanderson H, Epstein JI

Am J Surg Pathol 2003; 27: 206-12
 Atypia in Non-neoplastic Prostate Glands after
Radiotherapy

• More atypia in cases treated with IRT (seeds) than XRT

• RT atypia may persist for a long time: Prominent RT atypia detected 72
months after IRT
• No change in epithelial atypia over time in men treated with IRT

• XRT, less epithelial atypia in cases biopsies >48 months after treatment

• Some cases clinicians not aware of remote h/o of RT or do not relay to

pathologists.
Pathologists must be able to recognize RT atypia w/o relying on the
clinician to provide this history
 Mimickers of Low Grade PCa (GS6/GG1)

• Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic
mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
FOAMY GLAND PCa
FOAMY GLAND PCa
FOAMY GLAND PCa
 Mimickers of Low Grade PCa (GS6/GG1)

• Adenosis
• Atrophy/Partial Atrophy
• Mesonephric hyperplasia
• Nephrogenic adenoma
• Radiation atypia
• Verumontanum hyperplasia
• Normal Structures: Cowper’s glands, SVED, Colonic mucosa
• Basal cell hyperplasia with nuclear atypia (also mimics PIN)
Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
Central Zone Histology
High Grade PIN
High Grade PIN
Clear Cribriform Hyperplasia
Cribriform Acinar Adenocarcinoma
Cribriform Acinar Adenocarcinoma
Cribriform Acinar Adenocarcinoma
Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
GS:4+4=8
Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
Sclerosing Adenosis of the Prostate: Histologic Features in Needle Biopsy
Specimens
Luque RJ, Lopez-Beltran A, Perez-Seone C, Suzigan S
Arch Pathol Lab Med 2003; 127: e14-6.

Sclerosing Adenosis of the Prostate Gland: A Lesion Showing

Myoepithelial Differentiation
Grignon DJ, Ro JY, Srigley JR, Troncoso P, Raymond AK, Ayala AG
Am J Surg Pathol 1992; 16: 383-91

Sclerosing Adenosis of the Prostate Gland: A Clinicopathologic and

Immunohistochemical
Study of 11 Cases
Jones EC, Clement PB, Young RH
Am J Surg Pathol 1991; 15: 1171-80
 Key Features
Sclerosing Adenosis
• Rare lesion, more likely to be encountered in TURP

• Glands and individual epithelial cell: AE1/AE3 (+) and PSA (+)
• Basal cells in the glands positive for HMWCK (CK903)
• Dense spindle cell component and basally located cells with
true myo-epithelial differentiation (coexpression of
cytokeratin, Actin/S100)
 Sclerosing Adenosis
Pitfalls

• Infiltrative perimeter
• Crowded glands
• Individual cells
• Prominent nucleoli
• Mitoses
• Crystalloids
 Clues to DDx From PCa

• Usually limited extent as opposed to most high grade PCa

• Dense spindle cell component
• Hyaline collarettes
• Basal and spindle cells with myoepithelial differentiation is
not seen in PCa
CK903
S100
 Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
Prostatic Xanthoma: A Mimic of Prostatic Adenocarcinoma
Sebo TJ, Bostwick DG, Farrow GM, Eble JN. Hum Pathol 1994

• 7 cases
• Not associated with hyperlipidemia
 Key Features
Xanthoma

• Rare
• Usually encountered in needle biopsies as a single small focus
• Circumscribed cluster of uniform foamy cells
• Bland nuclei and inconspicuous nucleoli
• Occasional infiltrative pattern
• IHC: CD 68 (+) AE1/AE3 (-) PSA (-)
CD68
PCa Gleason Grade 9
PCa Gleason Grade 9
PSA
PIN4
PCa Gleason Grade 7
PCa Gleason Grade 9
PCa Gleason Grade 8
 Mimickers of High Grade PCa (GS 7-10/GG2-5)

•Clear cell cribriform hyperplasia

•Basal cell hyperplasia
•Nonspecific granulomatous prostatitis (NSGP)
•Sclerosing adenosis
•Xanthoma
•Paraganglia
 Key Features
Paraganglia

• Usually in extraprostatic soft tissue

• DDx of small focus of high grade Pca that is entirely extraprostatic

• Cluster of cells with clear to amphophilic cytoplasm & vascular

network
• “Degenerative” nuclear atypia/Nucleoli
• Neuroendocrine nature and sustentacular cells on IHC
Paraganglia of Prostate: Location, Frequency, and
Differentiation from Prostatic Adenocarcinoma

Ostrowski ML, Wheeler TM

Am J Surg Pathol 1994; 18:412-20
 Intraductal Carcinoma (IDC-P)

VS

Prostatic Intraepithelial Neoplasia (HGPIN)

 IDC-P
Historic Perspective

• Kovi J et al. ; Cancer 1985

“ductal permeation by carcinoma the basement membrane remained intact “

• McNeal JE and Yemoto CE; AJSP 1996

“complete spanning of ductal/acinar lumen by several trabeculae of malignant epithelial cells”
 Prostatic Intraepithelial Neoplasia (HGPIN)

• Architecturally benign glands with malignant appearing cells containing

prominent nucleoli.

• No uniform definition as to how prominent nucleoli or how many nucleoli per

gland

• Architecturally most common is tufting and then micropapillary with flat and
cribriform least common.
• No need to comment on pattern as no difference in risk of subsequent
cancer, except maybe for cribriform.
Tufted HGPIN
 Modern Pathology 2006

27 cases of isolated IDC-P in Needle Bx

IDC-P Definition
• Malignant epithelial cells filling large acini and ducts
• Preservation of basal cells: H&E or IHC

• solid or dense cribriform patterns

• loose cribriform or micropapillary patterns
+
marked nuclear atypia (≥ 6 x normal) or comedonecrosis

Outcome
• 6 RP
• Gleason score 8 or 9 with 5 cases with prominent IDC-P
• Non-focal EPE in 5/6 and LVI in 2/6
• 3/16 pts without RP developed bone metastases
 Prostatic Intraductal Carcinoma (IDC-P)

• Distinctive morphology from HGPIN

• Associated with high grade invasive cancer and poor pathology at RP &
relatively poor prognosis with other therapies

• An advanced stage of tumor progression with intraductal spread of

tumor (mostly)

• Justified to treat patients with intraductal carcinoma on biopsy even in

the absence of documented infiltrating cancer
 IDC-P
Intraductal Spread
 HGPIN
IDC-P
IDC-P
HGPIN
Am J Surg Pathol 2016;40:e67–e82
 Summary
Prostate biopsies are some of the most difficult
specimens to evaluate, in part due to the wide
range of mimickers of both low and high grade
adenocarcinoma PCa

Recognition of these mimickers’ unique histologic

features can prevent over-diagnosis of PCa
Thank You !