New Frontiers in Pathology GU case presentation

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New Frontiers in PathologyGU case presentation

• Rajal B. Shah, M.D.
• Associate Professor - Pathology and Urology

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Case 13

• A 65 year-old white American male with serum PSA
  of 4 ng/ml, underwent extended 12 core biopsies

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34ßE12 p63
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P504S
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P504S
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Summary of atypical findings

• Disorganized growth pattern
• Presence of some round and poorly formed small
  glands
• Micro nucleoli
• Lack of basal cell staining in some glands
• AMACR reactivity

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Diagnosis

• Benign prostate parenchyma with focus of partial
  atrophy

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Diagnosis of Limited Cancer in Prostate Biopsy
Critical Issues

• Recognize cancer and avoid under-diagnosis (false
  negative)
• Recognize benign mimics and avoid over-diagnosis
  (false positive)

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Mimics of Prostate Cancer
Pattern 1 Small glandular growth pattern
Pattern 2 Cribriform/large growth pattern
Pattern 3 Fused gland/solid growth pattern
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Pattern 1-Small gland mimics

• Seminal vesicle/ejaculatory duct epithelium
• Cowpers glands
• Verumontenum hyperplasia
• Crowding of small glands
• Mucinous metaplasia
• Mesonephric gland hyperplasia

• Post atrophic hyperplasia/atrophy
• Partial atrophy
• Adenosis
• Radiation atypia
• Nephrogenic adenoma
• Basal cell hyperplasia

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PA Among the most common reasons for second
opinion
Herawi M et al, AJSP, 2005
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Partial atrophy (PA) - Background

• Experts have utiized various terms to describe
  partial atrophy
• Some have used the term post atrophic hyperplasia
  (PAH) to describe similar lesions
• (Amin MB et al, 1999, Srigley JR et al, 2004)
• Recently PA and PAH recognized as a distinct
  types of focal atrophy in the Working Group
  Classification of Focal Prostate Atrophy Lesions
  (De Marzo et al, 2006)

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Partial atrophy - Significance

• Potential for confusion with prostatic
  adenocarcinoma (PCa)
• Among the most common reasons for second opinion
  in a consultation practice (Herawi et al, 2005)
• Potential immunohistochemical (basal cell markers
  and P504S (monoclonal antibody to AMACR)) overlap
  with PCa
• Association with inflammation and proliferation
  found in certain forms of atrophy such as post
  atrophic hyperplasia (Ruska et al, 1998 De Marzo
  et al, 1999 Shah R et al, 2001)

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AJSP, 32(1), 2008

• Architectural indices
• Gland size
• Gland shape
• Circumscription
• Stromal characteristics
• Associated completely atrophic glands within the
  focus
• Luminal secretions
• Inflammation

• Cytological indices
• Character of cytoplasm
• Nuclear size in relation to benign glands
• Micronucleoli (visible only at 40x) and
  macronucleoli (visible easily at 10X)

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AJSP, 32(1), 2008

• Basal cell marker cocktail(34ßE12 p63)
• Completely positive
• Patchy positive
• Completely negative
• P504S - Rabbit monoclonal antibody to AMACR (Zeta
  corporation, Sierra Madre, CA )
• Negative
• Weak
• Moderate-to-strong
• (Expression evaluated in relation to benign
  glands)

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Study design - Proliferation status

• Ki-67 (MIB-1 clone) immunohistochemistry
• Quantitative analysis by ChromaVision ACIS
• Measurement of stain intensity of
• PA foci compared with benign glands (range
  0-225, 0-100)
• Manual delineation of foci

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Results - Morphology (architectural features)
N73 foci
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Circumscribed focus with stellate star shaped
glands
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Disorganized poorly formed round glands
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Results - Morphology (architectural features)
FEATURES
CASES
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Complete dark atrophic glands within the focus
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Results - Morphology (cytologic features)
FEATURES
CASES
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Micro nucleoli visible at high power
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• Other benign conditions known to contain
  nucleoli
• gt Basal cell hyperplasia
• gt Post atrophic hyperplasia
• gt Adenosis
• gt Radiation atypia
• gt Benign glands associated with
  inflammation

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Clear cytoplasm similar to adjacent benign
glands, placed laterally to Nuclei giving them
partially atrophic look
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Results IHC Basal cell markers cocktail 34ßE12
p63
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Other lesions with patchy/negative basal cell
reactions

• PIN
• Adenosis
• Lack of basal cell staining in few atypical
  glands is not necessarily diagnostic of cancer

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Results IHC P504S
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Comparison with published literature

• AMACR results
• 79 (15/19 cases) (Herawi et al, 2005)
• Series consisting of selected consultation cases
  with AMACR staining performed at multiple
  institutions
• 31 (38/122 foci) (Adley et al, 2006)
• Hospital based series, AMACR staining using the
  triple antibody (P504S CK 903 p63)

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AMACR-specificity issues
PIN Prostatic intraepithelial neoplasia, NA
Nephrogenic adenoma NS Not studied
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Results - Basal cell markers and P504S antibody
as a panel
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Results - Proliferation status

• N54 foci
• Mean proliferative indices
• PA foci5.5 (range 0-30)
• Benign glands5.6 (range 0-31)
• P0.97 (paired t-test)

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Summary - Features that potentially mimic
prostate cancer

• Morphology
• Disorganized growth pattern
• Small, round, poorly-formed glands
• Visible nucleoli
• Immunohistochemistry
• Very patchy/negative staining for basal cells
• Possible AMACR positivity

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Summary - Reliable morphologic features of PA

• Stellate/undulated gland lumina
• Pale cytoplasm similar to adjacent benign glands
• Presence of completely atrophic glands within the
  focus
• Lack of nuclear enlargement or macronucleoli

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Morphological low-power comparison of PAH and PA
PAH
PA
PAH post atrophic hyperplasia, PA partial
atrophy
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So where to draw a line between partial atrophy
and atypia/cancer?

• Infiltrative glands
• Amphophilic cytoplasm
• Macronucleoli
• Presence of blue mucin
• Lack of basal cell markers and/or AMACR
  positivity with any of the above features

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Architectural/cytological features not specific
but suggest the benign diagnosis
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Architecture Lobular/circumscribed growth
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Pseudo infiltrative appearance patch like
growth pattern
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Benign glands as reference Similar cytoplasmic
character
Benign gland
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Cellular spindle cell stroma
BCH Adenosis Sclerosing adenosis
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Complete atrophy BCH
Nuclei occupy full cell height
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SV Radiation atypia
Random cytological atypia
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Radiation atypia
Random cytological atypia, smudgy nuclei,
prominent nucleoli, cytoplasmic vacuolization
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Conclusions

• A systemic approach using constellation of
  architectural and cytological features necessary
  to work up atypical small glandular
  proliferations
• Diagnosis relies on constellation of features
• Use markers to support your impression, use them
  as a panel
• An expert second opinion can help reduce atypia
  rate

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Thank You