New Frontiers in PathologyNew Frontiers in PathologyGU case presentationGU case presentation
Rajal B. Shah, M.D.Rajal B. Shah, M.D.Associate Professor - Pathology and UrologyAssociate Professor - Pathology and Urology
Case 13Case 13
A 65 year-old white American male with A 65 year-old white American male with serum PSA of 4 ng/ml, underwent serum PSA of 4 ng/ml, underwent extended 12 core biopsiesextended 12 core biopsies
34βE12 + p63
P504S
P504S
Summary of atypical findingsSummary of atypical findings
Disorganized growth patternDisorganized growth pattern
Presence of some round and poorly Presence of some round and poorly formed small glandsformed small glands
Micro nucleoliMicro nucleoli
Lack of basal cell staining in some glandsLack of basal cell staining in some glands
AMACR reactivityAMACR reactivity
DiagnosisDiagnosis
Benign prostate parenchyma with focus of Benign prostate parenchyma with focus of partial atrophypartial atrophy
Diagnosis of Limited Cancer in Prostate Biopsy: Critical Issues
Recognize cancer and avoid under-Recognize cancer and avoid under-diagnosis (false negative) diagnosis (false negative)
Recognize benign mimics and avoid Recognize benign mimics and avoid over-diagnosis (false positive)over-diagnosis (false positive)
Pattern 2Cribriform/largegrowth pattern
Pattern 1Small glandulargrowth pattern
Pattern 3Fused gland/solidgrowth pattern
Mimics of Prostate Cancer
Pattern 1-Small gland Pattern 1-Small gland mimicsmimics
Seminal Seminal vesicle/ejaculatory duct vesicle/ejaculatory duct epitheliumepithelium
Cowper’s glandsCowper’s glands
Verumontenum Verumontenum hyperplasiahyperplasia
Crowding of small Crowding of small glandsglands
Mucinous metaplasiaMucinous metaplasia
Mesonephric gland Mesonephric gland hyperplasiahyperplasia
Post atrophic Post atrophic hyperplasia/atrophyhyperplasia/atrophy
Partial atrophyPartial atrophy
AdenosisAdenosis
Radiation atypiaRadiation atypia
Nephrogenic adenomaNephrogenic adenoma
Basal cell hyperplasiaBasal cell hyperplasia
PA: Among the most common reasons PA: Among the most common reasons for second opinionfor second opinion
Herawi M et al, AJSP, 2005
Partial atrophy (PA) - BackgroundPartial atrophy (PA) - Background
Experts have utiized various terms to Experts have utiized various terms to describe partial atrophydescribe partial atrophy
Some have used the term post atrophic Some have used the term post atrophic hyperplasia (PAH) to describe similar lesionshyperplasia (PAH) to describe similar lesions(Amin MB et al, 1999, Srigley JR et al, 2004)(Amin MB et al, 1999, Srigley JR et al, 2004)
Recently PA and PAH recognized as a Recently PA and PAH recognized as a distinct types of focal atrophy in the Working distinct types of focal atrophy in the Working Group Classification of Focal Prostate Group Classification of Focal Prostate Atrophy Lesions Atrophy Lesions (De Marzo et al, 2006)(De Marzo et al, 2006)
Partial atrophy - SignificancePartial atrophy - Significance
Potential for confusion with prostatic Potential for confusion with prostatic adenocarcinoma (PCa)adenocarcinoma (PCa)– Among the most common reasons for second Among the most common reasons for second
opinion in a consultation practice opinion in a consultation practice (Herawi et al, (Herawi et al, 2005)2005)
– Potential immunohistochemical (basal cell Potential immunohistochemical (basal cell markers and P504S (monoclonal antibody to markers and P504S (monoclonal antibody to AMACR)) overlap with PCaAMACR)) overlap with PCa
Association with inflammation and proliferation Association with inflammation and proliferation found in certain forms of atrophy such as post found in certain forms of atrophy such as post atrophic hyperplasia atrophic hyperplasia (Ruska et al, 1998; De Marzo et al, (Ruska et al, 1998; De Marzo et al, 1999; Shah R et al, 2001)1999; Shah R et al, 2001)
Architectural indicesArchitectural indices– Gland sizeGland size– Gland shapeGland shape– CircumscriptionCircumscription– Stromal characteristicsStromal characteristics– Associated completely Associated completely
atrophic glands within atrophic glands within the focusthe focus
– Luminal secretionsLuminal secretions– InflammationInflammation
Cytological indicesCytological indices– Character of Character of
cytoplasmcytoplasm– Nuclear size in relation Nuclear size in relation
to benign glandsto benign glands– Micronucleoli (visible Micronucleoli (visible
only at 40x) and only at 40x) and macronucleoli (visible macronucleoli (visible easily at 10X)easily at 10X)
AJSP, 32(1), 2008
Basal cell marker “cocktail”(34Basal cell marker “cocktail”(34ββE12 + p63)E12 + p63)– Completely positiveCompletely positive– Patchy positivePatchy positive– Completely negativeCompletely negative
P504S - Rabbit monoclonal antibody to AMACRP504S - Rabbit monoclonal antibody to AMACR (Zeta (Zeta corporation, Sierra Madre, CAcorporation, Sierra Madre, CA ))– NegativeNegative– WeakWeak– Moderate-to-strongModerate-to-strong(Expression evaluated in relation to benign glands)(Expression evaluated in relation to benign glands)
AJSP, 32(1), 2008
Study design - Proliferation statusStudy design - Proliferation status
Ki-67 (MIB-1 clone) immunohistochemistryKi-67 (MIB-1 clone) immunohistochemistry
Quantitative analysis by ChromaVision Quantitative analysis by ChromaVision ACISACIS– Measurement of stain intensity ofMeasurement of stain intensity of
PA foci compared with benign glands (range PA foci compared with benign glands (range 0-225, 0%-100%)0-225, 0%-100%)
– Manual delineation of fociManual delineation of foci
Results - Morphology (architectural Results - Morphology (architectural features)features)
Gland Shape
89%
3%
8%
Stellate & roundStellate onlyRound, poorly-formed
Growth Pattern
70%
30%
Circumscribed Disorganized
N=73 foci
Circumscribed focus with stellate – “star” shaped glands
Disorganized poorly formed round glands
Results - Morphology (architectural Results - Morphology (architectural features)features)
0 20 40 60 80 100
completely atrophic glands withinfocus
stromal sclerosis
inflammation
% CASES
FEA
TU
RE
S
Complete dark atrophic glands within the focus
Results - Morphology (cytologic Results - Morphology (cytologic features)features)
0 20 40 60 80 100
Clearcytoplasm
Micronucleoli
Macronucleoli
Nucleomegaly
% CASES
FEA
TU
RE
S
“Micro” nucleoli visible at high power
Other benign conditions known to Other benign conditions known to contain nucleoli:contain nucleoli:
> Basal cell hyperplasia> Basal cell hyperplasia
> Post atrophic hyperplasia> Post atrophic hyperplasia
> Adenosis> Adenosis
> Radiation atypia> Radiation atypia
> Benign glands associated with > Benign glands associated with inflammationinflammation
Clear cytoplasm similar to adjacent benign glands, placed laterally to Nuclei giving them partially atrophic look
Results: IHC – Basal cell markers Results: IHC – Basal cell markers cocktail 34cocktail 34ββE12 + p63E12 + p63
N=71
21%
73%
6%
Completely positive Patchy
Completely negative
Other lesions with Other lesions with patchy/negative basal cell patchy/negative basal cell
reactionsreactions
PINPIN
AdenosisAdenosis
Lack of basal cell staining in few atypical Lack of basal cell staining in few atypical glands is not necessarily diagnostic of glands is not necessarily diagnostic of cancercancer
Results: IHC – P504SResults: IHC – P504S
N=7290%
6% 4%
Negative Weak Moderate-strong
Comparison with published literatureComparison with published literature
AMACR resultsAMACR results– 79% (15/19 cases)79% (15/19 cases) (Herawi et al, 2005)(Herawi et al, 2005)
Series consisting of selected consultation cases Series consisting of selected consultation cases with AMACR staining performed at multiple with AMACR staining performed at multiple institutionsinstitutions
– 31% (38/122 foci)31% (38/122 foci) (Adley et al, 2006)(Adley et al, 2006)
Hospital based series, AMACR staining using the Hospital based series, AMACR staining using the triple antibody (P504S + CK 903+ p63)triple antibody (P504S + CK 903+ p63)
AMACR-specificity issuesAMACR-specificity issues
Study PIN(%) NA(%) Adenosis(%)Jiang et al Positive NS 27Jiang et al NS NS NSYang et al NS NS 17.5Beach et al 39 NS NSLuo et al Majority NS NSRubin et al Increased NS NSMagi-Galluzi et NS NS NSKunju et al 88 NS 14Zhou et al 100 NS NSSkinnider et al NS 35 NSGupta et al NS 58 NS
PIN= Prostatic intraepithelial neoplasia, NA= Nephrogenic adenomaNS= Not studied
Results - Basal cell markers and Results - Basal cell markers and P504S antibody as a panelP504S antibody as a panel
Profile of Antibody PanelProfile of Antibody Panel Number of foci Number of foci (%)(%)
N=70N=70
P504S(-)/basal cell markers(+)P504S(-)/basal cell markers(+) 58/70 58/70 (83%)(83%)
P504S(+)/basal cell markers(+)P504S(+)/basal cell markers(+) 7/70 7/70 (10%)(10%)
P504S(-)/basal cell markers(-)P504S(-)/basal cell markers(-) 5/70 5/70 (7%)(7%)
P504S(+)/basal cell markers(-)P504S(+)/basal cell markers(-) 0/70 0/70 (0%)(0%)
Results - Proliferation statusResults - Proliferation status
N=54 fociN=54 foci
Mean proliferative indices:Mean proliferative indices:– PA foci=5.5 (range 0-30)PA foci=5.5 (range 0-30)– Benign glands=5.6 (range 0-31)Benign glands=5.6 (range 0-31)– P=0.97P=0.97 (paired t-test) (paired t-test)
Summary - Features that potentially Summary - Features that potentially mimic prostate cancermimic prostate cancer
MorphologyMorphology– Disorganized growth patternDisorganized growth pattern– Small, round, poorly-formed glandsSmall, round, poorly-formed glands– Visible nucleoliVisible nucleoli
ImmunohistochemistryImmunohistochemistry– Very patchy/negative staining for basal cellsVery patchy/negative staining for basal cells– Possible AMACR positivityPossible AMACR positivity
Summary - Reliable morphologic Summary - Reliable morphologic features of PAfeatures of PA
Stellate/undulated gland luminaStellate/undulated gland lumina
Pale cytoplasm similar to adjacent benign glandsPale cytoplasm similar to adjacent benign glands
Presence of completely atrophic glands within Presence of completely atrophic glands within the focusthe focus
Lack of nuclear enlargement or macronucleoliLack of nuclear enlargement or macronucleoli
PAH PA
PAH = post atrophic hyperplasia, PA = partial atrophy
Morphological low-power comparison of PAH and PA
So where to draw a line between So where to draw a line between partial atrophy and atypia/cancer?partial atrophy and atypia/cancer?
Infiltrative glandsInfiltrative glands
Amphophilic cytoplasmAmphophilic cytoplasm
MacronucleoliMacronucleoli
Presence of blue mucinPresence of blue mucin
Lack of basal cell markers and/or AMACR Lack of basal cell markers and/or AMACR positivity with any of the above featurespositivity with any of the above features
Architectural/cytological Architectural/cytological features not specific but features not specific but
suggest the benign diagnosis:suggest the benign diagnosis:
ArchitectureLobular/circumscribed growth
Pseudo infiltrative appearance – “patch” like growth pattern
Benign glands as referenceSimilar cytoplasmic character
Benign gland
Cellular spindle cell stroma
BCHAdenosisSclerosing adenosis
Nuclei occupy full cell height
Complete atrophyBCH
“Random” cytological atypia
SVRadiation atypia
Random cytological atypia, smudgy nuclei, prominent nucleoli, cytoplasmic vacuolization
Radiation atypia
ConclusionsConclusions
A systemic approach using constellation of A systemic approach using constellation of architectural and cytological features necessary architectural and cytological features necessary to work up atypical small glandular proliferations to work up atypical small glandular proliferations
Diagnosis relies on constellation of features Diagnosis relies on constellation of features
Use markers to support your impression, use Use markers to support your impression, use them as a panelthem as a panel
An expert second opinion can help reduce An expert second opinion can help reduce atypia rate atypia rate
Thank You