48 Prostate Needle Biopsy Interpretation and Reporting...

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48 Prostate Needle Biopsy Interpretation and Reporting: Contemporary Issues and Emerging Concepts Ming Zhou MD, PhD Rajal Shah MD, FASCP 2011 Annual Meeting – Las Vegas, NV AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600 Chicago, IL 60603

Transcript of 48 Prostate Needle Biopsy Interpretation and Reporting...

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48 Prostate Needle Biopsy Interpretation and Reporting: Contemporary Issues and Emerging Concepts

Ming Zhou MD, PhD Rajal Shah MD, FASCP

2011 Annual Meeting – Las Vegas, NV

AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600

Chicago, IL 60603

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48 Prostate Needle Biopsy Interpretation and Reporting: Contemporary Issues and Emerging Concepts Prostate needle biopsy is one of the most common specimen types received in surgical pathology laboratories. However, there is significant error rate in diagnosing cancer in prostate biopsy, slow adoption of the modified Gleason grading system, and considerable variation in reporting. ;This course will use real-life prostate biopsy cases to discuss the practical issues pathologists encounter in their daily practice. The topics will include: ;1.Comprehensive review of the histological criteria for diagnosis of limited cancer in prostate needle biopsy and use of immunohistochemical markers in such setting. ;2.Benign mimickers of prostate cancer and cancer that mimics benign prostate lesions;3.New concepts and entities of important clinical significance in prostate pathology. ;4.Modified Gleason grading system on prostate biopsy.;5.Reporting of prostate biopsy to include clinically relevant histological parameters.;6.Brief overview of new molecular and genetic markers that have potential to impact the prostate biopsy diagnosis.

• Provide practical guideline and tips for using the modified Gleason grading scheme • Provide an update on new concepts and entities of important clinical significance in prostate pathology • Identify clinically relevant histological parameters that should be included in the surgical pathology

report FACULTY: Ming Zhou MD, PhD Rajal Shah MD, FASCP Practicing Pathologists Surgical Pathology Surgical Pathology (GI, GU, Etc.) 2.0 CME/CMLE Credits Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). Credit Designation: The ASCP designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCP continuing education activities are accepted by California, Florida, and many other states for relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s Maintenance of Certification Program.

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Prostate Needle Biopsy Interpretation and Reporting:

Contemporary Issues and Emerging Concepts

Ming Zhou, M.D., PhDAssociate ProfessorPathology, Urology & Cancer [email protected]

Cleveland Clinic

Rajal B. Shah, M.D.Director, Urologic PathologyCaris Life [email protected] Associate Professor of Pathology and Urology, The University of Michigan

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Disclosure

• No conflict of interest*

* Dr. Rajal B. Shah works for Caris Life Sciences but has no conflict of interest related to this presentation

Case 1

67 year-old male with elevated PSA (5.2 ng/ml). Digital rectal examination was normal. He underwent sextant biopsy.

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Case 1

Which of the following is the best diagnosis? Low grade prostatic intraepithelial neoplasia (low grade PIN) High grade PIN Benign central zone glands Basal cell hyperplasia

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Prostatic Intraepithelial Neoplasia (PIN)

Preferred diagnostic term for a putative pre-malignant proliferation of atypical epithelial cells within the pre-existing prostatic ducts and acini

Can only be diagnosed by histology

No specific clinical, radiological findings

Does not cause PSA elevation

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Prostatic Intraepithelial Neoplasia (PIN)

Preferred diagnostic term for a putative pre-malignant proliferation of atypical epithelial cells within the pre-existing prostatic ducts and acini

Can only be diagnosed by histology

No specific clinical, radiological findings

Does not cause PSA elevation

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PIN: Histological Features

Feature Low grade PIN High grade PIN

Architecture

Luminal cell cytology

Nuclei

Cytoplasm

Nucleoli

Chromatin

Basal cell layer

Basophilic appearanceNormal glandular architecture

Luminal cell crowding, irregular spacing, multi-

layering

Similar to LGPIN, but more pronounced

Enlarge, marked size variation

Normal

Inconspicuous

Amphophilic

Intact

Enlarge, size and shape variation

Coarse and clumped

Large and prominent, similar to PCa

Amphophilic

Often discontinuous, or absent

Modified from Humphrey PA: Prostate Pathology

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Low-grade PIN: A Diagnosis That Should Not Be Made

Poor interobserver reproducibility

Not associated with cancer risk in subsequent biopsy

Humphrey PA: Prostate Pathology

Low-grade PIN

Benign

18%

20%

Diagnosis Cancer Risk

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PIN: Histological Diagnosis

Distinct, prominent nucleoli: the best discriminator between LGPIN & HGPIN

Mitosis, marked nuclear pleomorphismor hyperchromasia (Egevad et al, Mod Pathol 2006)

Diagnosis is subjective: err on conservative side

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LGPIN, signed as benign prostatic tissue

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High-grade PIN with Mitosis

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High-grade PIN with pleomorphic nuclei

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Tufting (56%) Micropapillary (29%)

Flat (15%) Cribriform (0-5%)

High Grade PIN: Major Architectural Patterns

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High Grade PIN

Differential Diagnosis Benign Prostatic central zone glands Seminal vesicle/ejaculatory duct epithelium Reactive atypia due to inflammation, infarction or

radiation Metaplasia (transitional cell, squamous cell) Hyperplasia (clear cell cribriform hyperplasia,

basal cell hyperplasia)

Malignant Prostate carcinoma with cribriform pattern PIN-like prostate carcinoma Intraductal carcinoma of the prostate Ductal adenocarcinoma Urothelial carcinoma

Significance of High Grade PINSignificance of High Grade PIN

Short-term cancer risk (marker for concomitant, but missed, cancer in initial biopsy, within 12 months)

Long-term cancer risk (precursor lesion to prostate cancer, within 1-3 years?)

HGPIN: Risk of HGPIN: Risk of PCaPCa in Repeat in Repeat BxBx

1995 and before(n=796)

1996-1999(n=623)

2000 and later(n=10838)

48.4%

32.4%

21.9%

Year

Cancer Risk

17.6%

17.7%

19.4%

BenignHGPIN

P value <0.001 0.42

<0.001

<0.001

0.002

P value

Analysis by M Zhou using data in Epstein & Herawi, J Urol 2006

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< 8 (n= 5379)

> 8 (n=716)

24.9%

16.1%

# Bx cores

Cancer Risk

18.4%

12.7%

BenignHGPIN

P value <0.001 0.048

<0.001

0.26

P value

HGPIN Cancer Risk Is Related to the HGPIN Cancer Risk Is Related to the Extent of Initial Extent of Initial BxBx

Analysis by M Zhou using data in Epstein & Herawi, J Urol 2006

HGPIN diagnosed on extended bx is not associated with increase cancer risk and probably does not need repeat bx

ClinicopathologicalClinicopathological Parameters Predicting Parameters Predicting Cancer Risk Associated with HGPINCancer Risk Associated with HGPIN

Clinicoradiologicall parameters PSA (total PSA, free PSA, PSA velocity) and DRE not

associated with the risk of PCa in repeat bx Imaging (ultrasound or MRI) does not predict cancer

risk Tumor markers Maybe useful, but not in clinical use yet

Pathological parametersMorphology (flat vs. tufting vs. micropapillary vs.

cribriform) not associated with cancer risk in repeat bx # cores involved by HGPIN

o Uni-focal HGPIN not associated with increase Ca risko Multi-focal (>2) associated with a significantly increased

cancer risk

LongLong--term Risk of Cancer Following High term Risk of Cancer Following High Grade PIN DiagnosisGrade PIN Diagnosis

Scant data on the natural history of HGPIN

Recommend repeat biopsy 2-3 years after initial HGPIN diagnosis

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If HGPIN is multi-focal, consider rebiopsy

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Predictive value of HGPIN for PCa declined significantly in recent years due to a variety of factors

Use stringent diagnostic criteria

Report extent of HGPIN

High Grade PINSummary

Case 2

76 year-old man with elevated PSA (6.4 ng/mL). He underwent extended 12-core biopsy.

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Case 2

Which of the following is the best diagnosis? Benign Atypical glands suspicious for cancer Prostate carcinoma

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Atypical Glands Suspicious for PCa (ATYP)

Diagnostic term: a gland or a focus of glands suspicious for PCa, but lack sufficient architectural/cytological atypia to establish a definitive dx

Not a biological entity, but to convey pathologist’s uncertainty regarding the diagnosis

Many terms have been used Atypia Atypical hyperplasia Borderline lesion Uncertain biological behavior Atypical small acinar proliferation (ASAP)

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Histological Features Resulting in ATYP Limited number of glands (PCa minimally sampled in biopsy) Biopsy and tissue processing artifact

o Crush artifactr obscuring histologyo Atypical glands at the tip or edge of biopsy core

Atypical morphology not cancer specifico Crowded glands with minimal cytological atypia (cancer

vs adenosis)o Atypia in atrophic glands (atrophic PCa vs benign

atrophy)o ATYP adjacent to HGPIN (PINATYP, microinvasive

cancer vs outpouching or tangential sectioning off HGPIN)

o Atypia in the presence of inflammation (inflamed PCa vsreactive atypia)

Confusing immunohistochemistryo Non-PCa glands with + AMACR

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ATYP: due to limited number of glands

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ATYP: due to limited atypical histological features

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ATYP: due to atrophic glands

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ATYP: Atypical Glands at the Edge of the Biopsy Core

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ATYP: Can’t Rule Out HGPIN

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ATYP: Can’t Rule Out Adenosis

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ATYP: due to inflamed glands

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HGPIN with Adjacent Atypical Glands (PINATYP)

HGPIN

ATYP

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Epstein and Herawi J Urol 2006

Atypical Glands Suspicious for PCa (ATYP)Incidence in Needle Biopsy

Mean: 5.0%Median: 4.4% (range 0.7-23.4%) Trend towards lower incidence in recent studies

Pre-1996

1997-1999

2000-2005

45%

39%

41%

Year Cancer Risk

Schlesinger et al, AJSP 2005

Atypical Glands Suspicious for PCa (ATYP)Cancer Risk in Subsequent Biopsy

Epstein and Herawi J Urol 2006

Atypical Glands Suspicious for PCa (ATYP)Clinicopathological Predictors of Cancer in Subsequent Bx

No correlation between PSA measurements (PSA, free PSA, PSA velocity), DRE, TRUS and subsequent PCa detection Pathological parameters ATYP favor cancer: Cancer risk: 60% ATYP indeterminate: Cancer risk: 25-55% ATYP favor benign: Cancer risk: 20-33%Multiple repeat biopsies ~ 90% PCa detected in the 1st repeat bx

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Case 3

72 year-old man with elevated PSA. He underwent extended 12-core biopsy.

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K903 AMACR

Case 3

Which of the following is the best diagnosis? Prostate carcinoma, as some glands are negative for K903 and positive for AMACR (P504S) Definitely benign Atypical glands (ASAP, ATYP)

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Immunohistochemistry for Differential Diagnosis of PCa

To distinguish PCa from benign mimics Basal cell markers (High molecular weight

Cytokeratin [HMWCK], P63) Alpha-methylacyl-CoA-Racemase (AMACR,

P504S) ERG rearrangement product (Park et al, Neoplasia 2010; Furusato et al, Prostate Cancer Prostatic Dis, 2010)

To distinguish poorly differentiated PCa from TCC, colonic adenocarcinoma, etc Prostate-specific markers (PSA, PSAP, PSMA,

P501S) Cytokeratins (CK7, CK20) P63, HMWCK Lineage-specific markers (CDX-2, TTF-1, etc)

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Prostate Basal Cell Markers

HMWCK P63 Cocktail

34E12 (CK 1, 5, 10, 14) CK 5/6CK14

P63 34E12 + P63

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Useful in resolving atypical diagnoses Establish, confirm or change diagnosis in 64% Nbx (Wojno and Epstein, AJSP, 1995)

Reduce ASAP from 8.3% to 0.4% (Kahane, Urology, 1995)

Useful in diagnosing Pseudohyperplastic, foamy gland, atrophic PCa, radiation atypia

Cocktail > P63 > HMWCK, especially in TURP with cautery artifact (Zhou, AJSP, 2003, Shah RB, AJCP, 2004)

Diagnostic Utility of Basal Cell Markers

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Diagnostic Pitfall: Basal Cell Markers Can Occasionally Be Absent in Non-PCa Lesions

HMWCK sensitive to formalin fixation with progressive loss of immunoreactivity with increased fixation time (Varma, Mod Pathol, 1999)

Centrifugal decrease of HMWCK staining in benign glands (Goldstein, AJCP,1999)

HGPIN, adenosis, partial atrophy: fragmented, patchy basal cell staining

Absolutely critical to study the benign glands as internal positive control

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HMWCK in Prostate Cancer

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CK903 P63

P63-positive Prostate Cancer

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Alpha-Methylacyl-CoA Racemase(AMACR, P504S)

Key enzyme in metabolism of branched-chain fatty acids and bile acid intermediates

Preferentially overexpressedin PCa (Xu 2000; Rubin 2002; Luo 2002)

Detected with monoclonal antibody P504S

Also overexpressed in other tumors (colon, lung, breast, papillary RCC, etc ) (Zhou 2003)

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AMACR Expression May Be Detected in Morphologically Benign Glands

BenignPCa

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Heterogeneous AMACR Expression in PCa

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Staining frequently weak and heterogeneousStaining frequently weak and heterogeneous Foamy and Foamy and PseudohyperplasticPseudohyperplastic PCaPCa: lower : lower

sensitivitysensitivity Positive staining in Positive staining in PCaPCa 6262-- 95% in needle 95% in needle

biopsies (average 80%)biopsies (average 80%) Positive staining supports Positive staining supports PCaPCa diagnosisdiagnosis Negative staining in suspicious focus may not Negative staining in suspicious focus may not

exclude exclude PCaPCa

Utility of AMACR in Diagnosis of PCa

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Expression of AMACR in PCaand Non-PCa Lesions

Study Year Antibody Type

Pca HGPIN Benign NA AAH

Jiang et al 2001 P504S 100% + 12% 27%

Jiang et al 2002 P504S 94.50% NA 0%

Yang et al 2002 P504S 100% NA 0% 17.50%

Beach et al 2002 P504S 82% 38.50% 21%

Luo et al 2002 P-AMACR 88% Majority 0%

Rubin et al 2002 P-AMACR 97%

Kunju et al 2003 P504S 90% 88% 26% 14%

Skinnider et al 2004 P504S 35%

Gupta et al 2004 P504S 58%

Wu et al 2004 P504S 90%

NA=Nephrogenic adenoma, AAH= adenosis

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Antibody Cocktails in PCa Diagnosis

Benign

PCa

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AMACR + basal cell marker cocktail AMACR+ basal cell markers equivalent to each antibody alone in staining pattern, sensitivity and specificity (Hameed, AJSP 2005; Trpkov, AJCP 2009)

Useful on biopsy with small focus of cancer

Diagnostic Utility of Antibody Cocktails in PCa Diagnosis

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TMPRSS2 and ERG Gene Fusion in Prostate Cancer

Fusion between androgen-activated TMPRSS2 and ERG genes occurs in 40-50% of prostate cancer in PSA-screened radical prostatectomy series

Immunohistochemistry using ERG antibody highly correlates with the gene fusion status (Park et al,

2010; Furusato et al, 2010)

Potentially useful for prostate biopsy evaluation (Yaskiv et al, 2011)

P63 + ERG Cocktail

Yaskiv et al, AJSP, 2011

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Immunohistochemistry in DDx of PCaSummary

Not a screening test Applied to selected cases whose ddx includes PCabased on H&E morphology

IHC must be interpreted in the context of H&E morphology Clearly define benign and atypical glands on H&E Nature of atypical glands: favor PCa vs favor benign Use IHC to support/verify H&E diagnosis

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Disclosure

• No conflict of interest*

* Dr. Rajal B. Shah works for Caris Life Sciences but has no conflict of interest related to this presentation

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Ductal adenocarcinoma with solid-papillary growth patterns

Case 4A 60-year-old male presented with an elevated PSA of 5 ng/ml. The patient underwent 12 core biopsies. Representative images are shown.

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64Haphazard proliferation of several large to mid size glands, frequent undulated architecture resembling benign proliferation like BPH

Case #

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Single layer of cells, nuclear enlargement and frequent prominent nucleoli

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Basal cell cocktail antibodies: p63+34betaE12

P504S

Adenocarcinoma of prostate with pseudohyperplastic features:3+3=6.

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Foamy gland carcinoma

Pseudohyperplastic carcinoma

Adenocarcinoma with atrophic features

Adenocarcinoma with glomeruloid features

Ductal adenocarcinoma

Mucinous (colloid) carcinoma

Small cell neuroendocrine carcinoma

Sarcomatoid carcinoma (carcinosarcoma)

Signet ring cell carcinoma

Squamous and adenosquamous carcinoma

Adenoid cystic basal cell carcinoma

Urothelial carcinoma

Histologic Variants of Prostate Carcinoma

Histologic variants account for 5% to10% of prostate carcinomas

Typically associated with ordinary acinar prostate adenocarcinoma

Morphologic spectrum range fromtumors resembling benign conditionsto highly aggressive forms

Often differ from acinar carcinomain clinical, immunophenotypic, andgenetic features

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Histological pattern of cancerBenign condition they may mimic

Foamy gland carcinoma

Cowper’s glandsMucinous metaplasiaXanthomatous inflammation

Atrophic carcinoma Benign atrophy

Pseudohyperplastic carcinoma

Benign prostatic hyperplasia (BPH)Prostatic intraepithelial neoplasia (PIN)

Carcinomas Mimicking Benign Condition

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70Crowded glands with abundant “xanthomatous” cytoplasm, low N:C ratio, eosinophilic secretions and concomitant ordinary cancer

Foamy gland carcinomaGleason score 3+3=6

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Poorly differentiated Foamy gland carcinoma mimicking Xanthoma cells- CD 68 negative, CK positive

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Adenocarcinoma of prostate withpseudohyperplastic features, Gleason Score 3+3=6

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?HGPIN or ?PCA with pseudohyperplastic features

P504S

Dx: Atypical glands, suspicious for pseudohyperplastic carcinoma.Cannot rule out HGPIN

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Prostate adenocarcinoma with atrophic features

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Carcinomas mimicking benign lesions: take home points

• Be aware about these histologic variations

• Diagnosis should be made cautiously in presence of few glands only

• Concomitant conventional acinar cancer usually present

• IHC helpful – though AMACR can be negative due to low sensitivity

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Ductal Adenocarcinoma, Gleason score 4+4=8

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PIN – like Ductal Adenocarcinoma

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Ductal adenocarcinoma with solid-papillary growth patterns

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Ductal Adenocarcinoma: Immunoprofile

PSA +PSMA +HMWCK -P63 -Thrombomodulin -Beta catenin -CDX2 -

D/D:Urothelial carcinomaColonic adenocarcinoma

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Ductal adenocarinoma with intraductal spread

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Ductal adenocarcinoma: Large individual gland morphology

Case 5:A 70-year-old male presented with an abnormal digital rectal examination and elevated PSA of 10 ng/ml. The patient underwent 12 core biopsies. The representative images are shown.

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Case 5

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A contemporary approach to the Gleason grading in needle

biopsies/2005 ISUP Gleason grading recommendations

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Natural history of prostate cancer progression

• Which localized cancers will recur biochemically, metastasize and can be lethal?

• Which localized cancers are clinically innocuous and can be conservatively managed?

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TABLE I. Clinical Stage T1c (nonpalpable, PSA elevated)

PSA Range (ng/mL)

Pathologic StageGleason Score

2-4 5-6 3+4=7 4+3=7 8-10

0–2.5

Organ confined 95 (89–99) 90 (88–93) 79 (74–85) 71 (62–79) 66 (54–76)

Extraprostatic extension 5 (1–11) 9 (7–12) 17 (13–23) 25 (18–34) 28 (20–38)

Seminal vesicle (+) — 0 (0–1) 2 (1–5) 2 (1–5) 4 (1–10)

Lymph node (+) — — 1 (0–2) 1 (0–4) 1 (0–4)

2.6–4.0

Organ confined 92 (82–98) 84 (81–86) 68 (62–74) 58 (48–67) 52 (41–63)

Extraprostatic extension 8 (2–18) 15 (13–18) 27 (22–33) 37 (29–46) 40 (31–50)

Seminal vesicle (+) — 1 (0–1) 4 (2–7) 4 (1–7) 6 (3–12)

Lymph node (+) — — 1 (0–2) 1 (0–3) 1 (0–4)

4.1–6.0

Organ confined 90 (78–98) 80 (78–83) 63 (58–68) 52 (43–60) 46 (36–56)

Extraprostatic extension 10 (2–22) 19 (16–21) 32 (27–36) 42 (35–50) 45 (36–54)

Seminal vesicle (+) — 1 (0–1) 3 (2–5) 3 (1–6) 5 (3–9)

Lymph node (+) — 0 (0–1) 2 (1–3) 3 (1–5) 3 (1–6)

6.1–10.0

Organ confined 87 (73–97) 75 (72–77) 54 (49–59) 43 (35–51) 37 (28–46)

Extraprostatic extension 13 (3–27) 23 (21–25) 36 (32–40) 47 (40–54) 48 (39–57)

Seminal vesicle (+) — 2 (2–3) 8 (6–11) 8 (4–12) 13 (8–19)

Lymph node (+) — 0 (0–1) 2 (1–3) 2 (1–4) 3 (1–5)

>10.0

Organ confined 80 (61–95) 62 (58–64) 37 (32–42) 27 (21–34) 22 (16–30)

Extraprostatic extension 20 (5–39) 33 (30–36) 43 (38–48) 51 (44–59) 50 (42–59)

Seminal vesicle (+) — 4 (3–5) 12 (9–17) 11 (6–17) 17 (10–25)

Lymph node (+) — 2 (1–3) 8 (5–11) 10 (5–17) 11 (5–18)

KEY: PSA = prostate-specific antigen.

Partin Table

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Risk Category DefinitionVery low T1c plus Gleason score 2–6 plus PSA < 10 ng/mLLow T1‐T2a plus Gleason score 2–6 plus PSA < 10 ng/mL

(only 1 in 14 will die from prostate cancer)Intermediate T2b‐T2c or Gleason score 7 or PSA 10–20 ng/mL (11% 

will die from prostate cancer within 15 y)High T3a or Gleason score 8–10 or PSA > 20 ng/mLVery high T3b‐T4 (locally advanced) or metastasis present

NCCN Recurrence Risk Categories

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Significance of Gleason score

• Predicts outcome after various forms of treatments (active surveillance (watchful waiting), radical prostatectomy, radiation)

• Low GS (<=6) may be candidate for active surveillance treatment

• GS 7 often a critical decision making step – need for some type of definitive therapeutic intervention (e.g. lymph node dissection for pt. undergoing prostatectomy)

• Gleason score 8-10 often candidate for adjuvant therapy or radiation therapy

90

Contemporary approach to Gleason grading-Why?

• Practice change in 40 years– Stage migration– Sampling strategy

• Special techniques– Immunoperoxidase (CribriformPIN / Adenosis)

• Variants• Tertiary grade issue • Correlation between biopsy and RP is not very

good – under grading of biopsy a significant problem

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91

2005 ISUP Modified Gleason Grading of Prostate Cancer : Key Issues

• Clean Gleason pattern 3 or less group

• Clarify Gleason pattern 4

• Grading recommendations for newly described variants

• Grading approach in extended needle biopsies

92

Diagnosis of low grade Gleason score 2-5 carcinomas on needle biopsy

should be rarely if ever utilized

93

ISUP Consensus Conference on Gleason Grading

(Epstein JI, et al. AJSP 2005 29:1237 fig 12) with permission

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94

Gleason Pattern 3

• Variably sized, infiltrative, individual glands, typically smaller than 1 and 2

• “Individual cells” not allowed in 3

• Only “rounded, well circumscribed cribriformglands of same size as of normal glands, resembling cribriform PIN is 3”

95

Gleason pattern 3

96

Only rare rounded, well-circumscribed glands of same size of normal glands is Cribriformpattern 3

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97

Pitfalls in grading pattern 3: “U” and“Y” – shaped glands

98

Majority (>95%) of cribriformcarcinomas are Gleason pattern 4

99Gleason pattern 4: Small irregular and infiltrative cribriform cancer glands

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100Gleason pattern 4: Round and regular but larger cribriform glands

101Gleason pattern 4: Ductal (large duct) cancer

Grading of invasive cribriform carcinoma on prostate needle biopsy: an interobserver study among experts in genitourinary pathology.Latour M, Amin MB, Billis A, Egevad L, Grignon DJ, Humphrey PA, Reuter VE, Sakr WA, Srigley JR, Wheeler TM, Yang XJ, Epstein JI.

Am J Surg Pathol; 32(10):1532-9, 2008

30 needle biopsy cases that possibly represented cribriform Gleason pattern 3carcinoma were shared amongst the group of experts

Sixty seven percent cases (n=24) which reached consensus (defined as 6/10 experts agreement): 23 pattern were classified as 4 and 1 pattern as 3

Some experts now classify all cribriform carcinomas regardless of its architecture as Gleason pattern 4 or 5 if associated with necrosis

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103

Ill-defined glands cluster with poorly formed lumina where tangential sectioning is ruled out is Gleason pattern 4

104

105

Pitfalls in grading pattern 3:tangentially sectioned glands mimicking as pattern 4

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106

Gleason 4 - Raggedly infiltrating fused glands

107

Gleason 4- Hypernephroid pattern

108

Gleason Pattern 4

• Fused glands

• Ill-defined glands with poorly formed glandular lumina (tangential sectioning is ruled out)

• Large cribriform glands,

• Cribriforming glands with irregular lumina

• Hypernephroidmorphology

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109

Gleason Pattern 5

• Solid sheets, cords, or raw of single cells with essentially no glandular differentiation

• Comedocarcinomawith central necrosis surrounded by papillary, cribriform, or solid masses

110

111

Pitfalls of Gleason pattern 5-Pseudo comedonecrosis

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112

2005 ISUP Modified Gleason Grading of Prostate Cancer : Key Issues

• Documentation of current practice

• Clean Gleason pattern 3 or less group

• Clarify Gleason pattern 4

• Newly described variants

• Extended needle biopsies

113

Gleason Grading of Unusual “Variant” Histology Types and Patterns

Histologic type or pattern Gleason pattern

Foamy gland pattern Grade based on underlying architecture

Pseudohyperplastic Pattern 3

Atrophic  Pattern 3

Intracytoplasmic clear vacuoles Grade based on underlying architecture

Ductal adenocarcinoma Pattern 4, pattern 5 with necrosis

Signet‐ring cell carcinoma Pattern 5

Small cell carcinoma Not graded

Adenosquamous and squamouscarcinoma

Not graded

Sarcomatoid carcinoma Not graded

Glomeruloid pattern 3 or 4; recent data suggest pattern 4

Collagenous micronodules Grade based on underlying architecture

Mucinous (colloid) carcinomaGrade based on underlying architecture (3 or 4)

114

Mucinous fibroplasia

– Subtract away the mucinous fibroplasiagrade based on underlying architecture

– Most Score 6

– Do not misinterpret fibrous invaginations as cribriformarchitecture

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115

Glomerulation –no consensus, new data suggest 4

116

Small cell high grade neuroendocrine carcinoma

Indicates an aggressive phase ofprostate cancer differentiation

Should not be graded due to different therapeutic significance

Resistant to androgen deprivationtherapy but often respond toplatinum based chemotherapeuticagents

1173+4=7

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118

2005 ISUP Modified Gleason Grading of Prostate Cancer : Key Issues

• Documentation of current practice

• Clean Gleason pattern 3 or less group

• Clarify Gleason pattern 4

• Newly describes variants

• Extended needle biopsies

119

Grading when the different cores demonstrate different Gleason grades:

Each core should be assigned Gleason score as long asurologist has defined their location or in separate container

Report of Global Gleason score optional

120

Extended sampling – Effect on Gleason score

Sextant biopsy accuracy average 42%( range 28%-68%),Significant risk of underestimation average 43% (25-57%)

Downgradeat RP (%)

No Change at RP (%)

Upgraded at RP (%)

Global GS 6 64 30Worst GS 12 64 24Highest

Volume GS8 57 35

Correlation of 200 extended (>10 cores) biopsies GS with subsequent Radical prostatectomy GS

GS= Gleason score, RP = Radical Prostatectomy

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121

Rationale for not compressing into only one Global grade

• One core with 4+4 and other cores with 3+3, the pathologic stage at RRP is comparable to all cores demonstrating 4+4 (Kunz et al, Hum Pathol, 2003)

• Majority of Urologist would pick highest grade and would label the patient accordingly (Rubin et al, Am J Surg Pathol, 2004)

122

Should multiple cores with different grades within the same container without specific site identifiers or “right” or “left” should be assigned individual grades?

Kunju LP, Shah RB et al, Hum Pathol, 40, 558-564, 2009

If cores are not fragmented:Attempt to provide information of corewith worst Gleason grade

Provides better correlationwith radical prostatectomyGleason grade

123

Reporting in needle biopsy 1) Limited (<5%) secondary patterns of lower grade2) Limited higher grade 3) Tertiary pattern of higher grade in needle biopsy

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Pattern distribution: 3,4,5Call 3+5=8

Pathology outcomes similar to Gleason 8-10 cancerCurrent nomograms incorporate only primary and

secondary patternsBe conservative but don’t ignore it if visible

at low power examination!

125

Impact of ISUP-modified Gleason grading system

• Increased utilization of secondary Gleason pattern 4 is the most noticeable impact of ISUP grading recommendations

(Zareba P et al, Histopathology 2009, 55:384-391)

• Modified but not conventional Gleason score better predicts PSA failure after radical prostatectomy

(Billis A et al, J Urol 2008, 180:548-552)

• Large scale impact of new recommendations for patient management remains to be validated

Case 6:A 55-year-old male presented with an abnormal digital rectal examination and elevated PSA of 8 ng/ml. The patient underwent 12 core biopsies. Representative images are shown

126

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127

Case #

128

Intraductal Carcinoma of the Prostate (IDC-P)

Intraductal Carcinoma of the Prostate (IDC-P)

Intraductal carcinoma of the prostate (McNeal & Yemoto, 1996)

Almost never seen in the absence of invasive carcinoma Concomitant invasive carcinoma almost always high grade and high volume Significantly worse prognosis

Morphological criteria Solid/loose cribriform, marked nuclear atypia, comedonecrosis (Guo & Epstein, 2006)

Large glands with cells spanning the lumen, branching contour, comedonecrosis (Cohen et al, 2007)

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IDC-P or Cribriform HGPIN?

PCa

Isolated ACL

ACL-PCa

Morphological And Molecular Differences of IDC-P & Cribriform HGPIN

ACL-PCa (PCaassociated cribriform lesion – IDC-P)

Atypical cribriformlesions with basal cells

Intermixed with invasive PCa

Within 3 mm from the border of invasive cancer

Isolated ACL (Non-PCaassociated cribriform lesion –Cribriform PIN)

Atypical cribriformlesions with basal cells

Not associated with invasive PCa

> 3 mm distant from the border of invasive cancer

ACL = Atypical cribriform lesions with basal cells

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Summary of 2 studies

Atypical cribriform lesions without associated invasive PCa(cribriform HGPIN) are uncommon; overwhelming majority of atypical cribriform lesions are associated with PCa (IDC-P)

Majority of IDC-P are associated with high grade and high volume PCa

Cribriform HGPIN and IDC-P overlap at the “low grade”morphologic spectrum

IDC-P is enriched with ERG gene fusions while isolated cribriform HGPIN lack ERG gene fusions

Shah RB et al, Am J Surg Pathol, 34(4): 440-77, 2010

Han B et al, Am J Surg Pathol, 34(4): 478-85, 2010

134

Approach to Atypical Cribriform Lesion in Biopsy

135

High grade PCa + IDC-P

No need to mention IDC-P

Gleason pattern 3 PCa + IDC-P

document IDC-P and its poor prognostic significance

or grade IDC-P as pattern 4 or 5 if associated with necrosis

Invasive PCa not present in prostate biopsy

diagnose IDC-P

Comment: IDC-P is often associated with high grade PCaand advise immediate rebiopsy and recommend definitive therapy

Intraductal Carcinoma of the Prostate (IDC-P)(Reporting)

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136

137

Diagnostic and prognostic:GSTP1 HypermethylationUrinary PCA3 TMPRSS2: ETS gene fusions

Prognostic:PTEN deletions Reduced p27 AR gene mutations/amplifications

Promising Biomarkers for Prostate cancer:

Science, 2005

50-60% of prostate cancers harbor these gene fusionsTMPRSS2:ERG is the most common class of gene fusions,

accounting for 40-50% of prostate cancers in prostatectomy cohortsAn early molecular event, present in a small fraction (~18%) of

HGPIN intermingled with adjacent cancer demonstrating identicalgene fusionsTMPRSS2:ETS gene fusions are highly specific to prostate cancerPromising diagnostic and prognostic marker

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PCA3 urine test: A genetic marker for prostate cancer

• Much greater degree of specificity than PSA

• Quantitated in urine using QRT-PCR method and reported as a ratio of PCA3 and PSA mRNA

• Higher the ratio (≥ 35), stronger the likelihood of detecting cancer at biopsy

• A higher PCA3 correlate with tumor volume and Gleason grade (indicative of significant disease) (HaeseA et al, Eur Urol, 2008)

LS Mark et al, Rev Uro 2008: 10(3):175-181

140

Men 50-70 years – DRE and Initial PSA

Elevated PSA

Prostate Biopsy

Negative Positive

TreatmentPCA3<35 PCA3≥35

Repeat biopsy

Negative Positive

Monitor

Current Application Model of PCA3 in the management of prostate cancerAdopted from Y. Frader et al

141

Reporting of Prostate Biopsy

Correct diagnosis

Histological information Prognosis Therapeutic decision-making

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142

Archives of Pathology & Laboratory Medicine, Vol 133 (10): October 2009

143

Reporting of Prostate BiopsyBenign Biopsy

Benign prostatic glands and stroma Do not use “glandular/stromal hyperplasia”Mention scant tissue or stroma only in biopsy

Optional: Benign mimickers of cancer Chronic and acute inflammation

Do not use “prostatitis”

Granulomatous prostatitis Atypical adenomatous hyperplasia (adenosis) Severe atrophy

Amin et al, 2005

144

Do not report LGPINOptional:

Extent of HGPIN (focal vs multifocal) # of cores involved Laterality (uni- vs bilateral)

Amin et al, 2005

Designating the atypical biopsy as suspicious for PCa Recommend not to use ASAP Recommend re-biopsy?

Reporting of Prostate BiopsyHGPIN

Reporting of Prostate BiopsyAtypical glands, suspicious for cancer

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145

Location and distribution of tumor (site of biopsy if specified)

Significance of knowing the location and distribution of PCa

Prognosis Therapy planning Subsequent prostate gland sampling

How to preserve the biopsy location information Submit individual biopsy core in separate container Biopsy cores from left and right sides submitted separately Ink cores from different sites in different color

Amin et al, 2005

Reporting of Prostate BiopsyProstate Cancer

146

Histopathologic type

Conventional acinar type: Need not specify Morphological variants (atrophic, pseudohyperplasic, foamy gland): Need not specify PCa with ductal features PCa with signet ring cell features PCa with mucinous differentiation Small cell carcinoma Sarcomatoid carcinoma of prostate Adenosquamous carcinoma Urothelial carcinoma Basal cell carcinoma

Gleason score, including primary and secondary patterns

Minute focus does not equate to low grade cancer

Reporting of Prostate BiopsyProstate Cancer

147

Extent of involvement

Tumor volume in needle biopsy: an extremely important histological parameter Correlates with the pathological parameters in radical prostatectomy

Predicts PSA recurrence, disease progression, therapy failure

How to report tumor volume in biopsy

# of cores involved

Amount of PCa in biopsy

Linear length of PCa (in mm)

% of cores involved

Reporting of Prostate BiopsyProstate Cancer

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148

Local invasion

Extraprostatic extension PCa in fat in a biopsy = extraprostatic extension

PCa involving skeletal muscle/ganglion cells = extraprostatic extension

Seminal vesicle invasion Seminal vesicle/ejaculatory duct not always distinguishable

PCa involving seminal vesicle/ejaculatory duct

Targeted biopsy: should mention if whether seminal vesicle is represented in the biopsy

Reporting of Prostate BiopsyProstate Cancer

149

SV

PCa

Lymphovascular invasion (report only if identified)

Therapy-related changes (if clinical history of radiation or hormonal therapy)

Perineural invasion (report only if identified)Optional: Extent (focal, multifocal)

Caliber of nerve bundles

Reporting of Prostate BiopsyProstate Cancer