remember! best! · 03/10/2019 · testis 9,560 cases; penis 2,080 cases 4 5 6. 10/16/2019 3 ten...
TRANSCRIPT
10/16/2019
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Intraductal Carcinoma and Prognostic Stage
Group of Prostate, Recent Advances
Jae Y. Ro, M.D., Ph.D.
Houston Methodist Hospital
Weill Medical College of Cornell University,
The University of Texas MD Anderson Cancer Center, Houston, Texas
October 27, 2019 Cornell University
Texas Medical Center
Remember!➢BeST!• Basic
• (effort) Study
• Think
• Enjoy
➢I CARE (integrity, compassion, accountability, respect and excellence)
➢3 Cs (communication, consultation, collaboration)
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1. Basic
• How common prostate cancers?
• Diagnostic approach?
• IDC of prostate and grade group
• WHO Classification of GU
tumors, 4th edition, 2016
• AJCC staging manual, 8th edition
What % of cancers is expected to occur in
GU tract in men in USA in 2019?
• ~10%
• ~20%
• ~30%
• ~50%
• ~70%
What % of cancers occur in GU
tract in men in USA?
• ~10%
• ~20%
* ~30% (32%)
• ~50%
• ~70%• Prostate, 20% (174,650 cases); bladder, 7% (61,700
cases) and kidney, 5% (44,120 cases)
Testis 9,560 cases; penis 2,080 cases
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Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths By Sex, United States, 2019
CA Cancer J Clin 2019; 69(1):7-34
2. Study
❖Prostate Cancers
• Diagnostic approach
• Intraductal carcinoma
• Grade group
• 8th AJCC staging with prognostic
stage groups
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You have to look for three (3) things!
In any specimens
• Small glands
• Medium/Large glands with architectural
and cytologic atypia
• Stromal abnormalities
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Prostate lesions
Small gland
lesions Large gland
lesions
Stromal
lesions
Basal cells
+ -
Cancer
Mimickers Microacinar
Cancer
Discuss
later
1. Inflammation
2.Stromal tumors,
benign, borderline
and malignant
3.High grade prostate
cancer
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Stromal Lesions
⚫ Inflammation
⚫Poorly diff. adenoca (Gleason pattern 4/5)
⚫Stromal lesions
➢ Stromal hyperplasia
➢ STUMP
➢ Stromal sarcoma
Prostate Carcinoma
Well-diff. and poorly diff. adenocarcinoma
⚫ well-diff. adenocarcinoma
- For screening: three Too’s
(too small, too crowded, and too clear)
- For confirmation: nuclear enlargement,
prominent nucleoli and lack of basal cells
⚫ poorly diff. adenoca
- Uniformity, p. nucleolus, no or low mitoses
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PIN4 cocktail (AMACR, P63, HMCK)
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Erg
Adenocarcinoma
Other helpful features:
• Acid mucin
• crystalloids
• collagenous micronodules (mucinous fibroplasia)
• glomerulation
• Circumferential perineural invasion
• Glands in fat
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Atypical small acinar proliferation (ASAP)
• Size:
1) small number of acini in focus of concern
2) small focus size, average 0.4 mm in greatest dimension
3) lesion breakage at core tip
• Histology:
1) lack of clear histologic detail
2) distortion of acini
3) lack of convincing malignant features
4) clustered growth pattern mimicking benign process such as AAH or atrophy
5) loss of the focus of concern in deeper
6) focal positive HMWCK or negative racemase
7) presence of PIN raising the possibility of tangential cutting
• Inflammation:
1) overdiagnosis of reactive changes or atrophy
2) reactive atypia with nuclear and nucleolar enlargement
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ASAP
• ASAP is a valid diagnostic
category
• Clinical significance: predictive
value for cancer on repeat biopsy
• ASAP predicts cancer : 34% to 60%
• Repeat biopsy and close clinical
follow up
PCA 3 (DD3)• PROGENSA® PCA3 Assay
• mRNA in male urine
• Can reduce unnecessary biopsies
** Not clear whether PCA3 score independently predicts the Gleason score;
not sure whether it can use in active surveillance
High grade prostatic carcinoma
vs. Non-prostatic carcinoma
Prostate Non-prostate
N. monotony + -
Nucleolus prominent variable
Mitoses rare frequent
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Gleason grading
• Gleason grading scheme, original 1977
• Modification, 2005
• Recent, 2015 and 2016 modification
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Gleason ScoringAdenoca
Isolate
gland
Infiltrative:
Pattern 3-5
Fused gl
Incomp gl
Nodular:
Pattern 1 vs. 2
Pattern1 Pattern 2
1)Well defined2)Gl. Size/shape uniform
3) scant stroma
1) Ill defined2) Gl. Size/shape
irregular
3) More stroma
Solid, isolate
cells
Pattern 3 Pattern 4 Pattern 5
Crib/glom glands
No necrosis Necrosis
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Gleason grading, pattern 4
• Fused microacinar glands
• Cribriform glands/Glomeruloid
pattern
• Glands with “poorly formed lumina”
✓Mucinous (colloid) with complex
architecture
✓Ductal-endometrioid with no necrosis
➢No grading for intraductal carcinoma
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Diagnosis of “Poorly Formed Glands” Gleason
Pattern 4 on Needle Biopsy: AJSP2015;39:1331
1. Glands with no or only rare discernible
lumens, 2. Elongated compressed glands and
3. Elongated nests or small cords with no or
rare lumens: “poorly formed” by consensus
and assigned GP4
*** Well-formed but diminutive
• lumens; mixed well-formed
• and diminutive glands, and
• glands with vague lumens
• were not considered “poorly
formed glands”
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Diagnosis of “Poorly Formed Glands” Gleason
Pattern 4 on Needle Biopsy: AJSP2015;39:1331
• Histologic features that are “diagnostic of” GP4:
“poorly formed glands” >10 poorly formed glands
that are not immediately adjacent to other well-
formed glands
• Histologic features that are “against” GP4 “poorly
formed glands: “poorly formed glands” intermixed
with or immediately adjacent to (with < 1 gland
distance from) well-formed glands regardless of their
number
✓ < 5 poorly formed glands regardless of their location
P4
P4
P4
P4
P4
A to C, against pattern 4; D to F, P4
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Gleason 4
Gleason 3
???
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Cribriform glands • In original Gleason grading: small and large
cribriform glands, regular and round, pattern 3:
• In 2005: small cribriform, regular contour and round evenly spaced lumina
• 2014, 2016 grading: all grade 4
• Strong evidence of biochemical recurrence,
extraprostatic extension, positive surgical
margins, distant metastases, and disease-
specific death
• Proposal and vote: 100% agreement
Pattern 3 vs. Pattern 4
Pattern 3 Pattern 4
Gland fusion Discrete gland
units
Fused,
microacinar
gland;
incomplete gland
Cribriform Not allowed Any cribriform
glands/glomerula
-tion with no
necrosis
Other Small but
discrete glands
Hypernephroid:
Not assigned
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Against p5
P5
P5
P5
Pattern 5
• Small cylinders in solid nests
represent Gleason pattern 5.
VOTE: 87% Yes
• Rosette-like spaces in solid medium
to large nests should be
considered to represent Gleason
pattern 5.
VOTE: 88% Yes
Diagnosis of Gleason Pattern 5 on Core
Needle Biopsy: AJSP2015;39:1242
• Diagnostic of GP5 PCa
✓ Large solid tumor nests
✓ Intraluminal coagulative necrosis with or without
karyorrhectic debris
✓ Single cells/cords, 6-10 in a cluster or >10 in a cluster
or intermixed with adjacent well formed glands
✓ Signet ring–like cells in single cells or within nests
• Histologic features “against” GP5 PCa
✓ Small and medium-sized solid tumor nests
✓ Intraluminal amorphous material only
✓ Single cells/cords < 5
✓ Paneth cell–like change in tumor nests
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Variants of Prostate Ca
• Mucinous adenocarcinoma: Gleason pattern 4
may be 3
• Ductal-endometrioid ca: 4 to 5
• Sarcomatoid ca: 5
• Signet ring cell ca: 5
• LELC: 5 and oncocytic ca: 5
• Foamy gland carcinoma: 3, may be higher
• Ca with atrophic & hyperplastic features: 3
• Transition zone ca: 2
• Small cell, TCC, squamous and adenosq ca: not be assigned GG
Intraductal carcinoma
• High grade prostatic intraepithelial
neoplasia
VS.
• Intraductal carcinoma
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Large Cribriform Gland Lesions
Large glands
Cytologic atypia
PIN vs.
Intraductal ca***
No cytologic atypia
CCCH,Central zone
Basal cells
+ _
Ductal/ cribriform Ca
***: > 6 glands, > 1mm, branching contour, dense
cribriform/solid, comedonecrosis, pleomorphism
***Atypical
Cribriform Lesion
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Intraductal carcinoma (IDC-P)
• McNeal & Yemoto, AJSP 1996;20:802
• Guo and Epstein, 2006, Mod Pathol 19:1528
➢ Epithelial cells filling large ducts/acinar with
preservation of basal cells
1) Solid or dense cribriform pattern
2) Loose cribriform or micropapillary with marked
cellular atypia (6 normal or larger) or presence of
comedonecrosis
• Shah et al, 2010, AJSP, 34:470 (ACLs)
➢ > 6 glands with cribriform hyperplastic epithelium
with pleomorphic nuclei, nucleomegaly and
complex architecture (necrosis, solid
architecture, or branching): > 1mm
Intraductal carcinoma (IDC-P)
• Isolated lesion in biopsy: 0.1-0.3%
• With invasive carcinoma: 2.8%
• In radical prostatectomy: 20-40%
• PTEN loss, ERG expression more
common than HG PIN
• Not assigned Gleason grading
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High grade PIN vs. IDCa:Dr. Ro’s modification (Triad)
1. # of glands > 6; > 1mm <6, <1mm
2. Branching contour; Smooth contour
dense cribriform/solid loose cribriform
3. Comedonecrosis; Not present
significant pleomorphism
> 6 times of adjacent nuclei
HGPIN
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IDC-P
IDC-P, solid pattern
IDC-P, micropapillary & necrosis
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Atypical cribriform lesion (ACL). A and B, Two cases with ACLs showing greater
architectural complexity when compared to HGPIN (more than 6 gland
involvement, > 1 mm in size, and branching/irregular contour of glands;×40). Cand D, Each lesion showing micropapillary/loose cribriform patterns, but lacking
nuclear pleomorphism and comedonecrosis (×200). These lesions do not fit witheither HGPINor IDC-P criteria.
Atypical cribriform lesion
• Recent studies have reported that ACL lesions
diagnosed on core needle biopsies were
associated with a substantially increased risk
(55%) of coexistent prostate cancer on
subsequent biopsy and, therefore, require
immediate repeat biopsy.
• 901 radical prostatectomy cases, 22 (2.4%)
cases with ACL in our study.
Atypical cribriform lesions
With cytologic atypia
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• LOH (TP53, RB): 29% in Gleason pattern 4 ca, 60% of IDC-P;
rarely found in HGPIN and Gleason pattern 3 cancers. Prostate.
44:265–70, 2000
• ERG rearrangement: rare in HGPIN, majority seen in IDC-P.
Am J Surg Pathol. 34:478–85, 2010
• Cytoplasmic PTEN loss in 84% of IDC-P, yet very uncommonly
observed in HGPIN. Mod Pathol. 26:587–603, 2013.
• BRCA2 mutation. Eur Urol. 2015;67:496-503
• Molecular studies support the idea that IDC-P is a distinct
lesion from HGPIN and represents a late event in prostate
cancer evolution.
• No genetic markers useful in DX of IDC-P.
IDC-P (Molecular Profiles)
PIN vs IDC-P
• HGPIN is the earliest accepted stage in
carcinogenesis, possessing most of the
phenotypic, biochemical and genetic changes
of cancer without invasion of the basement
membrane of the acini (i.e., precursor lesion
of invasive prostatic adenocarcinoma).
• The pathogenesis of IDC-P remains
controversial. Precursor?
IDC-P• Histologic and molecular evidence strongly
suggests that IDC-P represents late-stage
intraductal spread of existing high-grade
invasive ca, but there are a few reported
cases of pure IDC-P without an associated
invasive ca element.
• In our study, 3 cases with isolated IDC-P
were found, not associated with adjoining
invasive ca component.
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IDC-P
• Rare cases of “precursor-like” IDC-P
have been described in previous studies
• At least a subset of IDC-P may act as
precursor lesion in the HGPIN pathway
of invasive cancer or possibly as a
separate de novo pathway.
Gleason Grading (score):
• Grade (pattern): 1-5, most and second most
common --- most and worst patterns together-
--score
• Score: 2 to 10
• Score 6?
✓Well differentiated?
✓Intermediate (moderately differentiated)?
✓Poorly differentiated?
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Problems with Gleason Score
• Gleason 6 is the lowest biopsy score although the
scale goes from 2-10
• Score 2-5, no longer assigned in biopsies: most
low, score 6, misleading clinicians and patients
• Gleason 7 not homogeneous: 4+3=7 has worse
prognosis than 3+4=7
• Gleason 8-10 is often considered as one group -
high grade disease
Gleason Grade Group
• Grade group 1: Gleason score <6
• Grade group 2: Gleason score 7 (3+4)
• Grade group 3: Gleason score 7 (4+3)
• Grade group 4: Gleason score 8
• Grade group 5: Gleason score 9, 10
Reporting of Gleason Score
Prognostic Grade Groups
• Gleason score ≤ 6:
• Gleason score 3 + 4
• Gleason score 4 + 3
• Gleason score 8
• Gleason score 9-10
• Prognostic Grade Group 1
• Prognostic Grade Group 2
• Prognostic Grade Group 3
• Prognostic Grade Group 4
• Prognostic Grade Group 5
•First reported in BJU Int 2013;111:753-60
•Meta-analysis with >20,000 radical
prostatectomy at 5 institution (Eur Urol
2016;69:428-35)
•.
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BJU Int 2013;115:753-60
• INCORPORTATION
OF PROGNOSTIC
GROUPS
• ENDORSED BY THE
ISUP (2015) & WHO
(2016)
GG1GG2
GG3GG4
GG5
Eur Urol 2016;69-428-35
TNM Stage
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TNM Classification of ProstatePrimary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Clinically inapparent
T2 Organ confined
T3 T3a: EPE, microscopic bladder neck
invasion; T3b: seminal vesicle (s)
T4 Tumor fixed or invade adjacent
structures (ext sphincter, rectum,
bladder, levator muscle, pelvic wall
TNM ClassificationRegional lymph nodes (N)
NX Regional LNs cannot be assessed
N0 No regional LN metastasis
N1 Metastasis to regional node (s)
(Number, size, location of regional LNs involvement)
Distant metastasis (M)
MX no MX in 7th and 8th editions:
M0 No distant metastasis (no pM0, only cM0)
M1 Distant metastasis
M1a Nonregional lymph node (s)
M1b Bone (s)
M1c other sites with or without bone met
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Summary of changes from 7th edition (2010)
• Definition of primary
tumor (T)
• Histologic grade
• AJCC prognostic stage
group
• pT2 only with no substage of
pT2a, b, and c
• Gleason score (2014 criteria)
and Grade group should both
be reported
• Stage III includes select organ-
confined disease tumors based
on PSA and Gleason/Grade
group status
✓PSA > 20, Grade group 5
Level I-IV
AJCC level of evidence, prostate
➢Prostate Cancer
• Level I: PSA, Grade
group/Gleason score
(Integrated in AJCC Prognostic
stage groups)
• Level II: Surgical margin status
• Level III: Histologic types
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AJCC Prognostic Stage Groups
T N M PSA Grade Group Stage group
cT1a-c N0 M0 < 10 1 I
cT2a
pT2 N0 M0 < 10 1 I
cT1-c N0 M0 > 10 < 20 1 IIA
cT2a
cT2b-c N0 M0 < 20 1 IIA
T1-2 N0 M0 < 20 2 IIB
T1-2 N0 M0 < 20 3 or 4 IIC
T1-2 N0 M0 > 20 1-4 IIIA
T3-4 N0 M0 Any 1-4 IIIB
Any T N0 M0 Any 5 IIIC
Any T N1 M0 Any Any IVA
Any T N0 M1 Any Any IVB
Molecular Tests
Molecular Testing: Myriad
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Molecular Testing : Genomic Health
Oncotype DX - Prostate
GPS: Genomic prostate score
Molecular Testing: Decipher
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3. Think!
3. Think
• IDC-P and Grade Groups
• Why important?
• Reflect treatment and prognosis?
• Staging and grading?
• Future targeted therapy?
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4. BeST (Enjoy)
Take Home Messages
• Do your BeST!
1. Basic
2. (effort) Study
3. Think
4. Enjoy
• I CARE/3C practiceOctober 27, 2019
Thank you for
your attention!
October 27, 2018
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