limitations of the who i have acted as consultant for msd
TRANSCRIPT
05/07/2018
1
Limitations of the WHO classification of lung cancer
The Pathological Society of Great Britain and IrelandMaastricht, June 19 2018
Erik Thunnissen, [email protected]
Disclosures: NONE• I have acted as consultant for MSD, Pfizer, Clovis, BMS,
AstraZeneca
• I have received honoraria for speaker AstraZeneca, Pfizer, Roche trainer SP142, Sp263
• The VUmc received Grants: IIR Pfizer, AstraZeneca
• Consultant for Histogenex, VUmc, AstraZeneca
Limitations of the WHO classification of lung cancer
TOPICS
• Classificationof adenocarcinomas• Initially 5 subtypes plus recent 6th.
• Diagnosis of LCNEC
05/07/2018
2
Invasion in pulmonary adenocarcinoma. An International Interobserver Study
E Thunnissen, M Beasley, A Borczuk, E Brambilla, L Chirieac, S. Dacic, D Flieder, A Gazdar, K Geisinger, P Hasleton, Y Ishikawa, K Kerr, S. Lantejoul, Y Matsuno, Y Minami, A Moreira, N Motoi, A Nicholson, M Noguchi, D Nonaka , G Pelosi , I Petersen, N Rekhtman, V Roggli , B Travis, M Tsao, I Wistuba, H Xu, Y
Yatabe, M. Zakowski,J Kuik, B. Witte
Thunnissen, et al. Reproducibility Modern pathology 2012, 25 (1574-83)
‘Unanimous’ NO invasion #73
Diagnosis on right image only
Unanimous Invasion #21
Diagnosis on right image onlyDiagnosis on right image only
Kappa: ‘TYPICAL’ patterns
MEAN ± SD = 0.77 ± 0.07
05/07/2018
3
Kappa ‘DIFFICULT’ patterns
MEAN ± SD = 0.38 ± 0.14
Figure 2 Box plot distribution of the dominant pattern score
Thunnissen, et al. Reproducibility Modern pathology 2012, 25 (1574-83)
Frequency of the 5 patterns
Thunnissen, et all. Translational lung cancer res. 2012, 1(276-9)
Diseasee Free Survival 5 patterns
Thunnissen, et all. Translational lung cancer res. 2012, 1(276-9)
05/07/2018
4
Case Mixed GGO
Presentation Number: Presentation Title – Presenting Author
Ye 2014 Ichinose 2014 Eguchi 2014 Son 2014Rx cT1a N0 M0 Rx pGGO Rx pGGO Rx GGO R0
Pure GGO Rx n=103 n=114 n=101 156/191 GGO?
Benign - 7% 0% 0%AAH 19% 5% 0% 0%AIS 76% 61% 47% 22%MIA 5% 14% 30% 34%inv AdC 0% 12% 24% 44%
Pure GGO pathology in resection specimen
M S01 how to treat Multiple GGO’s , Pathology, Thunnissen
Japanese literature diagnosis (non)-invasion in small Adenocarcinomas
• GGO studies definition pathological invasion:
• Adenocarcinoma with Lymphatic, pleural, vascular invasion, lymph node meta. (JCOG Suzuki 2011, Nakamura 2010; Aokage 2013)
• Definition at variance with the concept of the published WHO pathology classification 2004 and 2015, but may be functional
Presentation Number: Presentation Title – Presenting AuthorM S01 how to treat Multiple GGO’s , Pathology, Thunnissen
These SURGEONS do not use WHO adenocarcinoma classification !!??
Invasion yes ≥ 9 NO ≥ 9
• 7 3,25 1,69 8 3 0 8 9 28• 17 3,00 1,70 10 2 1 8 7 28• 28 3,00 1,56 8 4 1 10 5 28• 66 3,04 1,79 11 1 1 6 9 28• 52 3,18 1,81 9 3 2 2 12 28• 51 2,89 1,77 11 3 0 6 8 28• 64 3,00 1,72 9 4 2 4 9 28• 4 2,89 1,77 10 5 0 4 9 28• 36 2,82 1,76 11 4 0 5 8 28• 53 2,61 1,73 13 3 0 6 6 28• 14 2,54 1,69 13 3 2 4 6 28• 35 2,61 1,73 12 5 0 4 7 28• 55 2,64 1,83 13 4 0 2 9 28• 9 2,46 1,71 14 3 1 4 6 28• 19 2,46 1,45 10 7 2 6 3 28
yes NoProbably yes Probably NoCase#
05/07/2018
5
Expectation ET
• If all cases extremely difficult, • Then: scattered opinions
Expectation• If all cases extremely difficult, • Then
1
2
3
4
5
6
78
BUT
1
2
3
4
5
6
78
SAME 9 OTHER 9
Apparently calibration needed• What do we think while interpreting invasion?
• Reduction of air?• Irregular glands?• Stroma vs. alveolar walls?
• Artifacts?• Other confounding factors?
• Juridical: USA more invasive then rest of the world (p<0.05)
05/07/2018
6
Ex-vivo artifact: surgical collapsePulmonary lobectomy specimen
Reduced size: width 30%; collapse around hilum
Reduced
Normal width
reduced
Normal width
Collapse- Deflation: air goes out- Compression vessels: less
blood / lymph
Takes minutes during surgery(even longer in emphysema)
Peripheral collapse: more flexiblewith alveolar walls containing no tumor cells
Surgeon: Tumor location shows slower shrinking: slightly elevatedcompared non tumor lung
05/07/2018
7
Collapsed peripheral lung
2D looks papillary
05/07/2018
8
2D looks papillary, 3D collapse plus AIS
Arch. Pathol. Lab. Med 2013, 137 (1792-7)
SERIAL CUTS
LEVE
L-1
LEVE
L-7
LEVE
L-4
(B)
Hematoxylin & Eosin CK7Elastic Trichrome
Tumor edge continous with pre-existing alveolar wall • Elastin is part of pre-existing alveolar wall
05/07/2018
9
• Elastin is part of pre-existing alveolar wall
Elastin is NOT produced by papillary carcinoma
Chance
Reduction of alveolar air spacefrom 70 micron to ~10 micron
142 alveolar walls / cm
50 exact longitudinally cut papillae in one field?
One completely straight hair:
< 1 i% skin resection specimen
Collapsed lung
Correct diagnosis: Adenocarcinoma in situ: NOT to be mistaken for papillary carcinoma
05/07/2018
10
When to think of Adenocarcinoma in situ
• Collapsed lung and tumor with thin walls
• Edge of tumor continous withalveolar walls
• Elastin = pre-existing alveolarwall
• Low chance for true papillae
Partial collapse = ex-vivo artifact
Adenocarcinoma in situ (AIS)
Major line
• Calibration is needed in this category of adenocarcinomas
• Start with discussionabout 2D vs 3D on details of histologicarguments
• Working group of IASLC pathology panel committee
6th Subtype: Spread Through Air Spaces(STAS)
05/07/2018
11
STAS ??Ex-vivo artifact
v
Ex-vivo artifact
Autopsy lung: cartilage in bronchial lumen !!
Invasive aspergillosis: Invasion in vessel wall
Grocott Grocott
H&E EvG
05/07/2018
12
Other case Aspergilloma lobectomy
Cluster fungi in vascular lumen
NO vascular wall invasionNO necrosis
Is this real?
Cluster fungi in vascular lumen
NO vascular wall invasionNO necrosis
Patient walked out of hospital after 1 week,No clinical signs of illness
Interpreted as artifact (STAKS), not as invasiveaspergillosis
How do these artifacts occur?
05/07/2018
13
s o s
s o s
s o s s o s
s o
s Kni
febl
ade
s o s s o ss o s s o ss o s s o s
thickness of knife
Size of cells
Artifact during gross cutting
Arch Pathol Lab Med. 2016;140:212–220
Apple model for spread through a knife surface
Arch Pathol Lab Med. 2016;140:212–220
Spread through a (peeler) knife surface(STAKS) STAKS in other organs?
05/07/2018
14
Breast• Tumor cell displacement was observed in 32% of patients
who had undergone large-gauge (14 gauge = 2mm OD) needle core biopsies
• More displacement in poorly differentiated carcinoma
• Diaz et al. AJR 1999. Are Malignant Cells Displaced by Large-Gauge Needle Core Biopsy of the Breast?
Breast cytology dissociation
Breast cytology dissociation
Dissociation = sign of malignancy
Ex-vivo artifact, STAKS
Micropapillary carcinoma:Tendency of malignant cells to be less well adhered to each other
Biological association of worse prognosis with STAS = STAKS co-incident
Arch Pathol Lab Med. 2017;141 (1226-30)
05/07/2018
15
Limitations of the WHO classification of lung cancer
TOPICS
• Classificationof adenocarcinomas• Initially 5 subtypes plus recent 6th.
• Diagnosis of LCNEC
Journal of Thoracic Oncology2017, 12 (334-346)
Thunnissenet al. JTO 2017, 12 (334-346)
KAPPAH&E 0.43H&E plus IHC 0.64
Cytokeratin +NE markers (3x) +MIB1 +++p16 +++Rb -
Thunnissenet al. JTO 2017, 12 (334-346)
05/07/2018
16
Tumor fields5
CytoplasmMinimal Moderate / AbundantIn between
Moulding ++Salt/p chromatinNucleoli -/±
SCLC
Nucleus Monotonous nucleiSalt/pepper chromNucleoli -/+
Carcinoid7
Dot necrosis8
no
Mitosis2,15
yes
<2 2-109
TyC Atyp C
Pleomorphic nucleiVesicular chromatinNucleoli ++ / ±
Moulding +/-Dense / uneven chromatin Nucleoli -/+
NE morphology
IHC NE +
LCNEC9
yes
Yes
yes
No1
SqCC4 NSCLC FA13
yes yes
Mitosis high KI67 >25
No3
yesyes
Mitosis ++Ki67 high14
Surgical
Yes
Flow Diagram Neuroendocrine Lung Cancer
Architecture NE morphologyYes No1
IHC +P40
IHC -
SCLC High grade NEC, possibly LCNEC
SqCC4Biopsy
Mitosis high KI67 >25Yes
IHC NE +
IHC +P40
NSCLC FA SqCC4
LCNEC SqCC4
IHC -
>10
Atyp C
TyC AtyC
LCNECFA12
FA
Yes
Mitosis
CrowdedNecrosis ++/±
PANEL DX SCLC . NSCLCHigh grade NEC, possibly LCNEC
High grade NEC, possibly LCNEC
IHC Cytokeratin ‘dotlike’
Thunnissenet al. JTO 2017, 12 (334-346)
Tumor fields5
CytoplasmMinimal Moderate / AbundantIn between
Moulding ++Salt/p chromatinNucleoli -/±
SCLC
Nucleus Monotonous nucleiSalt/pepper chromNucleoli -/+
Carcinoid7
Dot necrosis8
no
Mitosis2,15
yes
<2 2-109
TyC Atyp C
Pleomorphic nucleiVesicular chromatinNucleoli ++ / ±
Moulding +/-Dense / uneven chromatin Nucleoli -/+
NE morphology
IHC NE +
LCNEC9
yes
Yes
yes
No1
SqCC4 NSCLC FA13
yes yes
Mitosis high KI67 >25
No3
yesyes
Mitosis ++Ki67 high14
Surgical
Yes
Flow Diagram Neuroendocrine Lung Cancer
Architecture NE morphologyYes No1
IHC +P40
IHC -
SCLC High grade NEC, possibly LCNEC
SqCC4Biopsy
Mitosis high KI67 >25Yes
IHC NE +
IHC +P40
NSCLC FA SqCC4
LCNEC SqCC4
IHC -
>10
Atyp C
TyC AtyC
LCNECFA12
FA
Yes
Mitosis
CrowdedNecrosis ++/±
PANEL DX SCLC . NSCLCHigh grade NEC, possibly LCNEC
High grade NEC, possibly LCNEC
IHC Cytokeratin ‘dotlike’
Tumor fields5
Cytoplasm
Minimal Moderate / AbundantIn between
Moulding ++Salt/p chromatinNucleoli -/±
SCLC
Nucleus Monotonous nucleiSalt/pepper chromNucleoli -/+
Carcinoid7
Dot necrosis8
no
Mitosis2,15
yes
<2 2-109
TyC Atyp C
Pleomorphic nucleiVesicular chromatinNucleoli ++ / ±
Moulding +/-Dense / uneven chromatin Nucleoli -/+
NE morphology
IHC NE +
LCNEC9
yes
Yes
yes
No1
SqCC4 NSCLC FA13
yes yes
Mitosis high KI67 >25
No3
yesyes
Mitosis ++Ki67 high14
Surgical
Yes
Flow Diagram Neuroendocrine Lung Cancer
Architecture NE morphologyYes No1
IHC +P40
IHC -
SCLC High grade NEC, possibly LCNEC
SqCC4Biopsy
Mitosis high KI67 >25Yes
IHC NE +
IHC +P40
NSCLC FA SqCC4
LCNEC SqCC4
IHC -
>10
Atyp C
TyC AtyC
LCNECFA12
FA
Yes
Mitosis
CrowdedNecrosis ++/±
PANEL DX SCLC . NSCLC
High grade NEC, possibly LCNEC
High grade NEC, possibly LCNEC
IHC Cytokeratin ‘dotlike’
Tumor fields5
CytoplasmMinimal Moderate / AbundantIn between
Moulding ++Salt/p chromatinNucleoli -/±
SCLC
Nucleus Monotonous nucleiSalt/pepper chromNucleoli -/+
Carcinoid7
Dot necrosis8
no
Mitosis2,15
yes
<2 2-109
TyC Atyp C
Pleomorphic nucleiVesicular chromatinNucleoli ++ / ±
Moulding +/-Dense / uneven chromatin Nucleoli -/+
NE morphology
IHC NE +
LCNEC9
yes
Yes
yes
No1
SqCC4 NSCLC FA13
yes yes
Mitosis high KI67 >25
No3
yesyes
Mitosis ++Ki67 high14
Surgical
Yes
Flow Diagram Neuroendocrine Lung Cancer
Architecture NE morphologyYes No1
IHC +P40
IHC -
SCLC High grade NEC, possibly LCNEC
SqCC4Biopsy
Mitosis high KI67 >25Yes
IHC NE +
IHC +P40
NSCLC FA SqCC4
LCNEC SqCC4
IHC -
>10
Atyp C
TyC AtyC
LCNECFA12
FA
Yes
Mitosis
CrowdedNecrosis ++/±
PANEL DX SCLC . NSCLCHigh grade NEC, possibly LCNEC
High grade NEC, possibly LCNEC
IHC Cytokeratin ‘dotlike’
05/07/2018
17
Tumor fields1
Cytoplasm
Minimal Moderate / AbundantIn between
Moulding ++Dense chromatinNucleoli -/±
SCLC
Nucleus Monotonous nucleiSalt/pepper chromNucleoli -/+
Carcinoid7
Dot necrosis8
no
Mitosis2,15
yes
<2 2-109
TyC Atyp C
Pleomorphic nucleiVesicular chromatinNucleoli ++ / ±
Moulding +/-Dense / uneven chromatin Nucleoli -/+
NE morphology
IHC NE +
LCNEC9
yes
Yes
yes
No5
SqCC4 NSCLC FA13
yes yes
Mitosis high KI67 >25
No3
yesyes
Mitosis ++Ki67 high14
Surgical
Yes
Flow Diagram Neuroendocrine Lung Cancer
Architecture NE morphologyYes No5
IHC +P40
IHC -
SCLC High grade NEC
SqCC4Biopsy
Mitosis high KI67 >25Yes
IHC NE +
IHC +P40
NSCLC FA SqCC4
LCNEC SqCC4
IHC -
>10
Atyp C
TyC AtyC
LCNECFA12
FA
Yes
Mitosis
CrowdedNecrosis ++/±
PANEL DX SCLC . NSCLC
High grade NEC
High grade NEC
IHC Cytokeratin‘dotlike’
LCNEC Umbrella Diagnostic term
• Overlap with SCLC (RB-, p16++, MIB high, NE+)
• Overlap with NSCLC (RB+, p16-, MIB1 variable) NE 1 marker)
• Overlap with Atypical Carcinoid (RB+/-, p16 +/-; MIB1 low, NE+++)
Normal (WT) : Rb negative feedback loop on p16:WT Rb = low p16
P16Rb
SCLC
Rb negative
High p16
In NSCLC p16 protein loss:LOH, hypermethylation , mutationThunnissen, JTO 2017, 12 (334-46)
Normal (WT) : Rb negative feedback loop on p16:WT Rb = low p16
P16Rb
SCLC
Rb negative
High p16
In NSCLC p16 protein loss:LOH, hypermethylation , mutationThunnissen, JTO 2017, 12 (334-46)
This combination of stains gives confidence in case of doubt, or diffential diagnostic considerations
‘Separation in LCNEC’ of SCLC from other LCNEC possibilities (NSCLC with NE features, Atypical carcinoid)
05/07/2018
18
H&EH&E
Synaptophysine MIB1
LCNEC Resection
H&EH&E
CD56
Synaptophysin
Chromogranin A
MIB1
H&EH&E
CD56
Synaptophysin
Chromogranin A
MIB1
- MIB1 to low for SCLC /LCNEC
Crushed Carcinoid?
Summary
• Classificationof adenocarcinomas• Collapse (3D) not taken into account in 2D descriptions of current WHO
classification• STAS is an artifact with (frequently) poor prognosis
• Diagnosis of LCNEC• Umbrella term containing overlap cases from SCLC, NSCLC, Atypical carcinoid• Diagnosed only on resection specimen• Biopsy study follows