Limitations of the WHO I have acted as consultant for MSD ...

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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


TOPICS

• Classificationof adenocarcinomas• Initially 5 subtypes plus recent 6th.

• Diagnosis of LCNEC

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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

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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)

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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#

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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)

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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

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Collapsed peripheral lung

2D looks papillary

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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

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• 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

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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)

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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

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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?

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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?

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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)

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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 -


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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



SCLC


Carcinoid7

Dot necrosis8

no

Mitosis2,15

yes

<2 2-109

TyC Atyp C



NE morphology

IHC NE +

LCNEC9

yes

Yes

yes

No1

SqCC4 NSCLC FA13

yes yes


No3

yesyes


Surgical

Yes



IHC +P40

IHC -


SqCC4Biopsy


IHC NE +

IHC +P40

NSCLC FA SqCC4

LCNEC SqCC4

IHC -

>10

Atyp C

TyC AtyC

LCNECFA12

FA

Yes

Mitosis





Tumor fields5

Cytoplasm

Minimal Moderate / AbundantIn between


SCLC


Carcinoid7

Dot necrosis8

no

Mitosis2,15

yes

<2 2-109

TyC Atyp C



NE morphology

IHC NE +

LCNEC9

yes

Yes

yes

No1

SqCC4 NSCLC FA13

yes yes


No3

yesyes


Surgical

Yes



IHC +P40

IHC -


SqCC4Biopsy


IHC NE +

IHC +P40

NSCLC FA SqCC4

LCNEC SqCC4

IHC -

>10

Atyp C

TyC AtyC

LCNECFA12

FA

Yes

Mitosis


PANEL DX SCLC . NSCLC




Tumor fields5



SCLC


Carcinoid7

Dot necrosis8

no

Mitosis2,15

yes

<2 2-109

TyC Atyp C



NE morphology

IHC NE +

LCNEC9

yes

Yes

yes

No1

SqCC4 NSCLC FA13

yes yes


No3

yesyes


Surgical

Yes



IHC +P40

IHC -


SqCC4Biopsy


IHC NE +

IHC +P40

NSCLC FA SqCC4

LCNEC SqCC4

IHC -

>10

Atyp C

TyC AtyC

LCNECFA12

FA

Yes

Mitosis





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Tumor fields1

Cytoplasm

Minimal Moderate / AbundantIn between

Moulding ++Dense chromatinNucleoli -/±

SCLC


Carcinoid7

Dot necrosis8

no

Mitosis2,15

yes

<2 2-109

TyC Atyp C



NE morphology

IHC NE +

LCNEC9

yes

Yes

yes

No5

SqCC4 NSCLC FA13

yes yes


No3

yesyes


Surgical

Yes



IHC +P40

IHC -

SCLC High grade NEC

SqCC4Biopsy


IHC NE +

IHC +P40

NSCLC FA SqCC4

LCNEC SqCC4

IHC -

>10

Atyp C

TyC AtyC

LCNECFA12

FA

Yes

Mitosis


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)

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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

Limitations of the WHO I have acted as consultant for MSD ...

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