Early colorectal cancer Quality and rules for a good …...Early colorectal cancer Quality and rules...

Early colorectal cancer Quality and rules for a good pathology reportHistoprognostic factors

Pr Frédéric Bibeau, MD, PhD

Head, Pathology department

CHU de Caen,

Normandy University,

France

ESMO preceptorship, Barcelona, 20.10.17

Quality and rules of a good pathology report

Simple but rigourous

Reporting proforma for colorectal resection specimen

Early colorectal cancer (CRC)

Useful histopronostic factors

Micrometastaticdisease

Adjuvantchemotherapy

Useful histopronostic factors

- Tumour

- Depth of invasion

- Distant extension

- Margins

Useful histopronostic factors

Content

- Tumour

- Depth of invasion

- Distant extension

- Margins

Useful histopronostic factors

Colorectal cancer (CRC): heterogeneous disease

Different histologic types

CRC histologic types

Adenocarcinoma

Mucinous

Signet ring cells

Medullary

Lieberkühnian micropapillary

Serrated

adenosquamous

Small cells

Carcinoma

90%

Mucinous

Signet ring cells

Medullary CD3+

Tumour Microenvironment

Crohn-like reaction

Lymphocytic infiltrate

MSI histologic features

CRC grading

Low grade (well, moderatly differenciated)

High grade (poorly/indifferenciated)

modulation according to MSI status

- Tumour

- Depth of invasion

- Distant extension

- Margins

Useful histopronostic factors

Tis T1 T2 T3 T4

MUCOSA

SUB-MUCOSA

MUSCULARIS

SUB-SEROSA -->SEROSA -->

pT

pN

pM

Muscularis Muscosae -->

N0 : no positive lymph node (LN)N1 : 3 positive LNN2 : ≥ 4 positive LN

M0 : No distant metastasisM1 : Distant metastasis

Organe infiltrationand / or visceral

peritoneal perforation

pTNM classification

TNM UICC 2016 8th Classification

Serosal involvement

Gross examination +++

Serosal involvement

8th TNM UICC 2016 classification

pT4a

Frankel et al. Mod Pathol 2015

pT4a

Frankel et al. Mod Pathol 2015

Serosa involvement +

reactive phenomenons ✻

pT3

✻Mesothelial Hyperplasia , inflammation, erosion, ulceration

<1mm

Serosal involvement

8th TNM UICC 2016 classification

Deeper block levels

pT4a

Frankel et al. Mod Pathol 2015

8th TNM UICC 2016 classification

Serosal involvement

Tumour budding

Invasion front

Wang LM, Am J Surg Path 2009

optionnal

Tumor budding Score (0,785 mm2)

(Hot Spot method , X 20)

HE staining

1 (Budd 1) < 5 Faible

2 (Budd 2) 5-10 Intermédiaire

3 (Budd 3) ≥ 10 Elevé

Tumour budding

Recommandations AJCC 8th edition, Bern International Consensus Lugli et al, Modern Path 2017

optionnal

Galon et al. Cancer Res 2007

Immune adaptative microenvironment

optionnal

Prognostic impact of immune response

Immune adaptative microenvironnement

optionnal

- Tumour

- Depth of invasion

- Distant extension

- Margins

Useful histopronostic factors

Tis T1 T2 T3 T4

MUCOSA

SUB-MUCOSA

MUSCULARIS

SUB-SEROSA -->SEROSA -->

pT

pN

pM

Muscularis Muscosae -->

N0 : no positive lymph node (LN)N1 : 3 positive LNN2 : ≥ 4 positive LN

M0 : No distant metastasisM1 : Distant metastasis

Organe infiltrationand / or visceral

peritoneal perforation

TNM UICC 2016 8thClassification

pTNM classification

Adjuvant

chemotherapy

N+

Recommendations > 12But… More = Better

Distant extension: lymph nodes

Nx Lymph node status not asessable

N0 No positive regional lymph node

N1 Metastase(s) in 1-3 regional lymph node(s)

• N1a

• N1b

• N1c

1 positive lymph node

➢ 2-3 positive regional lymph node

➢ Tumour deposits, satellites, in the sub-serosa or peri-rectal or

peri-colic non peritonised tissue, without regional metastatic

lymph node

N2 ≥ 4 or more positive regional lymph nodes

• N2a

• N2b

• ≥ 4-6 regional positive lymph nodes

• ≥ 7 regional positive lymph nodes

TNM UICC 2016 8thClassification

Distant extension : tumour deposits

Pericolic or -rectal tissu location

Puppa et al. Modern Pathol 2007

Distant extension : tumour deposits

Recommendations for interprétation(F.A.Q*)

- N1c only if negative lymph node

- No N1c if positive lymph node

- Do not add tumour deposits to positive lymph node

- Do not modify T stage

*Frequently Asked Question

Distant extension : tumour deposits

Nagtegaal et al. J Clin Oncol 2017 35:1119-1127

Impact of « tumour deposits »

N+/TD+: Next TNM classification (9th edition) ?

Nx Lymph node status non assessable

N0 No positive regional lymph node

N1 Metastase(s) in 1-3 regional lymph node(s)

• N1a

• N1b

• N1c

1 positive lymph node

➢ 2-3 positive regional lymph node

➢ Tumour deposits, satellites, in the sub-serosa or peri-rectal or

peri-colic non peritonised tissu without regional metastatic lymph

node

N2 ≥ 4 or more positive regional lymph nodes

• N2a

• N2b

• ≥ 4-6 regional positive lymph nodes

• ≥ 7 regional positive lymph nodes

TNM UICC 2017 8thClassification

Distant extension : N+ subdivision

3 vs 6 months CT ?

Clinical trials stratification

Liebig et al J Clin Oncol 2010Mori et al. Histopathology 2009 Harris et al, Am J Surg Path 2008

Lymphatic invasion Venous invasion Perineural invasion

Distant extension : VELIPI*

*Venous emboli and lymphatic and perineural invasion

L category V category

8th TNM UICC 2016 classification

Pn1 category

Extra-mural venous invasion

30%: frequent underestimation ?

Nagtegaal et al. histopathology 2015

Perineural invasion

DFS CSS

OS

Knijn et al. Am J Surg Path 2015

- Tumour

- Depth of invasion

- Distant extension

- Margins

Useful histopronostic factors

Margins

Distal ans proximal

very rarely positive

Circumferential (Rectum)

- Tumour

- Depth of invasion

- Distant extension

- Margins

Useful histopronostic factors

Molecular profileMicrosatellite instability (15%)

Immunohistochemistry Molecular biology

Favorable prognosis in CCR stage II

Normal DNA

MSI tumour

Less or

supple-

mentary

nucleotides

• Impact of KRAS et BRAF mutations

• Poor prognosis in stage III CRC (MSS)*

• Not used as prognostic factors in 2017…

• Stratification for clinical trials ?

• MSI, RAS, BRAF status for all CRC, tomorrow ?

*Taieb et al JAMA Oncol 2016

Molecular profile

Cellule tumorale circulante (CTC)

ADN tumoral circulant (ADN ct)

MicroARN (miRNA)

Adapted from Diaz et al J Clin Oncol 2014; 32:579-86

Perspectives: liquid biopsyMinimal residual disease Tie J, sci Transl Med 2016

Pierre Laurent-Puig

lecture +++

Perspectives

- Treatment for particular stage II ?- No treatment for certain stage III ?

Take home messages

- pTNM

- Grade

- VELIPI

- MSI

Early CRC in 2017

Useful histopronostic factors for treatment

- pTNM

- Grade

- VELIPI

- MSI

N+ (including N1c= tumour dep.) adjuvant CT

Stage III

Early CRC in 2016

Useful histopronostic factors for treatment

- pTNM

- Grade high (poor differenciation)

- VELIPI +

- MSI -

N0 pT4 (serosa +), <12 N

Adjuvant CT

(Multidisciplinaryteam discussion)

Stage II

Early CRC in 2016

Useful histopronostic factors for treatment

Differenciation (Grade)

Extension- Tumour (pT)- Lymph node (pN)

Margins- Distal/proximal - Circumferential

(Rectum)

Histologic type

OMS

Vasculo-lymphatic and perineural invasions

Lymphatics Veins Nerves

Pathology report key elementsMultidisciplinary board

• www.sfpathol.org

• www.ecancer.fr

Reporting proforma for colorectal cancer

Translationnal research

Back up slides

Goldstein et al. Am J Surg Pathol 2002

Distant extension: lymph nodes

Recommendations > 12But…

Tougeron et al. Modern Path 2009.

Distant extension: lymph nodes

Gross examination +++

No magic number !More = better

Distant extension: lymph nodes

TNM 5th edition

>3 mm

Lymph node

No residual lymph node

Tumour deposit

Smooth shape

Lymph node

Distant extension : tumour deposits

Frankel et al. Mod Pathol 2015

TNM 6th edition TNM 7, 8th edition

Impact of « tumour deposits » (N1c)

P< 0.001

Jin et al. Am J Surg Path 2014

Jin et al. Am J Surg Path 2014

P= 0.087

Impact of « tumour deposits » (N1c)

Invasion front

Expansive InfiltrativeSvrcek et al. Cancero Dig. 2012

TNM Classification of Malignant

Tumours - 8th edition

Changes between the 7th and 8th editions

“We unite the cancer community to reduce the global cancer

burden, to promote greater equity, and to integrate cancer

control into the world health and development agenda.”

December 2016

Colon and Rectum

Definition of tumour deposit clarified

Tumour deposits (satellites) are discrete macroscopic or microscopic nodules of cancer in the

pericolorectal adipose tissue’s lymph drainage area of a primary carcinoma that are

discontinuous from the primary and without histological evidence of residual lymph node or

identifiable vascular or neural structures. If a vessel wall is identifiable on H&E, elastic or

other stains, it should be classified as venous invasion (V1/2) or lymphatic invasion (L1).

Similarly, if neural structures are identifiable, the lesion should be classified as perineural

invasion (Pn1). The presence of tumour deposits does not change the primary tumour T

category, but changes the node status (N) to N1c if all regional lymph nodes are negative

on pathological examination

Colon and Rectum

• T and N categories Unchanged

M1 Distant metastasis

M1a Metastasis confined to one

organ (liver, lung, ovary,

non regional lymph node(s))

without peritoneal

metastases

M1b Metastasis in more than one

organ

M1c Metastasis to the

peritoneum with or without

other organ involvement

Stage Unchanged except for Stage IVA,

IVB, IVC as below

Stage IV Any T Any N M1

Stage IVA Any T Any N M1a

Stage IVB Any T Any N M1b

Stage IVC Any T Any N M1c

Conclusion

New TNM

Ratio tumeur/stroma

Mesker WE et al. Cell Oncol Cell Oncol. 2007;29(5):387-98. Cell Oncol. 2009;31(3):169-78

Huijbers A et al. Ann Oncol. 2013 Jan;24(1):179-85.

Pronostic défavorable

Voie CIN Voie MSIVoie CIMP≈20 % 15- 20 %80-85 %

Syndrome de

Lynch

Tumeurs

festonnéesCarcinome classique

Cancer du

sujet âgé

Classification moléculaire CCR

Lieberkühnien Festonné Médullaire/ lymphocytes

Instabilité chromosomique Instabilité épigénétique Instabilité microsatellitaire

KRAS TP 53 BRAF

Profil moléculaire CCR

- Corrélation morphologique?

- Intégration clinique ?

RAS et BRAF WT

Mutation

KRAS exon 2

Mut KRAS

ex 3, 4

40%

Mut

NRAS

50%

RAS muté

HER-2

BRAF

10%

MSI

15%

Amplifications: 2,5%

Mutations: 1,9%

Courtoisie Astrid Lièvre

Penault-Llorca et al.ESMO 2016

Taieb et al. Jama Oncology 2016

Profil moléculaire CCR

Individualisation pronostique par IHC ?

BRAF +muté

BRAF +muté

MSI

MSS

Toon et al. Modern Pathol 2014, Dalerba et al. N Eng J Med 2015

CDX2- CDX2+