Early colorectal cancer Quality and rules for a good pathology report Histoprognostic factors

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1 Early colorectal cancer Quality and rules for a good pathology report Histoprognostic factors Pr Frédéric Bibeau, MD, PhD Head, Pathology department CHU de Caen, Normandy University, France ESMO preceptorship, Barcelona,

2 Quality and rules of a good pathology report Simple but rigourous

3 Reporting proforma for colorectal resection specimen

4 Useful histopronostic factors Early colorectal cancer (CRC)

5 Useful histopronostic factors Micrometastatic disease Adjuvant chemotherapy

6 Useful histopronostic factors Content - Tumour - Depth of invasion - Distant extension - Margins

7 Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins

8 Colorectal cancer (CRC): heterogeneous disease Different histologic types

9 CRC histologic types 90% Lieberkühnian Mucinous micropapillary adenosquamous Signet ring cells Serrated Small cells Medullary Adenocarcinoma Carcinoma

10 MSI histologic features Tumour Microenvironment Mucinous Crohn-like reaction Signet ring cells Medullary Lymphocytic infiltrate CD3+

11 CRC grading Low grade (well, moderatly differenciated) High grade (poorly/indifferenciated) modulation according to MSI status

12 Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins

13 ptnm classification MUCOSA Muscularis Muscosae --> SUB-MUCOSA MUSCULARIS SUB-SEROSA --> SEROSA --> pt Tis T1 T2 T3 T4 pn pm N0 : no positive lymph node (LN) N1 : 3 positive LN N2 : 4 positive LN M0 : No distant metastasis M1 : Distant metastasis TNM UICC th Classification Organe infiltration and / or visceral peritoneal perforation

14 Serosal involvement Gross examination +++

15 Serosal involvement pt4a 8 th TNM UICC 2016 classification Frankel et al. Mod Pathol 2015

16 <1mm Serosal involvement Deeper block levels Serosa involvement + reactive phenomenons pt3 pt4a 8 th TNM UICC 2016 classification Mesothelial Hyperplasia, inflammation, erosion, ulceration Frankel et al. Mod Pathol 2015

17 Serosal involvement pt4a 8 th TNM UICC 2016 classification Frankel et al. Mod Pathol 2015

18 Tumour budding optionnal Invasion front Wang LM, Am J Surg Path 2009

19 Tumour budding optionnal Tumor budding Score (0,785 mm 2 ) (Hot Spot method, X 20) HE staining 1 (Budd 1) < 5 Faible 2 (Budd 2) 5-10 Intermédiaire 3 (Budd 3) 10 Elevé Recommandations AJCC 8 th edition, Bern International Consensus Lugli et al, Modern Path 2017

20 Immune adaptative microenvironment optionnal Galon et al. Cancer Res 2007

21 Prognostic impact of immune response

22 Immune adaptative microenvironnement optionnal

23 Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins

24 ptnm classification MUCOSA Muscularis Muscosae --> SUB-MUCOSA MUSCULARIS SUB-SEROSA --> SEROSA --> pt Tis T1 T2 T3 T4 pn N0 : no positive lymph node (LN) N1 : 3 positive LN N2 : 4 positive LN N+ Organe infiltration and / or visceral peritoneal perforation pm M0 : No distant metastasis M1 : Distant metastasis Adjuvant chemotherapy TNM UICC th Classification

25 Distant extension: lymph nodes Recommendations > 12 But More = Better

26 Distant extension : tumour deposits Nx N0 N1 N2 N1a N1b N1c N2a N2b Lymph node status not asessable No positive regional lymph node Metastase(s) in 1-3 regional lymph node(s) 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 4 or more positive regional lymph nodes 4-6 regional positive lymph nodes 7 regional positive lymph nodes TNM UICC th Classification

27 Distant extension : tumour deposits Pericolic or -rectal tissu location Puppa et al. Modern Pathol 2007

28 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

29 Impact of «tumour deposits» N+/TD+: Next TNM classification (9 th edition)? Nagtegaal et al. J Clin Oncol :

30 Distant extension : N+ subdivision Nx N0 N1 N2 N1a N1b N1c N2a N2b Lymph node status non assessable No positive regional lymph node Metastase(s) in 1-3 regional lymph node(s) 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 4 or more positive regional lymph nodes 4-6 regional positive lymph nodes 7 regional positive lymph nodes TNM UICC th Classification 3 vs 6 months CT? Clinical trials stratification

31 Distant extension : VELIPI* Lymphatic invasion Venous invasion Perineural invasion Harris et al, Am J Surg Path 2008 Mori et al. Histopathology 2009 Liebig et al J Clin Oncol 2010 L category V category Pn1 category 8 th TNM UICC 2016 classification *Venous emboli and lymphatic and perineural invasion

32 Extra-mural venous invasion 30%: frequent underestimation? Nagtegaal et al. histopathology 2015

33 Perineural invasion OS DFS CSS Knijn et al. Am J Surg Path 2015

34 Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins

35 Margins Circumferential (Rectum) Distal ans proximal very rarely positive

36 Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins

37 Molecular profile Microsatellite instability (15%) Immunohistochemistry Molecular biology Normal DNA MSI tumour Less or supplementary nucleotides Favorable prognosis in CCR stage II

38 Molecular profile 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

39 Perspectives: liquid biopsy Minimal residual disease Tie J, sci Transl Med 2016 Pierre Laurent-Puig lecture +++ ADN tumoral circulant (ADN ct) Cellule tumorale circulante (CTC) MicroARN (mirna) Adapted from Diaz et al J Clin Oncol 2014; 32:579-86

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

41 Take home messages

42 Useful histopronostic factors for treatment Early CRC in ptnm - Grade - VELIPI - MSI

43 Useful histopronostic factors for treatment Early CRC in 2016 Stage III - ptnm N+ (including N1c= tumour dep.) adjuvant CT - Grade - VELIPI - MSI

44 Useful histopronostic factors for treatment Early CRC in 2016 Stage II - ptnm N0 pt4 (serosa +), <12 N - Grade high (poor differenciation) - VELIPI + - MSI - Adjuvant CT (Multidisciplinary team discussion)

45 Pathology report key elements Multidisciplinary board OMS Histologic type Differenciation (Grade) Extension - Tumour (pt) - Lymph node (pn) Margins - Distal/proximal - Circumferential (Rectum) Lymphatics Veins Nerves Vasculo-lymphatic and perineural invasions

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47 Reporting proforma for colorectal cancer

48 Translationnal research

49 Back up slides

50 Distant extension: lymph nodes Recommendations > 12 But Goldstein et al. Am J Surg Pathol 2002

51 Distant extension: lymph nodes Tougeron et al. Modern Path 2009.

52 Distant extension: lymph nodes Gross examination +++ No magic number! More = better

53 Distant extension : tumour deposits TNM 5 th edition TNM 6 th edition TNM 7, 8 th edition >3 mm Lymph node Smooth shape Lymph node No residual lymph node Tumour deposit Frankel et al. Mod Pathol 2015

54 Impact of «tumour deposits» (N1c) P< Jin et al. Am J Surg Path 2014

55 Impact of «tumour deposits» (N1c) P= Jin et al. Am J Surg Path 2014

56 Invasion front Expansive Infiltrative Svrcek et al. Cancero Dig. 2012

57 TNM Classification of Malignant Tumours - 8 th edition Changes between the 7 th and 8 th editions December 2016 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.

58 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

59 Colon and Rectum T and N categories Unchanged M1 M1a M1b M1c Distant metastasis Metastasis confined to one organ (liver, lung, ovary, non regional lymph node(s)) without peritoneal metastases Metastasis in more than one organ 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

60 New TNM Conclusion

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62 Ratio tumeur/stroma Pronostic défavorable Mesker WE et al. Cell Oncol Cell Oncol. 2007;29(5): Cell Oncol. 2009;31(3): Huijbers A et al. Ann Oncol Jan;24(1):

63 Classification moléculaire CCR Instabilité chromosomique Instabilité épigénétique Instabilité microsatellitaire Voie CIN % Voie CIMP Voie MSI 20 % % Carcinome classique Tumeurs festonnées Cancer du sujet âgé Syndrome de Lynch Lieberkühnien Festonné Médullaire/ lymphocytes KRAS TP 53 BRAF

64 Profil moléculaire CCR - Corrélation morphologique? - Intégration clinique?

65 Profil moléculaire CCR Amplifications: 2,5% Mutations: 1,9% HER-2 Mutation KRAS exon 2 RAS et BRAF WT 40% RAS muté 50% MSI 15% Penault-Llorca et al.esmo 2016 Taieb et al. Jama Oncology 2016 BRAF 10% Mut KRAS ex 3, 4 Mut NRAS Courtoisie Astrid Lièvre

66 Individualisation pronostique par IHC? CDX2- CDX2+ BRAF + muté MSI BRAF + muté MSS Toon et al. Modern Pathol 2014, Dalerba et al. N Eng J Med 2015