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, 20.10.17
Quality and rules of a good pathology report Simple but rigourous
Reporting proforma for colorectal resection specimen
Useful histopronostic factors Early colorectal cancer (CRC)
Useful histopronostic factors Micrometastatic disease Adjuvant chemotherapy
Useful histopronostic factors Content - Tumour - Depth of invasion - Distant extension - Margins
Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins
Colorectal cancer (CRC): heterogeneous disease Different histologic types
CRC histologic types 90% Lieberkühnian Mucinous micropapillary adenosquamous Signet ring cells Serrated Small cells Medullary Adenocarcinoma Carcinoma
MSI histologic features Tumour Microenvironment Mucinous Crohn-like reaction Signet ring cells Medullary Lymphocytic infiltrate CD3+
CRC grading Low grade (well, moderatly differenciated) High grade (poorly/indifferenciated) modulation according to MSI status
Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins
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 2016 8 th Classification Organe infiltration and / or visceral peritoneal perforation
Serosal involvement Gross examination +++
Serosal involvement pt4a 8 th TNM UICC 2016 classification Frankel et al. Mod Pathol 2015
<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
Serosal involvement pt4a 8 th TNM UICC 2016 classification Frankel et al. Mod Pathol 2015
Tumour budding optionnal Invasion front Wang LM, Am J Surg Path 2009
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
Immune adaptative microenvironment optionnal Galon et al. Cancer Res 2007
Prognostic impact of immune response
Immune adaptative microenvironnement optionnal
Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins
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 2016 8 th Classification
Distant extension: lymph nodes Recommendations > 12 But More = Better
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 2016 8 th Classification
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
Impact of «tumour deposits» N+/TD+: Next TNM classification (9 th edition)? Nagtegaal et al. J Clin Oncol 2017 35:1119-1127
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 2017 8 th Classification 3 vs 6 months CT? Clinical trials stratification
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
Extra-mural venous invasion 30%: frequent underestimation? Nagtegaal et al. histopathology 2015
Perineural invasion OS DFS CSS Knijn et al. Am J Surg Path 2015
Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins
Margins Circumferential (Rectum) Distal ans proximal very rarely positive
Useful histopronostic factors - Tumour - Depth of invasion - Distant extension - Margins
Molecular profile Microsatellite instability (15%) Immunohistochemistry Molecular biology Normal DNA MSI tumour Less or supplementary nucleotides Favorable prognosis in CCR stage II
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
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
Perspectives - Treatment for particular stage II? - No treatment for certain stage III?
Take home messages
Useful histopronostic factors for treatment Early CRC in 2017 - ptnm - Grade - VELIPI - MSI
Useful histopronostic factors for treatment Early CRC in 2016 Stage III - ptnm N+ (including N1c= tumour dep.) adjuvant CT - Grade - VELIPI - MSI
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)
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
Reporting proforma for colorectal cancer www.sfpathol.org www.ecancer.fr
Translationnal research
Back up slides
Distant extension: lymph nodes Recommendations > 12 But Goldstein et al. Am J Surg Pathol 2002
Distant extension: lymph nodes Tougeron et al. Modern Path 2009.
Distant extension: lymph nodes Gross examination +++ No magic number! More = better
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
Impact of «tumour deposits» (N1c) P< 0.001 Jin et al. Am J Surg Path 2014
Impact of «tumour deposits» (N1c) P= 0.087 Jin et al. Am J Surg Path 2014
Invasion front Expansive Infiltrative Svrcek et al. Cancero Dig. 2012
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.
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 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
New TNM Conclusion
Ratio tumeur/stroma Pronostic défavorable 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.
Classification moléculaire CCR Instabilité chromosomique Instabilité épigénétique Instabilité microsatellitaire Voie CIN 80-85 % Voie CIMP Voie MSI 20 % 15-20 % Carcinome classique Tumeurs festonnées Cancer du sujet âgé Syndrome de Lynch Lieberkühnien Festonné Médullaire/ lymphocytes KRAS TP 53 BRAF
Profil moléculaire CCR - Corrélation morphologique? - Intégration clinique?
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
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