Post on 05-Jul-2020
EARLY COLORECTAL CANCERThe point of view of the pathologist
Name
Cord Langner, MD
Diagnostic & Research Institute of Pathology, Medical University, Graz, Austria
DISCLOSURE OF INTEREST
No conflict of interest
AGENDA
Early colorectal cancer: pathology report of endoscopic resections Locally advanced colorectal cancer: pathology report of surgical
resections
„MALIGNANT POLYP“
Langner & Vieth in: Multidisciplinary Treatment of Colorectal Cancer, Springer 2015
„MALIGNANT POLYP“
Langner & Vieth in: Multidisciplinary Treatment of Colorectal Cancer, Springer 2015
>2000µm
D2-40
RISK ASSESSMENT
Resch & Langner, Cesk Patol 2015
0-3% N positive 8-10% N positive 20-25% N positive
N positive
Level 1/2 (head / neck invasion) 0
Level 3 (stalk invasion) 6%
Level 4 (invasion beyond the stalk) 20-25%
RISK ASSESSMENT
Resch & Langner, Cesk Patol 2015
Kikuchi level sm1 / Haggitt levels 1-3 / SM-invasion <1000µm
andNo poor differentiation (G1/G2)
andNo lymphatic invasion (L0)
andNo high grade tumour budding
andClear resection margin (R0)
Low Risk
Endoscopictherapy regarded
as sufficient
High Risk
Surgical therapyrecommended
Kikuchi level sm3 / Haggitt level 4 / SM-invasion >1000µm
orPoor differentiation (G3)
orPresence of lymphatic invasion (L0)
orHigh grade tumour budding
orPositive resection margin (R0)
RECENT DEVELOPMENTS
Debove et al. Colorectal Dis 2016
RECENT DEVELOPMENTS
Yasue et al. J Gastroenterol 2019
THE GOOD PATHOLOGY REPORTEarly colorectal cancer – endoscopic resection
In (suspected) early lesions it is not sufficient just to state the presence of colorectal cancer All features relevant for risk assessment and clinical decision making need to be considered
Depth of invasion Tumour grade Vascular invasion (L1, V1 – theoretically also perineural invasion) Tumour budding Margin status (measure distance to resection margin)
Pathological risk assessment (low risk versus high risk) has to be made (with or without a comment regarding the appropriate treatment strategy)
ASSESSMENT OF THE SURGICAL SPECIMEN
Distance to proximal, distal and circumferential margins should be documented (in millimetres, separately for primary tumour and involved lymph nodes), which is particularly important for rectum cancer specimens
ASSESSMENT OF THE SURGICAL SPECIMEN
LYMPH NODE STAGING (N CATEGORY)
Resch & Langner. World J Gastroenterol 2013
TNM 8 (2017)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 (…) it should be classified as venous invasion (V1/V2) 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 nodes are negative on pathological examination.
LYMPH NODE STAGING (N CATEGORY)
Resch & Langner. World J Gastroenterol 2013
Minimum number of 12 lymph nodes Thoroughness of the pathologist in dissecting the resection
specimen ≥ 95% of specimens without neoadjuvant therapy (DKG) Technical methods to increase lymph node yield: methylene blue
injection, fat clearing, acetone (with or without compression) Absolute number of retrieved lymph nodes Absolute number of positive lymph nodes Lymph node ratio Presence of extracapsular invasion Technical issues (number of histological sections and/or use of
immunohistochemistry to identify micrometastasis and/or isolated tumourcells)
LYMPH NODE STAGING (N CATEGORY)
Rössler, Langner et al. Mod Pathol 2017
Lymph node size is related to presence of lymph node metastasis. A, mean size of positive nodes is 5.6 ± 1.9 mm, compared to 3.6 ± 0.8 mm in
negative nodes (P<0.001). B, mean node size in N-positive tumors is 4.0 ±0.9 mm, compared to 3.6 ± 0.8 mm in N-negative tumors (P=0.008).
LYMPH NODE STAGING (N CATEGORY)
Rössler, Langner et al. Mod Pathol 2017
Lymph node size is related to presence of lymph node metastasis. A, mean size of positive nodes is 5.6 ± 1.9 mm, compared to 3.6 ± 0.8 mm in
negative nodes (P<0.001). B, mean node size in N-positive tumors is 4.0 ±0.9 mm, compared to 3.6 ± 0.8 mm in N-negative tumors (P=0.008).
LYMPH NODE STAGING (N CATEGORY)
Nagtegaal et al. J Clin Oncol 2017
HISTOLOGICAL TYPING
Langner et al. Histopathology 2012; Hugen et al. Ann Oncol 2014
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100 120Time (months)
Dis
ease
-free
sur
viva
l pro
babi
lity
Conventional adenocarcinoma
Adenocarcinoma with mucinous component
Mucinous adenocarcinoma
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100 120
Time (months)
Can
cer-
spec
ific
surv
ival
pro
babi
lity
Conventional adenocarcinoma
Adenocarcinoma with mucinous component
Mucinous adenocarcinoma
HISTOLOGICAL GRADING
Langner et al. Histopathology 2012; Nagtegaal et al. WHO Classification 5th Edition 2019
“Grading of CRC is based on gland formation: low-grade (formerly well to moderately differentiated differentiated) and high-grade (formerly poorly differentiated) tumours. Grading is based on the
least differentiated component. The invasion front, where formation of tumour budding and poorly differentiated clusters occurs as a sign of epithelial-mesenchymal transition, should not be taken
into account when grading the tumour, but should be reported separately.”
Low-grade
High-grade
“Grading in mucinous adenocarcinoma should be based upon glandular
formation and epithelial maturation.”
HISTOLOGICAL GRADING
Resch, Langner et al. Int J Colorectal Dis 2017
HISTOLOGICAL GRADING
Resch, Langner et al. J Clin Pathol 2015
MOLECULAR GRADING
Neumann & Kirchner. Pathologe 2014
MorphologicalGrading
G2 G3 G4
>95% glands
50-95% glands
>0-49% glands
0% glands
Adenocarcinoma(NOS)
UndifferentiatedCarcinoma
G1
Low Grade High Grade
Molecular Grading (MSI-Status)
Adenocarcinoma G3,undifferentiated carcinoma
and MSI-associated variants(mucinous, signet-ring cell,
medullary, serrated)
Low Grade High Grade
Immunohistochemistry for hMLH1/hMSH2
negative positive
LYMPHOVASCULAR INVASION
Betge, Langner et al. Cancer 2012
LYMPHOVASCULAR INVASION
Betge, Langner et al. Cancer 2012; Hwang et al. Cancer Res Treat 2016
Protrudingnose sign
LYMPHOVASCULAR INVASION
Betge, Langner et al. Cancer 2012; Dawson et al. Front Oncol 2015
LYMPHOVASCULAR INVASION
Betge, Langner et al. Cancer 2012; Knijn et al. Histopathology 2018
PERINEURAL INVASION
Pöschl, Langner et al. J Clin Oncol 2010
PERINEURAL INVASION
Knijn et al. Am J Surg Pathol 2016
n % range
Colorectal Cancer 11321 2 0.6-41.9%
Colon Cancer 4637 6 2.1-39.3%
Rectal Cancer 6942 10 6.3-35.4%
TUMOUR BUDDING
Betge, Langner et al. Ann Surg Oncol 2012; Max, Langner et al. Br J Cancer 2016; Rogers et al. Br J Cancer 2016; Lugli et al. Mod Pathol 2017
Tumour budding is defined as the presence of isolated single cells
or small clusters of cells (1-4 cells) at the invasive tumour margin
TUMOUR BUDDING
Betge, Langner et al. Ann Surg Oncol 2012; Max, Langner et al. Br J Cancer 2016; Rogers et al. Br J Cancer 2016; Lugli et al. Mod Pathol 2017
Assessment of tumour budding should be performed on H&E stained slides according to the ITBCC consensus
recommendation (Bd1-Bd3; Lugli et al.)
TUMOUR-ASSOCIATED INFLAMMATION
Klintrup, Mäkinen et al. Eur J Cancer 2005; Harbaum, Langner et al. Mod Pathol 2015; Max, Langner et al. Br J Cancer 2016
TUMOUR-ASSOCIATED INFLAMMATION
Pagès et al. Lancet 2018
“An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore Assay in patients with TNM stage I–III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology.”
TUMOUR-ASSOCIATED INFLAMMATION
Pagès et al. Lancet 2018
“An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I–III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology.”
CIRCUMFERENTIAL MARGIN & TME SURGERY
Parfitt & Drimann. J Clin Pathol 2007; Nagtegaal & Quirke. J Clin Oncol 2008; Bosch & Nagtegaal. Curr Colorectal Cancer Rep 2012
CIRCUMFERENTIAL MARGIN & TME SURGERY
Parfitt & Drimann. J Clin Pathol 2007; Nagtegaal & Quirke. J Clin Oncol 2008; Bosch & Nagtegaal. Curr Colorectal Cancer Rep 2012; Glynne-Jones et al. Ann Oncol 2017
CIRCUMFERENTIAL MARGIN & TME SURGERY
Parfitt & Drimann. J Clin Pathol 2007; Nagtegaal & Quirke. J Clin Oncol 2008; Bosch & Nagtegaal. Curr Colorectal Cancer Rep 2012
The distance to the CRM needs to bemeasured (in mm) and documented
in the pathology report
THE GOOD PATHOLOGY REPORT Locally advanced colorectal cancer – surgical resection
Typing (WHO classification) Grading of adenocarcinoma (WHO classification)
Low-grade: former grade 1 (>95% gland formation) and grade 2 (50-95% gland formation) High-grade: former grade 3 (<50% gland formation)
Assessment of prognostic parameters Lymphatic and venous invasion (L1, V1) Perineural invasion (Pn1) Tumour cell budding
Staging (AJCC/UICC TNM System, 8th edition) Margin status and R classification Special issues in rectal cancer
Quality of TME surgery (Grade 1 - Grade 3 or anatomic resection plane) Circumferential margin (CRM; in millimetres) Regression grading after neoadjuvant treatment
WHO CLASSIFICATION 5TH EDITION
Nagtegaal, Arends, and Salto-Tellez 2019
WHO CLASSIFICATION 5TH EDITION
Nagtegaal, Arends, and Salto-Tellez 2019
TAKE HOME MESSAGES
Pathology report of endoscopic resections Factors predicting recurrence and/or lymph node metastasis: depth of invasion,
differentiation, lymphatic (and venous) invasion, tumour budding, margin status Risk stratification (low-grade versus high-grade)
Pathology report of surgical resections Accurate staging (T and N classification), typing (adenocarcinoma NOS versus
variants, and grading (low-grade versus high-grade) Prognostic parameters: Lymphatic and venous invasion (extramural > intramural),
perineural invasion, budding, and tumour-associated inflammation (lymphatic cells: CD3 and CD8 positive T-cells; neutrophils, eosinophils, macrophages)
Special issue in rectal cancer
THANK YOU VERY MUCH FOR YOUR KIND ATTENTION!
Cord Langner MDDiagnostic and Research Institute of Pathology Diagnostic and Research Center for Molecular BioMedicineMedical University of Graz / Austria cord.langner@medunigraz.atEuropean Network of Gastrointestinal Pathology (ENGIP)www.medunigraz.at/ENGIPwww.facebook.com/ENGIPAdvanced Training Center of Gastrointestinal Pathology of the European Society of Pathology (ESP)