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)