Pathologie van het colorectaal

carcinoom

Iris Nagtegaal

Afdeling Pathologie

UMC St Radboud

68e Oncologiedag

Colorectale kanker

28 januari 2010

Klassieke pathologie

Moderne pathologie

• Stagering (hoog risico TNM II, TNM)

• Neoadjuvante therapie

• Kwaliteit van chirurgie

• Predictieve factoren (KRAS)

• Identificatie van erfelijke tumoren

• Therapie evaluatie?

Stagering

C.E. Dukes, 1932

Hoog risico TNM II

• Perforatie van het preparaat

• Minder dan 10 lymfklieren onderzocht

• Slechte differentiatie

• T4

• Extramurale veneuze invasie

7de editie van TNM

TNM staging

TNM4 TNM5 TNM6

III (T2N1) III (T2N1) III (T2N1)

I (T2N0) III (T2N1) II (T3N0)

2 mm

I (T2N0) II (T3N0) III (T2N1)

Definitions

• TNM4: -

• TNM5: tumor deposits greater than 3 mm

in diameter are classified as involved

lymph nodes

• TNM6: tumor nodules are classified as

lymph nodes if they have the form and

smooth contour of a lymph node

Importance of tumour deposits

Nagtegaal & Quirke, 2007

Conclusies TNM 7

• Impact op trial databases en registraties

• Niet evidence-based

• Tumor deposits: interobserver probleem

• Verwarring T4a en T4b

• UK, Zweden, Nederland: blijven bij TNM5

Effects of

neoadjuvant therapy

• Downstaging

• Decreased frequency of positive margins

• Tumor regression

Regression systems

Mandard, 1994; adapted by Dworak, 1997 for rectal cancer

Tumor cells easy to find

Tumor cells difficult to find

Obvious fibrosis/vasculopathy

Difficult to find; area?

Circumferential margin and quality of surgery

Positive margin;

poor quality of the

mesorectum

tumortumor

Mesorectal fat

tumor

Positive margin; good

quality of the mesorectum:

advanced tumor growth

Negative margin;

good quality of the

mesorectum

0

0.2

0.4

0.6

0.8 1

1.2

1.4

1.6

1.8 2

More LR with CRM+ Less LR with CRM+

no difference

no neoadjuvant therapy (n = 5585)

HR 2.2 (95%CI 1.5 – 3.2)

neoadjuvant therapy (n = 2560)

HR 6.3 (95% CI 3.6 – 16.7)

total (n = 8889)

Local recurrence

and CRM

Nagtegaal & Quirke, JCO 2008

WT, wild type; MT, mutant; cmab, cetuximab; CT, chemotherapy; pmab, panitumumab

Objective Response

N (%)

ReferenceTreatment

(panitumumab or cetuximab)No of patients (WT:MT) MT WT

A. Liévre, et al.

(AACR Proceedings, 2007) cmab CT 76 (49:27) 0 (0) 24 (49)

S. Benvenuti, et al.

(Cancer Res, 2007) pmab or cmab or cmab + CT 48 (32:16) 1 (6) 10 (31)

W. De Roock, et al.

(ASCO Proceedings, 2007) cmab or cmab + irinotecan 113 (67:46) 0 (0) 27 (40)

D. Finocchiaro, et al.

(ASCO Proceedings, 2007) cmab CT 81 (49:32) 2 (6) 13 (26)

F. Di Fiore, et al.

(Br J Cancer, 2007) cmab + CT 59 (43:16) 0 (0) 12 (28)

S. Khambata-Ford, et al.

(J Clin Oncol, 2007)cmab 80 (50:30) 0 (0) 5 (10)

Single-Arm Studies Support the Hypothesis for

KRAS as a Biomarker for EGFR Inhibitors

KRAS genotypering (n=520)CAIRO trial: effecten van KRAS mutatie

De rol van de patholoog in KRAS

mutatie-analyse

• Mutatie-analyse in eigen laboratorium of referentie-laboratorium

• Selectie meest geschikte weefselfragment

• Bepalen van de tumordichtheid, dit percentage is van belang voor

het type en de betrouwbaarheid van de gebruikte test

• Documentatie van de resultaten

• Een Europees “Quality Assurance program” is beschikbaar vanaf

2008, op initiatief van de “European Society of Pathology”

• KRAS mutation testing for predicting response to anti-EGFR therapy

for colorectal carcinoma: proposal for a European quality assurance

program (van Krieken et al, Virchows Archive, 2008)

A first activity of this European QA program is the pilot KRAS External

Quality Assessement (EQA) scheme, that was running in May – June

2009. A group of 11 laboratories out of 13 passed successfully the pilot

EQA scheme.

•Austria, Medical University of Graz

•Belgium, Leuven University Hospital

•Denmark, Odense University Hospital

•France, Laboratoire d’Oncogénétique St Cloud

•Germany, Ludwig-Maximilians Universität München

•Greece, University of Athens, Medical School

•Sweden, Clinical pathology Malmö

•Portugal, Medical Faculty of Porto

•Spain, Hospital Madrid Norte Sanchinarro

•The Netherlands, Radboud University Nijmegen Medical Centre

•UK, St James University Hospital Leeds

KRAS

European QA Program

Herkenning van erfelijke tumoren

Manders et al.

Herkenning van erfelijke tumoren

• CRC < 50 jaar

• 2e CRC < 70 jaar

• CRC <70 met gelijktijdig of daaraan

voorafgaand een Lynch syndroom

geassocieerde tumor

(baarmoeder, maag, dunnedarm, galgangen,

eierstokken, hogere urinewegen, talgklieren)

• Endometrium carcinoom < 50 jaar

Microsatelliet instabiliteit

Therapie evaluatie?

• Circulerende tumorcellen geven een

indicatie van de hoeveelheid tumorcellen

die zich in de circulatie bevinden

• Het risico op metastasering kan hierdoor

ingeschat worden

• Het effect van systemische therapie kan

hiermee geëvalueerd worden

MKG-1767 rev 2

For Internal and External Use

Circulating Tumor Cell Leukocyte

CD45

Anti -CD45-APC

CTC + HER-2/neu TPR*

Anti-EpCAMFerrofluid

EpCAMEpCAM

Anti-EpCAMFerrofluid

YHER2Anti-HER-2 fluorescein

NucleusDAPI

NucleusDAPI Nucleus

DAPI

Anti-CK-PE

CKCK

Anti-CK-PE

Immunomagnetic Labeling and

Immunofluorescent Identification of Cells

* CellSearch Tumor Phenotyping Reagent HER-2/neu is for Research Use Only and not for use in diagnostic

procedures.

MKG-1767 rev 2

For Internal and External Use

Circulating Tumor Cell

Anti-EpCAMFerrofluid

EpCAM

NucleusDAPI

Anti-CK-PE

CK

Immunomagnetic Labeling and

Immunofluorescent Identification of Cells

Therapie evaluatie?

Figure 3. The predictive value of

circulating tumour cells (CTC).

Progression-free survival (A)

and overall survival (B) in 250

patients with low baseline CTC

and low CTC after 1–2 weeks

of treatment (group I, solid black line)

in 89 patients with high baseline

CTC and low CTC after 1–2 weeks

(group II, dashed black line), and in

21 patients with high CTC at 1–2

weeks irrespective of baseline CTC

count (group III, dashed grey line)

Tol et al, Annals Oncol 2009

Moderne pathologen

• Multidisciplinair team

• Keuze van behandeling

• Kwaliteitsbewaking

• Identificeren van hoog-risico patiënten

• Vernieuwingen in de zorg van colorectale

patiënten

European Multidisciplinary

Colorectal Cancer

Congress 201028 – 30 March 2010

Nice, France

WWW.COLORECTAL2010.ORG