68e Oncologiedag Colorectale kanker 28 januari 2010
Pathologie van het colorectaal carcinoom
Iris Nagtegaal Afdeling Pathologie UMC St Radboud
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
2 mm
TNM4
TNM5
TNM6
III (T2N1)
III (T2N1)
III (T2N1)
I (T2N0)
III (T2N1)
II (T3N0)
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
Tumor cells difficult to find Tumor cells easy to find Obvious fibrosis/vasculopathy
Mandard, 1994; adapted by Dworak, 1997 for rectal cancer
Difficult to find; area?
Circumferential margin and quality of surgery
tumor
tumor
tumor
Mesorectal fat
Negative margin; good quality of the mesorectum
Positive margin; good quality of the mesorectum: advanced tumor growth
Positive margin; poor quality of the mesorectum
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Local recurrence and CRM
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) More LR with CRM+ no difference
Less LR with CRM+
Nagtegaal & Quirke, JCO 2008
Single-Arm Studies Support the Hypothesis for KRAS as a Biomarker for EGFR Inhibitors Objective Response N (%) Treatment (panitumumab or cetuximab)
No of patients (WT:MT)
MT
WT
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)
cmab
80 (50:30)
0 (0)
5 (10)
Reference A. Liévre, et al. (AACR Proceedings, 2007)
S. Khambata-Ford, et al. (J Clin Oncol, 2007)
WT, wild type; MT, mutant; cmab, cetuximab; CT, chemotherapy; pmab, panitumumab
CAIRO trial: effecten van KRAS mutatie KRAS genotypering (n=520)
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)
KRAS European QA Program 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
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
Immunomagnetic Labeling and Immunofluorescent Identification of Cells Anti-EpCAM Ferrofluid
Anti-EpCAM Ferrofluid
EpCAM
CD45
EpCAM Nucleus DAPI
HER2
CK
CK AntiCK-PE
Circulating Tumor Cell
* CellSearch procedures.
AntiHER-2 fluorescein
Nucleus DAPI
Y
Nucleus DAPI
Anti CD45-APC
AntiCK-PE CTC + HER-2/neu TPR*
Leukocyte
Tumor Phenotyping Reagent HER-2/neu is for Research Use Only and not for use in diagnostic
MKG-1767 rev 2 For Internal and External Use
Immunomagnetic Labeling and Immunofluorescent Identification of Cells
Anti-EpCAM Ferrofluid
EpCAM Nucleus DAPI
CK
AntiCK-PE Circulating Tumor Cell
MKG-1767 rev 2 For Internal and External Use
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 2010 28 – 30 March 2010 Nice, France
WWW.COLORECTAL2010.ORG
