68 e 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 TNM4 TNM5 TNM6 III (T2N1) III (T2N1) III (T2N1) I (T2N0) III (T2N1) II (T3N0) I (T2N0) II (T3N0) III (T2N1) 2 mm
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
0.2 0 0.6 0.4 1 0.8 1.4 1.2 2 1.8 1.6 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+ Less LR with CRM+ no difference Nagtegaal & Quirke, JCO 2008
Single-Arm Studies Support the Hypothesis for KRAS as a Biomarker for EGFR Inhibitors Reference Treatment (panitumumab or cetuximab) Objective Response N (%) 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) WT, wild type; MT, mutant; cmab, cetuximab; CT, chemotherapy; pmab, panitumumab cmab 80 (50:30) 0 (0) 5 (10)
KRAS CAIRO genotypering trial: effecten (n=520) 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)
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
Y Immunomagnetic Labeling and Immunofluorescent Identification of Cells Nucleus DAPI EpCAM CK Anti-EpCAM Ferrofluid Anti- CK-PE Nucleus DAPI EpCAM CK Anti-EpCAM Ferrofluid HER2 Anti- CK-PE Anti- HER-2 fluorescein Nucleus DAPI CD45 Anti - CD45-APC Circulating Tumor Cell CTC + HER-2/neu TPR* Leukocyte * 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
Immunomagnetic Labeling and Immunofluorescent Identification of Cells Anti-EpCAM Ferrofluid Nucleus DAPI EpCAM CK Anti- CK-PE Circulating Tumor Cell MKG-1767 rev 2 For Internal and External Use
Tol et al, Annals Oncol 2009 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)
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