Please Silence Your Cell Phones. Thank You

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2 Please Silence Your Cell Phones Thank You

3 TUMOR BUDDING IN PRE OPERATIVE BIOPSIES AND RESECTIONS Alessandro Lugli, MD Institute of Pathology and Translational Research Unit (TRU) University of Bern Bern, Switzerland

4 Disclosure of Relevant Financial Relationships The USCAP requires that anyone in a position to influence or control the content of all CME activities disclose any relevant relationship(s) which they or their spouse/partner have, or have had within the past 12 months with a commercial interest(s) [or the products or services of a commercial interest] that relate to the content of this educational activity and create a conflict of interest. Complete disclosure information is maintained in the USCAP office and has been reviewed by the CME Advisory Committee. Dr. Alessandro Lugli declares he has no conflict(s) of interest to disclose.

5 CONTENT DEFINITION AND CHARACTERISTICS OF TUMOR BUDDING CLINICAL IMPLICATIONS OF TUMOR BUDDING PRACTICAL ASPECTS OF TUMOR BUDDING SUMMARY & OPEN POINTS

6 TUMOR BUDDING At a glance Definition Single tumor cells or clusters of up to 5 tumor cells at the invasive margin Jass et al, JCP 2003 Characteristics Part of the tumor microenvironment (EMT like cells?) Transformation to a motile and invasive phenotype Low proliferation Marker of tumor progression

7 TUMOR BUDDING A motile and invasive phenotype Protein level Increased expression MMP2 (c), MMP 9 (c) CathB (c), CXCL12 (m/c) b Catenin (n) Beta III Tubulin (c) hmena (c), cyclin D1 (n) Laminin5y2 (c), p16 (n) ABCG5 (c), CD133 (c) Decreased expression Ki67 (n) E Cadherin (c) m: membraneous c: cytoplasmic n: nuclear Molecular level Deregulation of the wnt signalling pathway Activated p16ink4a Less frequent in MSI H CRC MSS/MSI, KRAS and BRAF mutational status (Zhao et al, Poster Session III # 62) Zlobec et al, Oncotarget 2010 Jass et al, JCP 2003 Zlobec et al, Histopathology 2012

8 TUMOR BUDDING Low proliferation Dawson et al, Histopathology 2014

9 TUMOR BUDDING A marker of tumor progression Tumor budding is associated with: Lymphovascular invasion (L and V stage) Selected references: Okuyama et al, J Surg Oncol 2003 Ueno et al, Gastroenterology 2004 Nakamura et al, Dis Colon Rectum 2008 Wang et al, Am J Surg Pathol 2009 Lymph node metastasis (N stage) Karamitopoulou et al, Mod Pathol 2013 Hase et al, Dis Colon Rectum 1993 Distant metastasis (M stage) Tateishi et al, Mod Pathol 2010 Choi et al, Int J Colorect Dis 2007

10 CONTENT DEFINITION AND CHARACTERISTICS OF TUMOR BUDDING CLINICAL IMPLICATIONS OF TUMOR BUDDING PRACTICAL ASPECTS OF TUMOR BUDDING SUMMARY & OPEN POINTS

11 TUMOR BUDDING Potential clinical scenarios Malignant polyps Tumor budding as a predictor of lymph node metastases Clinical implication: resection Stage II CRC Tumor budding as a factor of tumor progression Clinical implication: adjuvant therapy Pre operative biopsies of colon and rectal cancer Tumor budding as a factor of tumor progression and predictor of regression grade and (non ) response to neo adjuvant therapy Clinical implication: neo adjuvant therapy

12 TUMOR BUDDING Malignant polyps Risk factors for an adverse outcome in early invasive colorectal carcinoma Absence of Unfavourable tumor grade Vascular invasion Tumor budding Extensive submucosal invasion Ueno et al, Gastroenterology 2004 Watch and see policy Systematic review including 17 studies: tumor budding and nodal involvement Sensitivity: 74.7%; Specificity: 63.4% PPV: 21.3%; NPV: 95% Bosch et al, Endoscopy 2013

13 TUMOR BUDDING Malignant polyps Tumor budding in malignant polyps predicts pn+ status: In 22 of 24 studies Between 2002 and 2013 High grade budding frequency: 11.8% 50.5% Koelzer et al, Future Medicine Colorectal Cancer 2014 Tumor budding in stage I CRC predicts OS and DFS: In 8 of 10 studies Between 2005 and 2013 In 5 of 10 studies independent prognostic factor van Wyk et al, Cancer Treatment Reviews 2015

14 TUMOR BUDDING Stage II CRC Selected studies on stage II CRC and tumor budding as a marker of progression: Colon Cancer Tanaka et al, Dis Colon Rectum 2003 (n=138) Nakamura et al, Dis Colon Rectum 2008 (n=200) Rectal Cancer Okuyama et al, J Surg Oncol 2003 (n=83) Masaki et al, J Surg Oncol 2005 (n=72) Wang et al, Am J Surg Pathol 2009 (n=128) Betge et al, Ann Surg Oncol 2012 (n=120) Canney et al, Histopathology 2012 (n=205) Horcic et al, Hum Pathol 2013 (n=105)

15 TUMOR BUDDING Pre operative biopsies Intratumoral budding (ITB) canbeappliedin pre operative biopsies Lugli et al, Human Pathology 2011 ITB in pre operative biopsies is associated with nodal and distant metastases Giger et al, Mod Pathol 2012; Zlobec et al, BJC 2014 ITB is associated with higher T stage, higher N stage, lymphovascular invasion, response to neo adjuvant therapy and poor survival in pre operative rectal cancer biopsies Rogers et al, Mod Pathol 2014

16 Mitrovic et al, Modern Pathology 2012

17 TUMOR BUDDING Classifications and guidelines WHO Classification of Tumours of the Digestive System 2010 Bosman, Carneiro, Hruban, Theise Prognostic factors not included in the TNM staging of carcinoma of the colon and rectum: infiltrative pattern of invasion / budding UICC Prognostic Factors in Cancer 2006 Gospodarowicz, O Sullivan, Sobin Tumor budding: additional prognostic factor AJCC Cancer Staging Manual 2010 Tumor budding: not included CAP Protocol for the Examination of Specimens From Patients With Primary Carcinoma of the Colon and Rectum 2013 Tumor budding: not included Royal College of Pathologists 2014 Tumor budding: mentioned, but not implemented Uptodate 2014 Tumor budding: category IIB factor: shown to be promising in multiple studies; data insufficient for inclusion in category I or IIA.

18 TUMOR BUDDING Examples for other tumor types Breast cancer (ductal) N=160 Independent prognostic factor Liang et al, Pathol Res Pract 2013 Lung cancer N=485 Independent prognostic factor Kadota et al, J Torac Oncol 2014 Oesophageal and gastro oesophageal junction cancers N=356 Independent prognostic factor Brown et al, Histopathology 2010 Pancreatic cancer (PDAC) N=117 Independent prognostic factor Karamitopoulou et al, Eur J Cancer 2013 Head and neck squamous cell carcinoma Systematic review (N=5 studies) Marker of tumor progression and prognosis Almangush et al, Histopathology 2014

19 CONTENT DEFINITION AND CHARACTERISTICS OF TUMOR BUDDING CLINICAL IMPLICATIONS OF TUMOR BUDDING PRACTICAL ASPECTS OF TUMOR BUDDING SUMMARY & OPEN POINTS

20 TUMOR BUDDING Points to discuss H&E versus immunohistochemistry Scoring systems in the literature Which scoring systems for resections and biopsies?

21 TUMOR BUDDING H&E vs immunohistochemistry The aim should be: Optimal visualization Reflection of the real tumor bud count Reproducibility User friendly for daily diagnostics Detection of tumor buds in lymphatic and blood vessels panck/cd8

22 van Wyk et al, Cancer Treatment Reviews 2015

23 TUMOR BUDDING Practical example Elastin panck/d240

24 TUMOR BUDDING Selected scoring systems Hase method None/mild vs moderate/severe Predominant pattern at the invasive front Nakamura method None Mild (1/3 of the invasive front with tumor buds) Moderate (1/3 2/3 of the invasive front with tumor buds) Marked (>2/3 of the invasive front with tumor buds) Ueno method Low power, densest tumor budding region Positive: 5 buds in x20 visual field (0.785mm2) Wang method Densest region at x40, counting 5 HPFs (x200) Cut off: 9 buds (low grade) Rapid Wang method 9 buds: negative, 10 buds: positive 50% positive fields: high grade 1 HPF method Densest region (0.49mm2) 6 buds: low grade; >6 buds: high grade Continuous scale 10 HPF method Ten densest regions (0.49mm2) 100 buds: low grade; >100 buds: high grade Continuous scale

25 TUMOR BUDDING IN RESECTIONS 1 HPF & 10 HPF method Horcic et al, Hum Pathol 2011

26 TUMOR BUDDING IN RESECTIONS Validation of the 10 HPF method Karamitopoulou et al, Mod Pathol 2012

27 SWISS ASSOCIATION OF GASTROINTESTINAL PATHOLOGY (SAGIP) STUDY Reproducibility of the 1HPF and 10HPF method 6 centers (4 academic centers, 1 community hospital and 1 private practice) 50 CRC cases (all stages) Tumor buds criteria Single cells or clusters of up to 5 cells Clear panck staining Nucleus present Pseudofragments and necrosis excluded Koelzer et al, Poster Session III # 61

28 SWISS ASSOCIATION OF GASTROINTESTINAL PATHOLOGY (SAGIP) STUDY Reproducibility of the 1HPF and 10HPF method Koelzer et al, Poster Session III # 61

29 SWISS ASSOCIATION OF GASTROINTESTINAL PATHOLOGY (SAGIP) STUDY Reproducibility of the 1HPF and 10HPF method Koelzer et al, Poster Session III # 61

30 INTRATUMORAL BUDDING IN CRC Peritumoral budding (PTB) = tumor buds at the invasive front of CRC Intratumoral budding (ITB) = tumor buds within the CRC center ITB (>6 buds pro HPF) is associated with: Higher T stage Higher N stage Vascular invasion PTB Infiltrative margin Poor survival Lugli et al, Hum Pathol 2011

31 INTRATUMORAL BUDDING 1 HPF method in pre operative CRC biopsies Zlobec et al, BJC 2014

32 TUMOR BUDDING Application of the 1HPF & 10HPF method Koelzer et al, Poster Session III # 61

33 TUMOR BUDDING Possible workflow Colon & rectal cancer specimens Colon & rectal cancer biopsies Colon & rectal cancer resections 1 HPF hot spot Cut off: 6 buds or Continuous scale 1 HPF hot spot in malignant polyps Cut off: 6 buds Continuous scale 10 HPF in advanced CRC Cut off: 100 buds Continuous scale

34 CONTENT DEFINITION AND CHARACTERISTICS OF TUMOR BUDDING CLINICAL IMPLICATIONS OF TUMOR BUDDING PRACTICAL ASPECTS OF TUMOR BUDDING SUMMARY & OPEN POINTS

35 TUMOR BUDDING Summary Based on the literature tumor budding is a histomorphological biomarker of tumor progression and an independent prognostic factor The fields of action may include malignant polyps, stage II CRC and pre operative biopsies The prognostic power of tumor budding seems to be independent of the applied scoring system Our own experience in Bern: ITB (1HPF) can be used in pre operative biopsies as well as in malignant polyps whereas PTB (10HPF) can be applied in stage II CRC

36 TUMOR BUDDING Open points Three points need to be adressed for a standardized scoring system Consensus on the scoring system H&E vs immunohistochemistry Cut offs vs continuous probability scale Validation on retrospective and prospective large multicentric cohorts Shall tumor budding replace glandular formation for the definition of tumor grade (G) in the TNM classification? MULTICENTRIC STUDY IN PREPARATION

37 ACKNOWLEDGMENTS Interdisciplinary CRC Research Group, University and University Hospital Bern, Switzerland: Translational Research Unit (TRU) & Clinical Pathology Division Inti Zlobec, PhD Lena Sokol, PhD Viktor Kölzer, MD Heather Dawson, MD Gregor Rieger, MD Oncology Department Martin Berger, MD Visceral Surgery and Medicine Department Daniel Inderbitzin, MD Beat Schnüriger, MD Lukas Brügger, MD Marion Hädrich, MD

38 Important Information Regarding CME/SAMs The Online CME/Evaluations/SAM claim process will only be available on the USCAP website until October 2, No claims can be processed after that date! After October 2, 2015 you will NOT be able to obtain any CME or SAMs credits for attending this meeting.

39 Thank You! Please go to the USCAP website to complete your Evaluation of the course and claim CME and/or SAMs Credits.