Department of Gastroenterology- Pancreatology ESMO, Barcelona, 3 July 2013 The optimal algorithm for diagnosis and for obtaining a biopsy in pancreatic cancer Pascal HAMMEL, MD, PhD Department of Gastroenterology- Pancreatology Hôpital Beaujon 92110 Clichy France pascal.hammel@bjn.aphp.fr

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Diagnosis of pancreatic cancer 1- Take clinical context into account 2- Do not trust too much serum markers 3- Discuss biopsy - When ? - How ? - What results ? 4- Future demands for biopsy

1- Take clinical context into account - Differential diagnosis can be difficult, consequences of errors very deleterious - Importance of : age, general status, tobacco/alcohol consumption, history of pancreatitis, changes in weight, diabetes, familial history of cancers (digestive, gynecologic, skin)

Diagnosis of pancreatic cancer 1- Take clinical context into account 2- Do not trust too much serum markers 3- Discuss biopsy - When ? - How ? - What results ? 4- Future demands for biopsy

Steinberg Am J Gastroenterol 1990 2- Do not trust too much serum markers CA 19.9 False - False + Causes . Phenotype Lewis b - benign cholestasis chronic pancreatitis (50 %) liver cirrhosis (60%) Diabetes Other cancers : - biliary (70%), stomach (50%), colon (30%), oesophagus (10%), non digestive (14%) Comments 7-10% of the population No CA 19.9 on cells surface (even when pancreatic cancer) CA 19.9 not measurable (< 3U/mL) Values can be very high in common bile duct obstruction whatever cause (> 1000 U/mL) Diabetes : moderate elevation (2-3N), correlation between CA 19.9 and HbA1c Magnani J Biol Chem 1982 Steinberg Am J Gastroenterol 1990

Steinberg Am J Gastroenterol 1990 2- Do not trust too much serum markers CA 19.9 False - False + Causes . Phenotype Lewis b - benign cholestasis chronic pancreatitis (50 %) liver cirrhosis (60%) Diabetes Other cancers : - biliary (70%), stomach (50%), colon (30%), oesophagus (10%), non digestive (14%) Comments 7-10% of the population No CA 19.9 on cells surface (even when pancreatic cancer) CA 19.9 not measurable (< 3U/mL) Values can be very high in common bile duct obstruction whatever cause (> 1000 U/mL) Diabetes : moderate elevation (2-3N), correlation between CA 19.9 and HbA1c Magnani J Biol Chem 1982 Steinberg Am J Gastroenterol 1990

2- Do not trust too much serum markers Insuffisant validation, feasibility in routine practice, problems of sensitivity/specificity - KRAS (Maire, BJC 1998) - p53 (Hammel, Gut 1997) - Circulating tumor cells (Iwanicki-Caron I Am J Gastroenterol 2013, Clement-Bidard Ann Oncol 2013) - Others : CYFRA 21-1 (Boeck, BJC 2013), miR-27a-3p (Wang, Cancer Prev Res 2013), LCN2/TIMP1 (Slater, Translational Oncology 2013), serum metabolomics (Kobayashi, Cancer Epidemiol Biomarkers Prev 2013), PAM04 (Gold DV, ASCO GI 2010) … or specificity with jaundice (Tonack S, BJC 2013)

Pseudotumour : length of MPD stenose 2- Can we trust imaging methods ? Pseudotumour : length of MPD stenose CBD MPD CBD MPD Focal pancreatitis - Long/incomplete - Different level CBD Cancer Short /complete Same level CBD PMPD : Main pancreatic duct CBD : common bile duct

Suspicion of cancer on MRI : pitfall Suspect « stop » and upstream enlargement of MPD 10

Suspicion of cancer on MRI : pitfall CT CT To detect calcifications in chronic pancreatitis : CT scan > MRI

Pancreatic mass on imaging : pancreatitis or cancer ? Chronic pancreatitis often present beside a cancer… In a segment of pancreas, focal enlargement of main pancreatic duct upstream a mass … Chronic pancreatitis : risk factor for cancer (x 10-15) Relative risk high….but less than 5% of patients with old CP Chronic pancreatitis silent for long time becomes symptomatic again Calcifications are «pushed » around the mass Extrapancreatic spreading of the tumour

2- Can we trust imaging methods ? PET-18FDG Sensitivity and specificity in cancer do not exceed 80% Schick, Eur J Med Mol Imaging 2008 Kartalis Eur Radiol 2009: Dietrich Clin Gastroenterol Hepatol 2008 13

2- Can we trust imaging methods ? PET-18FDG Sensitivity and specificity in cancer do not exceed 80% Strong and diffuse signal in some benign pancreatitis False negatives in diabetes Steroid test Schick, Eur J Med Mol Imaging 2008 Kartalis Eur Radiol 2009: Dietrich Clin Gastroenterol Hepatol 2008 14

2- Can we trust imaging methods ? Endoscopic Ultrasonography (EUS) in experienced hands remains one of the best tools for diagnosis Locally advanced cancer (biopsy) Courtesy Dr Palazzo Screening of relative at risk for pancreatic cancer : islet of Pan-IN 3

Elastometry EUS 2- Can we trust imaging methods ? Contrast (E)US Hypovascularization 57/62 Differential diagnosis AIP/pNET Elastometry EUS Courtesy Dr L. Palazzo 16

Diagnosis of pancreatic cancer 1- Take clinical context into account 2- Do not trust too much serum markers 3- Discuss biopsy - When ? - How ? - What results ? 4- Future demands for biopsies

Pancreatic tumour and biopsy : why ? Gut 2008;57:1646-7 Unappropriate resection for pancreatitis Propose steroids in a patient with cancer 1- Adenocarcinoma is much more frequent than pseudotumoral pancreatitis ! 2- Do not hesitate to perform biopsy when doubtful

Pancreatic tumour and biopsy : when ? Pain, jaundice Imaging (US, CT, MRI, /+-EUS) : mass Benign or malignant ? Likely malignant (local signs, metastases) Type ? Adenocarcinoma no (pNET, autoimmune pancreatitis) Specific management

Pancreatic tumour and biopsy : when ? Pain, jaundice Imaging (US, CT, MRI, /+-EUS) : mass Benign or malignant ? Likely malignant (local signs, metastases) Type ? Adenocarcinoma yes no (pNET, autoimmune pancreatitis) Resectable ? Patient eligible ? Specific management no Biopsy Chemotherapy (CRT) or BSC

Pancreatic tumour and biopsy : when ? Pain, jaundice Imaging (CT, MRI, EUS) : mass Benign or malignant ? Likely malignant (locoregional signs, metastases) Type ? Adenocarcinoma yes no (pNET, autoimmune pancreatitis) Resectable ? Patient eligible ? Specific management yes : surgery envisaged no Neoadjuvant treatment ? biopsy yes no Chemotherapy/BSC biopsy resection

Pancreatic cancer : remind the limits of pathology EUS-FNA Cytology Conventional monolayer Courtesy Pr Couvelard

Pancreatic cancer : remind the limits of pathology EUS-FNA Cytology Microfragments Conventional monolayer Histology « cell-block » Conventional histology Informations needed : clinical context, conditions of FNA Courtesy Pr Couvelard

Pancreatic cancer : remind the limits of pathology Often poor material Mucus Blue Alcian

Pancreatic tumour and biopsy : how ? EUS-fine needle aspiration is not always the best tool !

Biopsy : more than « usual » histology ? In the near future, to only assess cancer will not be sufficient… Informations required for predictive, prognostic markers Cytoponction pancréatique. Expression membranaire intense hENT1 par cellules adénocarcinome Courtesy Dr J. Cros 26

EUS-FNA : more than « usual » histology with EUS-FNA? Cytoponction pancréatique. Expression membranaire intense hENT1 par cellules adénocarcinome hENT1 Courtesy Dr J. Cros 27

EUS-FNA : could we do more than « usual » histology ? hENT1 Différents secteurs de la meme tumeur. En haut, expression membranaire intensité modérée de hENT1 par les cellules tumorales. En bas, absence d’expression par les cellules tumorales. Problème possible d’échantillonage par la ponction. Problem of tumour heterogeneity Courtesy Dr J. Cros 28

EUS-FNA : could we do more than « usual » histology ? SPARC in the stroma and nab-paclitaxel Mantoni T et al, Cancer Biology and Therapy 2008

EUS-FNA : could we do more than « usual » histology ? Biological differences between primary and metastases ? Changes during the course of disease ?

Diagnosis of pancreatic cancer remains difficult to assess Take home messages Diagnosis of pancreatic cancer remains difficult to assess Clinical context is important Limitations of serum markers and imaging methods Cytoponction pancréatique. Expression membranaire intense hENT1 par cellules adénocarcinome 31

Diagnosis of pancreatic cancer remains difficult to assess Take home messages Diagnosis of pancreatic cancer remains difficult to assess Clinical context is important Limitations of serum markers and imaging methods Most convenient route for biopsy and close collaboration with pathologist Future: optimise analyses of material obtain Cytoponction pancréatique. Expression membranaire intense hENT1 par cellules adénocarcinome 32