ESMO, Barcelona, 3 July 2013

Pascal HAMMEL, MD, PhD

Department of Gastroenterology- Pancreatology Hôpital Beaujon

92110 ClichyFrance

pascal.hammel@bjn.aphp.fr

The optimal algorithm for diagnosis and for obtaining a biopsy in pancreatic

cancer

Disclosure form

No conflict of interest in relation with this lecture

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

Diagnosis of pancreatic cancer

- 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)

1- Take clinical context into account

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

Diagnosis of pancreatic cancer

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

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)

Focal pancreatitis

- Long/incomplete

- Different level CBD

Cancer

- Short /complete

- Same level CBD

Pseudotumour : length of MPD stenose

PMPD : Main pancreatic duct CBD : common bile duct

CBDMPD CBD

MPD

2- Can we trust imaging methods ?

Suspicion of cancer on MRI : pitfall

Suspect « stop » and upstream enlargement of MPD

To detect calcifications in chronic pancreatitis : CT scan > MRI

Suspicion of cancer on MRI : pitfall

CT CT

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)

Pancreatic mass on imaging : pancreatitis or cancer ?

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

• 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

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 diabetesSchick, Eur J Med Mol Imaging 2008

Kartalis Eur Radiol 2009:Dietrich Clin Gastroenterol Hepatol 2008

2- Can we trust imaging methods ?

Steroid test

Locally advanced cancer (biopsy)

Screening of relative at risk for pancreatic cancer : islet of Pan-IN 3

Endoscopic Ultrasonography (EUS) in experienced hands remains one of the best tools for diagnosis

2- Can we trust imaging methods ?

Courtesy Dr Palazzo

• Contrast (E)US– Hypovascularization 57/62– Differential diagnosis AIP/pNET

• Elastometry EUSCourtesy Dr L. Palazzo

2- Can we trust imaging methods ?

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

Diagnosis of pancreatic cancer

Gut 2008;57:1646-7

Unappropriateresectionfor pancreatitis

Propose steroidsin 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 : why ?

Pain, jaundice

Imaging (US, CT, MRI, /+-EUS) : mass

Benign or malignant ?

Likely malignant (local signs, metastases)

Type ? Adenocarcinoma

Specific management

Pancreatic tumour and biopsy : when ?

no (pNET, autoimmune pancreatitis)

Pain, jaundice

Imaging (US, CT, MRI, /+-EUS) : mass

Benign or malignant ?

Likely malignant (local signs, metastases)

Resectable ?Patient eligible ?

no

Chemotherapy (CRT) or BSC

Type ? Adenocarcinoma

yes

Specific management

Biopsy

no (pNET, autoimmune pancreatitis)

Pancreatic tumour and biopsy : when ?

Pancreatic tumour and biopsy : when ?

Pain, jaundice

Imaging (CT, MRI, EUS) : mass

Benign or malignant ?

Likely malignant (locoregional signs, metastases)

Resectable ?Patient eligible ?

Neoadjuvant treatment ?

no

yes

biopsy

no

resectionChemotherapy/BSC

yes : surgery envisaged

Type ? Adenocarcinoma

no (pNET, autoimmune pancreatitis)yes

Specific management

biopsy

Conventional

EUS-FNA

Cytology

monolayer

Courtesy Pr Couvelard

Pancreatic cancer : remind the limits of pathology

Conventional Conventionalhistology

EUS-FNA

Cytology Microfragments

monolayer Histology « cell-block »

Courtesy Pr CouvelardInformations needed : clinical context, conditions of FNA

Pancreatic cancer : remind the limits of pathology

Blue Alcian

Mucus

Pancreatic cancer : remind the limits of pathology

Often poor material

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

Courtesy Dr J. Cros

EUS-FNA : more than « usual » histology with EUS-FNA?

hENT1Courtesy Dr J. Cros

hENT1

Problem of tumour heterogeneity

EUS-FNA : could we do more than « usual » histology ?

Courtesy Dr J. Cros

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 ?

Take home messages

• Diagnosis of pancreatic cancer remains difficultto assess

• Clinical context is important

• Limitations of serum markers and imaging methods

Take home messages

• Diagnosis of pancreatic cancer remains difficultto assess

• Clinical context is important

• Limitations of serum markers and imaging methods

• Most convenient route for biopsy andclose collaboration with pathologist

• Future: optimise analyses of material obtain