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Josep Tabernero · Andrés Cervantes · Henk van Halteren

edited by

GASTROINTESTINAL GASTROINTESTINAL
Josep Tabernero
Andrés Cervantes

TRACT TUMOURS TRACT TUMOURS

Henk van Halteren

E S S E N T I A L S forC L I N I C I A N S E S S E N T I A L S forC L I N I C I A N S

GASTROINTESTINAL TRACT TUMOURS

AEG I AEG II AEG III

edited by
A B C D

Josep Tabernero
Andrés Cervantes
Henk van Halteren
Schematic representation of recommended
Gastrointestinal Tract Tumours: Essentials for Clinicians extent of surgical resection for oesophagogastric
junction adenocarcinomas
is the latest edition of the very popular ESMO Essentials for Clinicians
series. Gastrointestinal (GI) tumours have a significant incidence in
Europe and are among the most frequent tumours to be diagnosed
globally. The ESMO Publishing Working Group therefore decided
that GI tract tumours should be the next topic to be addressed
in this series of educational books.
The Essentials for Clinicians publications are intended primarily to be
E S S E N T I A L S forC L I N I C I A N S

read by young oncologists (residents at the beginning of their career)

by providing the reader with the essential information in a visual and
informative way. The series follows a distinct format that enables
the reader to easily assimilate the information and then test their
Pelvic MRI of a
knowledge by answering the revision questions at the end of each rectal cancer
with mesorectal
page. The second section of this publication allows the reader to build fascia invasion
and extramesorectal
on this essential knowledge, focussing on more advanced topics. lymph nodes

migration
survival
proliferation
ESMO Press

ISBN 978-88-941795-0-7
ESMO Press · ISBN 978-88-941795-0-7

ESMO Press ESMO Press

9 788894 179507

CM41 ESMO GI Tumors Essentials Sponsored cover v01.indd 1 23/05/2016 21:03

Gastrointestinal Tract Tumours
Essentials for Clinicians
 Gastrointestinal Tract Tumours
Essentials for Clinicians

Edited by

Josep Tabernero
Vall d’Hebron University Hospital and Institute of Oncology (VHIO)
Barcelona, Spain

Andrés Cervantes
Department of Hematology and Medical Oncology
Biomedical Research Institute INCLIVA, University of Valencia
Valencia, Spain

Henk van Halteren

Department of Medical Oncology, Admiraal de Ruijter Hospital
Goes, The Netherlands

Series editor
Michele Ghielmini
Oncology Institute of Southern Switzerland, Ospedale San Giovanni
Bellinzona, Switzerland

ESMO Press
First published in 2016 by ESMO Press

© 2016 European Society for Medical Oncology

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Contents
Preface vi
Contributors vii
Abbreviations ix
Acknowledgements x

A. What every oncologist should know

1. Biology of cancer development in the GI tract 1
HG Palmer
2. Diagnosis, staging, response assessment and interventional radiology in GI tumours 7
A Laghi & D Bellini
3. Oesophageal cancer 15
F Lordick, W Allum, K Haustermans & F Carneiro
4. Gastric cancer 22
V Gambardella, N Tarazona & A Cervantes
5. Colon cancer 28
J Raimbourg & JY Douillard
6. Rectal cancer 33
S Roselló & A Cervantes
7. Pancreatic cancer 37
T Seufferlein, F Mornex, T Hackert & MW Büchler
8. Hereditary colorectal cancer syndromes 45
L Moreira, F Balaguer & J Balmaña

B. More advanced knowledge

9. Aetiology and epidemiology 53
CA González & A Agudo
10. New targets and new drugs in colorectal cancer 57
S De Dosso & J Tabernero
11. Primary liver cancer and biliary cancer 62
M Reig, A Liccioni & J Bruix
12. Uncommon GI tumours: small intestine and anal cancer 66
C Verslype & H Prenen
13. Neuroendocrine GI tract tumours 70
K Oberg

Appendices
1. WHO Classification 77
2. Selected treatment schedules 80
Image sources 83
Declarations of interest 84
Index 85

v
Contents
 Preface

This next edition of ESMO’s Essentials for Clinicians focuses firmly on Gastrointestinal (GI) Tract Tumours.
In line with publications past, it has primarily been devised as a “must-have” educational tool to serve and
guide oncologists-in-training – the future of our profession. By providing a comprehensive update on some
of the very latest discoveries within the GI field, spanning a wide range of gastrointestinal malignancies and,
indeed, various perspectives, it will also be of general appeal to colleagues and oncoprofessionals working
across other specialities.
Organised into two main sections: “What every oncologist should know” and “More advanced knowledge”,
this book includes excellent contributions from internationally renowned leaders in oncology, tackling the
“everything you need to know” from the expanding understanding of the molecular basis of GI cancers, the
diagnosis, staging, tracking of response, and interventional radiology of GI tumours, to the latest updates
from leading physician–scientists in oesophageal, gastric, colon, rectal, pancreatic and hereditary colorectal
cancer.
The second section covers essential developments exploring epidemiological factors implicated in GI
cancer, disease prevention, the new opportunities that promise to advance our understanding, molecular
subtyping, and tailored treatment of these diseases, as well as an “under the lens” look at rarer GI tumours.
Importantly, we are now in an era of precision medicine against cancer, driven by the multidisciplinary
approach to cancer science, treatment and care, and resources aimed at crucially “lightening the load”
for clinicians. Therefore, medical oncologists, researchers and other cancer specialists and professionals
should seek to report and exchange expertise on a wide range of topics from different perspectives across
tumour types.
It is thanks to the superb co-editorship of Professor Andrés Cervantes and Dr Henk van Halteren that
ESMO’s Gastrointestinal Tract Tumours: Essentials for Clinicians has most certainly delivered on this ambition.

Josep Tabernero, MD, PhD

Barcelona, Spain

vi
Preface
Contributors

A Agudo
Unit of Nutrition and Cancer, Department of Cancer Epidemiology, Catalan Institute of Oncology, Barcelona, Spain

W Allum
Department of Surgery, Royal Marsden NHS Foundation Trust, London, UK

F Balaguer
Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades
Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Barcelona, Spain

J Balmaña
Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain

D Bellini
Department of Radiological Sciences, Oncology and Pathology, “Sapienza” University of Rome; I.C.O.T. Hospital,
Latina, Italy

J Bruix
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona;
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

MW Büchler
Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany

F Carneiro
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal

A Cervantes
Department of Hematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia,
Valencia, Spain

S De Dosso
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

JY Douillard
ICO R Gauducheau, University Medical School Nantes, Nantes, France

V Gambardella
Department of Medical Oncology, Biomedical Research, Institute INCLIVA, University of Valencia, Valencia, Spain

CA González
Unit of Nutrition and Cancer, Department of Cancer Epidemiology, Catalan Institute of Oncology, Barcelona, Spain

T Hackert
Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany

K Haustermans
Radiation Oncology, Leuven Cancer Institute, University Hospitals Leuven, and Department of Oncology, KU Leuven,
Leuven, Belgium

A Laghi
Department of Radiological Sciences, Oncology and Pathology, “Sapienza” University of Rome; I.C.O.T. Hospital,
Latina, Italy

vii
Contributors
 A Liccioni
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona;
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

F Lordick
University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany

L Moreira
Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades
Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Barcelona, Spain

F Mornex
Department of Radiation Oncology, Centre Hospitalier Lyon Sud, University Claude Bernard, Lyon, France

K Oberg
Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden

HG Palmer
Stem Cells and Cancer Laboratory, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO),
Barcelona, Spain

H Prenen
Digestive Oncology, University Hospitals Leuven, Leuven, Belgium

J Raimbourg
ICO R Gauducheau, University Medical School Nantes, Nantes, France

M Reig
Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona;
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

S Roselló
Department of Hematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia,
Valencia, Spain

T Seufferlein
Department of Internal Medicine I, Ulm University, Ulm, Germany

J Tabernero
Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain

N Tarazona
Department of Medical Oncology, Biomedical Research, Institute INCLIVA, University of Valencia, Valencia, Spain

H van Halteren
Department of Medical Oncology, Admiraal de Ruijter Hospital, Goes, The Netherlands

C Verslype
Digestive Oncology, University Hospitals Leuven, Leuven, Belgium

viii
Contributors
Abbreviations

18
FDG 18F-Fluorodeoxyglucose IV Intravenous
5-FU 5- Fluorouracil LA Locally advanced
5-HIAA 5-Hydroxyindoleacetic acid LN Lymph node
AASLD American Association for the Study of Liver Diseases LOH Loss of heterozygosity
AEG Adenocarcinoma of the oesophagogastric junction LT Liver transplantation
AFAP Attenuated familial adenomatous polyposis LV Leucovorin
Ang Angiopoietin mAb Monoclonal antibody
APR Abdominoperineal resection MAP MUTYH-associated polyposis
ASCC Anal squamous cell carcinoma mCRC Metastatic colorectal cancer
AT Adjuvant treatment MDCT Multidetector-row computed tomography
ATM Ataxia telangiectasia mutated MDT Multidisciplinary team
BCLC Barcelona Clinic Liver Cancer MEN-1 Multiple endocrine neoplasia type 1
BSC Best supportive care MET Mesenchymal epithelial transition
CDDP Cisplatin mFOLFOX Modified leucovorin, 5-fluorouracil, oxaliplatin
CDH1 E-cadherin MIP Maximum intensity projection
CF Cisplatin and 5-fluorouracil miRNA microRNA
ChT Chemotherapy MMC Mitomycin C
CI Confidence interval MMR Mismatch repair
CIMP CpG island methylator phenotype MPD Main pancreatic duct
CIN Chromosomal instability MRCP Magnetic resonance cholangiopancreatography
CLM Colorectal liver metastases MRF Mesorectal fascia
CM Contrast medium MRI Magnetic resonance imaging
CRC Colorectal cancer MSI Microsatellite instability
CNV Copy number variation N Node
CRM Circumferential resection margin NET Neuroendocrine tumour
CRT Chemoradiation NSCLC Non-small cell lung cancer
CT Computed tomography OAC Oesophageal adenocarcinoma
CTC Computed tomography colonography OC Oesophageal cancer
DCF Docetaxel, cisplatin and 5-fluorouracil OG Oesophagogastric
DP Partial duodenopancreatectomy ORR Objective response rate
DRE Digital rectal examination OS Overall survival
EASL European Association for the Study of the Liver OSCC Oesophageal squamous cell carcinomas
EBV Epstein–Barr virus PanIN Pancreatic intraepithelial neoplasia
ECD Extracellular domain PC Pancreatic cancer
ECF Epirubicin, cisplatin and 5-fluorouracil pCR Complete pathological response
ECOG Eastern Cooperative Oncology Group PD Progressive disease
EGF Epidermal growth factor PDAC Pancreatic ductal adenocarcinoma
eGFR Electronic glomerular filtration rate PDGF Platelet-derived growth factor
EGFR Epidermal growth factor receptor PDL1 Programmed death ligand 1
EMVI Extramural venous invasion PET Positron emission tomography
EOX Epirubicin, oxaliplatin and capecitabine PFS Progression-free survival
ERCP Endoscopic retrograde cholangiopancreatography PPI Proton pump inhibitor
ESMO European Society for Medical Oncology PRRT Peptide receptor radioactive treatment
EUS Endoscopic ultrasound PS Performance status
FAP Familial adenomatous polyposis PTC Percutaneous transhepatic cholangiography
FGF Fibroblast growth factor QOL Quality of life
FISH Fluorescence in situ hybridisation RR Response rate
FOBT Faecal occult bleeding testing RT Radiotherapy
FOLFIRI Leucovorin, 5-fluorouracil, irinotecan SB Sleeping Beauty
FOLFIRINOX 5-Fluorouracil, leucovorin, irinotecan and oxaliplatin SBC Small bowel cancer
FOLFOX Folinic acid, 5-fluorouracil, oxaliplatin SBRT Stereotactic radiotherapy
FOLFOXIRI Folinic acid, 5-fluorouracil, oxaliplatin, irinotecan SIRT Selective internal radiation therapy
FU 5-Fluorouracil SMA Superior mesenteric artery
GC Gastric cancer SNP Single nucleotide polymorphism
GEP-NET Gastroenteropancreatic neuroendocrine tumour T Tumour
GI Gastrointestinal TACE Transarterial chemoembolisation
GIST Gastrointestinal stromal tumour TCGA The Cancer Genome Atlas
GITSG Gastrointestinal tumour study group TEM Transanal endoscopic microsurgery
GWAS Genome wide association studies TGF Transforming growth factor
HCC Hepatocellular carcinoma Tis Carcinoma in situ
HER2 Human epidermal growth factor receptor 2 TKI Tyrosine kinase inhibitor
HER3 Human epidermal growth factor receptor 3 TME Total mesorectal excision
HGF Hepatocyte growth factor TNFα Tumour necrosis factor alpha
HNPCC Hereditary non-polyposis colorectal cancer TRG Tumour regression grade
Hp Helicobacter pylori TTP Time to progression
HPV Human papillomavirus UICC Union for International Cancer Control
HR Hazard ratio UFT Ftorafur and uracil
IGF-1 Insulin-like growth factor 1 ULN Upper limit of normal
IHC Immunohistochemistry VEGF Vascular endothelial growth factor
IMRT Intensity modulated radiotherapy VHL von Hippel-Lindau syndrome
IPMN Intraductal papillary mucinous neoplasm WHO World Health Organisation

ix
Abbreviations
 Acknowledgements

The editors would like to thank the members of the ESMO Publishing Working Group and the Educational
Steering Committee for their support in this initiative. The editors also wish to thank Dr Sara De Dosso
for her important role in starting this project by defining the book’s direction, in addition to her input and
revision of its content. Finally, the editors would like to acknowledge and thank Dr Keith McGregor,
Claire Bramley and Matthew Wallace of ESMO for their support in the preparation of this publication.

Josep Tabernero
Andrés Cervantes
Henk van Halteren

x
Acknowledgements
 A

What every oncologist should know

 1 Biology of cancer development in the GI tract
Genesis and progression of GI cancer – a genetic disease

Colorectal cancer
Fearon and Vogelstein proposed a genetic
Characteristics of the two major pathways in CRC
model to explain the stepwise formation of
colorectal cancer (CRC) from normal colonic
tissues.
Chromosomal instability pathway
Genetic alterations through chromosomal losses and gains
The model states: (1) CRC results from Deletion 1p Deletion 8p LOH 17p LOH 18q

mutations in genes with important functions

APC COX2 K-ras DCC/Smad4 p53
in regulating cell proliferation or DNA repair,
(2) mutations in >1 gene are required, and ? ? ? ?

(3) the sequence of mutations is important in Normal Early Intermediate Late Carcinoma Metastasis
mucosa adenoma adenoma adenoma
determining the formation of CRC. ? ? ? ?

BAX TCF-4 IGF-IIR TGF-βRII

These altered genes can be divided into two
β-catenin

classes: tumour suppressors that either inhibit

MLH1 MSH2 MSH6
cell proliferation or promote apoptosis, and Epigenetics CIMP hypermethylation

oncogenes that promote cell proliferation and Microsatellite instability pathway

Genetic alterations through defective DNA mismatch repair proteins
tumour progression.

CRC, Colorectal cancer.

Phylogenetically, CRCs can be divided

into two molecular subtypes: those with
chromosomal instability (CIN) and those with
microsatellite instability (MSI).

Carcinomas with MSI present cancer-

initiating mutations that inactivate the function
of mismatch repair (MMR) genes (e.g.
MSH2, MSH6, MLH1 and PMS2) leading to
hypermutated genomes. This is known as the
“mutator phenotype”. MSI tumours frequently
present a CpG island methylator phenotype
(CIMP) leading to the repression of tumour
suppressor genes including MLH1.

REVISION QUESTIONS
1. Is MSI always related to hereditary colon cancer?
2. Can you comment on potential therapies for hypermutated colon cancer?
3. Can you mention three genes involved in the chromosomal instability pathway?

1
Palmer
Genesis and progression of GI cancer – a genetic disease (continued)

Gastric cancer
The vast majority of gastric cancers are adenocarcinomas, which Genetic alterations in gastric cancer
can be further subdivided into intestinal and diffuse types according Diffuse type Intestinal type

to the Lauren classification.

Normal gastric mucosa
Most gastric cancers are associated with infectious agents, including MSI-H (0-6%) MSI-H (13-20%)

the bacterium Helicobacter pylori and Epstein–Barr virus (EBV). A E-cadherin mutation (41-50%)
Metaplasia Telomerase activation/
TERT expression
minority are associated with germline mutation in E-cadherin (CDH1) p53 mutation (25-63%)
K-ras mutation (10%)
or MMR genes, whereas sporadic MMR-deficient gastric cancers p53 mutation (0-33%) (Adenoma) Reduced p27 expression
APC mutation (40-60%)

have epigenetic silencing of MLH1 in the context of CIMP. CD44 aberrant transcript
Cyclin E overexpression (10%)
CDC25B overexpression
Bcl-2 loss (43%)
c-met amplification (19%)
Early cancer Cyclin E overexpression (14-20%)
18q (DCC) loss (50%)

Gene expression or DNA sequencing have been used in molecular β-Catenin mutation (27%)

N-cadherin overexpression (43%) c-erbB2 amplification (20%)

profiling of gastric cancer, but have not led to a clear biological Twist 1 overexpression (39%) Carcinoma
CD44 aberrant transcript
E-cadherin reduction (60%)
classification scheme. More recent studies by The Cancer Genome
K-sam amplification (33%)
SIP1 overexpression (55%)
c-met amplification (39%)

Atlas (TCGA) have permitted more precise molecular classification Reduced nm23 (<52%) Metastasis Reduced nm23 (52%)

of gastric cancer by identifying dysregulated pathways and Genetic alterations in gastric cancer
candidate drivers of distinct classes. Expert Reviews in Molecular Medicine C 2005 Cambridge University Press

Pancreatic cancer
Pancreatic adenocarcinoma presents a progression
from distinct types of precursor lesions, a propensity for
Normal tissue Cancerous tissue
both local invasion and distant metastasis, an extensive
Lumen
stromal reaction (desmoplasia) resulting in a hypovascular
of duct
and hypoxic microenvironment, reprogramming of cellular
metabolism, and evasion of tumour immunity. 1
Duct
epithelium
Submucosa There is a stepwise progression of pancreatic
Normal PanIN-1A PanIN-1B PanIN-2 PanIN-3 intraepithelial neoplasia (PanIN) from low grade to high
Overexpression of Her-2/neu
Inactivation of p16
grade in types 1, 2 and 3.
Inactivation of p53,
Point mutations of K-ras DPC4 and BRCA2
These types are associated with accumulating genetic
The genetic progression of pancreatic carcinoma
Published in Expert Reviews in Molecular Medicine by Cambridge University Press (2001) alterations.

More than 90% of cases of PanIN of all grades have KRAS

mutations. Mutational inactivation of the CDKN2A, p53 and
SMAD4 tumour suppressors occurs later in type 2 and type 3
lesions of PanIN.

In addition, 40%–80% have activating mutations in GNAS and more

than 50% have inactivation of RNF43 (an antagonist of Wnt signalling).
The pancreatic adenocarcinoma genome is also characterised
by diverse, large-scale chromosomal changes with frequent
amplifications, deletions and rearrangements.

REVISION QUESTIONS 1
1. Are there any gastric cancers with MSI?
2. How are diffuse type gastric carcinomas molecularly defined?
3. What is the most common molecular alteration in pancreatic carcinomas?

2
Biology of cancer development in the GI tract
 New molecular characterisation of GI tumours

Colorectal cancer
Recent studies by TCGA show that non- 500
hypermutated CRC tumours, irrespective of

Mutation rate (mutations per 10 6 bases)

MLH1
anatomical origin, present equivalent types 100 MLH3
of copy number, expression profile, DNA MSH2
MSH3
methylation and microRNA (miRNA) changes. MSH6
PMS2
POLE
10
Over 94% had a mutation in one or more Epigenetic
silencing
Frameshift
mutation
Missense/nonsense
mutation

members of the Wnt signalling pathway,

dominantly in APC. However, there were some
1
differences between tumours from the right
colon and all other sites.
Non-silent
Hypermutated Non-hypermutated
Hypermethylation was more common in the Silent 0.1
Tumour site
right colon, and three-quarters of hypermutated MSI status
CIMP status
samples came from the same site, although not MLH1 silencing

all had MSI.

Hypermutated tumours
93% of non-hypermutated and 97% of hypermutated
80 cases had a deregulated Wnt signalling pathway.
Mutation frequency (%)

63%

New findings included recurrent mutations in

51%
51%

60
46%

FAM123B, ARID1A and SOX9 and very high levels of

40%
40%
31%
31%

40 overexpression of the Wnt ligand receptor gene FZD10.

29%
29%
29%
29%
29%
26%
26%

20
Activation of Wnt signalling and inactivation of the TGF-β
0
2 A PC R 2 A F H3 H6 1B L 2 P8 27 D3 R3 G1 P7 12
signalling pathway result in activation of MYC. Mutational
V R A G F B B R M S M S M YO C F 7 C A S C D C F Z M I E C E R M A T P N
AC T T T P and integrative analyses emphasise the critical role of
MYC in CRC. Integrated analysis revealed a diverse set
Non-hypermutated tumours of changes in TCF/LEF-encoding genes, suggesting
81%

80 additional roles for TCF/LEF factors.

Mutation frequency (%)

60%

60 Mutations in the ubiquitin ligases RNF43 and ZNRF3 or

43%

fusions of RSPO2/3 genes are alterations that activate

31%

40
Wnt/beta-catenin oncogenic signalling and represent a
18%

promising level for drug intervention.

11%
10%

20
9%
9%
7%
6%
5%
4%
4%
4%
4%
3%

0
C 3 S N A 7 4 S 2 B 2 1 4 9 B 6 B
A P T P5 K R A T T IK3CBX W M A D NR A F 7L 123M A D NNBA180 SOX V R1 GPC DNR
P F S T C FA M S C T K I A AC E

REVISION QUESTIONS
1. Which oncogenic pathway is the most frequently altered by mutations in CRC?
2. Is the TGF-β pathway activated or inactivated by mutations in CRC?
3. Which genes present fusions that activate oncogenic Wnt signalling?

3
Palmer
New molecular characterisation of GI tumours (continued)

Gastric cancer

Recent studies by TCGA propose a molecular Subtype EBV MSI GS CIN Tumour purity
Tumour purity
classification dividing gastric cancer into four subtypes: TP53 mut.
SCNA high
Low High
Not available
Diffuse
MLH1 silencing Molecular/clinical
MSI high features
CDKN2A silencing Yes
PIK3CA mut. No
1. Tumours positive for EBV, which display recurrent EBV positive
100
Not available
50
PIK3CA mutations, extreme DNA hypermethylation,

Mutations
per Mb
10
5

and amplification of JAK2, CD274 (also known as 1

Chr 1

PD-L1) and DCD1LG2 (also known as PD-L2). Gain

number
Copy
Loss
Chr 22
High

methylation
DNA
Low

High

mRNA
Low

High

microRNA
Low

High
Protein

Low

227 tumours

295
V e
EB sitiv
po
26 2. M
 icrosatellite unstable tumours, which show elevated
EBV 269 mutation rates, including mutations of genes encoding
(EBV-CIMP) h
hig
M
SI targetable oncogenic signalling proteins.
64
205
SC
N 3. Genomically stable tumours, which are enriched for the
MSI clu A h
(hypermutated) st igh
er diffuse histological variant and mutations of RHOA or
fusions involving RHO-family GTPase-activating proteins.
58 147
GS
(Genomically stable) CIN
(chrom. instability)

100 120
Number of samples
Lauren classification

75 90
diffuse (%)

60
4. T
 umours with CIN, which show marked aneuploidy and 50

focal amplification of receptor tyrosine kinases. 25 30

0 0
Identification of these subtypes provides a roadmap GE junction Fundus Antrum
EBV MSI GS CIN
for patient stratification and trials of targeted therapies. cardia body pylorus
100 90
Age at initial diagnosis

80
75
70
Males (%)

50 60

25 50
40
0
EBV MSI GS CIN EBV MSI GS CIN

REVISION QUESTIONS
1. Do chromosome instability and mutations in tyrosine kinase receptors frequently co-occur in gastric cancer?
2. Are mutations in the PIK3CA gene frequent in microsatellite unstable gastric tumours?
3. With which molecular subtype of gastric cancer is a diffuse histology related?

4
Biology of cancer development in the GI tract
 New molecular characterisation of GI tumours (continued)

Pancreatic cancer
Somatic mutations in ataxia telangiectasia mutated
(ATM) are present in significant proportions of patients
(8%), highlighting the importance of BRCA-mediated
DNA damage repair mechanisms in sporadic pancreatic
ductal adenocarcinoma (PDAC) as well as familial disease.
Mutations in genes involved in chromatin remodelling such
as ARID1A, EPC1 and ARID2 are frequently observed,
indicating chromatin remodelling may have an important
role in PDAC.
Novel mutations in genes traditionally described for
their roles in axon guidance have been observed by a
combination of genomic data and supportive experimental
evidence from independent murine Sleeping Beauty
(SB) mutagenesis screens. Axon guidance is integral to
organogenesis, regeneration, wound healing and other
basic cellular processes.
The widespread genomic aberrations observed in axon
guidance genes suggest they may have a role in PDAC.
This observation joins mounting evidence in other
cancer, including a recent report demonstrating ROBO2
mutations in liver fluke-associated cholangiocarcinoma.

CNV, Copy number variation; IPMN, intraductal papillary mucinous neoplasm; LOH, loss of heterozygosity; PDAC, pancreatic ductal adenocarcinoma.

REVISION QUESTIONS
1. Which genes involved in chromatin remodelling are significantly mutated in pancreatic cancer?
2. Is BRCA-dependent DNA repair a cellular function altered by mutations in pancreatic cancer?
3. Are genes involved in axon guidance altered in pancreatic cancer?

5
Palmer
Summary: Biology of cancer development in the GI tract
• CRC progression is the consequence of a stepwise accumulation of mutations in tumour suppressor genes and
oncogenes, the most frequent alteration observed being activation of the Wnt/beta-catenin pathway
• Both CRC and gastric cancer present a major group of non-hypermutated tumours and a minor population of
hypermutated/MSI tumours
• Pancreatic cancer progressively accumulates mutations in KRAS, CDKN2A, p53 and SMAD4, but also presents
alterations in genes involved in chromatin remodelling and axon guidance

Further Reading
Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
Nature 2012; 491:399–405.
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;
487:330–337.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;
513:202–209.
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759–767.
Giannakis M, Hodis E, Jasmine Mu X, et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet 2014;
46:1264–1266.
Seshagiri S, Stawiski EW, Durinck S, et al. Recurrent R-spondin fusions in colon cancer. Nature 2012; 488:660–664.

6
Biology of cancer development in the GI tract
 2 Diagnosis, staging, response assessment and
interventional radiology in GI tumours
Technical aspects

Computed tomography (CT) is currently the imaging

modality of first choice in the study of gastrointestinal
(GI) tumours. A minimal requirement of 16 slices is
mandatory for optimal examination.

Dedicated protocols, based on clinical indications, patient

characteristics and scanner features, are necessary
to enhance diagnosis and minimise patient risks.
New technological developments, including iterative
reconstruction algorithms, keep radiation exposure as low
as reasonably achievable.
The use of iodinated contrast medium (CM) injection is
mandatory. Patient-related risk factors should be carefully
considered before intravenous administration of CM,
especially if eGFR value is below 45 ml/min/1.73m2. If CM
is administered, patient hydration is advisable.
CT, Computed tomography; IV, intravenous.

Magnetic resonance imaging (MRI) offers a

DANGER multiparametric approach in the evaluation of GI tumours,

and does not use ionising radiation. This is extremely
important in young patients and in pregnant women
with cancer.

The main drawbacks of MRI include longer imaging

protocols and difficult evaluation of poorly collaborative
and severely-ill patients, compared with CT.

STRONG MAGNETIC FIELD

18
F-Fluorodeoxyglucose positron emission tomography
(18FDG-PET)/CT is an important diagnostic tool at the time
of cancer diagnosis and in patient follow-up. Its diagnostic
role is different depending on the primary tumour.

A higher glucose uptake relative to that of surrounding

normal tissue reflects increased metabolic activity that
allows the identification of tumour foci.

Advantages of 18FDG-PET/CT are its high sensitivity and

the ability to examine the whole body. False positives
(uptake of inflammatory lesions) and false negatives
(absence of uptake in mucinous tumours and concurrent
therapy with metformin) must be taken into account.

REVISION QUESTIONS
1. What is the imaging test of first choice in GI tumours?
2. What are the absolute contraindications to MRI study?
3. What does glucose uptake mean in a PET/CT examination?

7
Laghi & Bellini
Oesophageal cancer

Endoscopy with biopsy is the primary test for the

diagnosis of oesophageal cancer.

In patients with alarm symptoms and no immediate

access to endoscopy, barium X-ray of the upper GI tract
can still be considered a useful imaging examination,
although it cannot identify carcinoma in situ.
Advanced Early

Endoscopic ultrasound (EUS) is important in the initial

local staging since it provides information about the depth
of tumour invasion (T) and the presence of enlarged
lymph nodes (N).

CT of the chest and abdomen is recommended for

staging and assessing tumour resectability.

FDG-PET/CT is an optional test for staging early

18

oesophageal cancer and is recommended for locally

advanced tumours.
MRI is a problem-solving imaging modality in the case of
suspected metastases to brain, adrenal, liver and bone.

CT is the best imaging method to assess post-surgical

anatomy and complications.
Response to chemotherapy is routinely assessed by
evaluation of tumour-related symptoms, endoscopy
and CT scan.
Tumour response to chemotherapy may be predicted
early by 18FDG-PET/CT. However, according to current
evidence, this approach does not change the therapeutic
strategy.

In the case of either intrinsic or extrinsic oesophageal

obstruction, insertion of an endoprosthesis (using
fluoroscopic or endoscopic guide) is a valuable
Oesophageal stent CT coronal image
palliative treatment.
CT, Computed tomography.

REVISION QUESTIONS
1. What is the most sensitive and specific test to detect oesophageal cancer?
2. What is the role of MRI in staging oesophageal cancer?
3. What is the most common palliative treatment for neoplastic oesophageal obstruction?

8
Diagnosis, staging, response assessment and interventional radiology in GI tumours
 Gastric cancer

Endoscopy with biopsy is the most sensitive and

specific test to detect gastric cancer. Sensitivity is
close to 98% if multiple biopsy specimens are taken
from a suspicious lesion.

Staging using CT scan (chest, abdomen and pelvis) with

or without EUS should be performed before surgery to
assess disease balance.
(GIST) Well demarcated polypoid
lesion with regular surface

(Gastric cancer) Superficial

elevated lesion with an irregular
surface pattern

GIST, Gastrointestinal stromal tumour.

A B

EUS is important in the initial staging, especially in

patients who are being considered for endoscopic
resection.

Pneumo/hydro-CT has proved to be a useful, safe and

C Circumferential mass (arrow) located accurate technique to identify gastric wall thickening and
at gastric angulus. Axial (A) and to stage gastric cancer.
Coronal Multiplanar Reformat (B)
images clearly demonstrate the
overall length of the neoplastic
18
FDG-PET/CT may improve staging through an
lesion and its relationship with increased detection of involved lymph nodes and/or
perigastric fat. Coronal Multiplanar metastatic disease. In diffuse or mucinous tumours,
Reformat using Maximum Intensity
Projection (MIP) (C) shows some
18
FDG-PET/CT can be inconclusive.
enlarged lymph nodes (arrows) along
mesenteric vessels.

Endoscopy with biopsy of any abnormalities is the best

method for postoperative surveillance of local recurrence.
The adjunct of EUS improves sensitivity.
18
FDG-PET/CT is accurate and it has high positive
predictive value in detecting local and distant recurrence
in patients with clinical or radiological suspicion after
surgical resection.
Percutaneous gastrostomy/jejunostomy and endoscopic
placement of self-expandable metallic stents are safe,
effective and minimally invasive palliative treatments for
patients with luminal obstruction.

REVISION QUESTIONS
1. What is the initial test for staging gastric cancer?
2. In which particular case can 18FDG-PET/CT be inconclusive?
3. What is the best imaging method to detect distant metastasis?

9
Laghi & Bellini
Colon cancer

Diagnosis of colon cancer is obtained with colonoscopy

and biopsy. A B C

CT colonography (CTC) is a valuable alternative

diagnostic method to detect colon cancer in both
asymptomatic and symptomatic patients.

The use of barium enema is no longer recommended

due to poorer performance compared with both
colonoscopy and CTC. Stenosing Colon Cancer: (A) 3D endoluminal image from
CTC, (B) optical colonoscopy and (C) double-contrast
barium enema reconstruction from CTC.

CTC, Computed tomography colonography.

Stenosing
cancer
Vascular Cancer
engorgement
CT of the chest, abdomen and pelvis is appropriate
to detect distant metastasis. If initial colonoscopy is
incomplete (also due to the presence of a stenosing
cancer), the adjunct of CTC to CT can be used to
detect synchronous colonic lesions.
Polyp Enlarged
(right colon) lymph nodes
Contrast-enhanced MRI is suggested if CT is
contraindicated or if liver lesions require further
Cancer characterisation.
Routine use of 18FDG-PET/CT is not recommended at the
time of initial diagnosis. 18FDG-PET/CT can help clarify
abnormal CT findings and improve detection of otherwise
Pulmonary unsuspected metastases.
nodule

CT is the best method to assess early postsurgical

complications. A B

Follow-up includes colonoscopy and a CT scan of the

chest, abdomen and pelvis, at different timings depending
on the patient’s risk of recurrence. 18FDG-PET/CT is
indicated in patients with equivocal findings at CT and in
those with abnormal carcinoembryonic antigen levels and
prior negative workup.

MRI is the best method to assess the effect of Liver metastases from breast cancer after chemotherapy, barely visible on
chemotherapy and interventional procedure on liver axial image (arrows in A), well defined and easily detectable on axial diffusion-
parenchyma. weighted image (arrows in B).

REVISION QUESTIONS
1. Which imaging test can be considered an alternative to colonoscopy in patients with suspected colon cancer?
2. What is the next test to characterise a focal liver lesion equivocal on CT?
3. What is the best method to assess response to chemotherapy of liver lesions?

10
Diagnosis, staging, response assessment and interventional radiology in GI tumours
 Rectal cancer

Diagnosis of rectal cancer is based on digital rectal

examination and proctoscopy with biopsy. Tumours
with distal extension ≤15 cm from the anal margin are
classified as rectal.

Infiltration of anal sphincter in low rectal cancer is best

assessed by digital rectal examination.
EUS is able to differentiate T1 and T2 tumours, selecting
patients for local excision.

MRI is the recommended technique for staging invasive

cancer (≥T3). It allows tailored treatment based on
evaluation of the tumour position, extramural spread,
circumferential resection margin (CRM), extramural
venous invasion (EMVI) and nodal status.

Local staging with CT can be an alternative to MRI in

advanced tumours located in the mid-high rectum.
CT of the chest, abdomen and pelvis is the best method
to detect distant metastases.
CRM 18
FDG-PET/CT should be preferred to CT in the evaluation
of distant extrahepatic metastases in locally advanced
Muscularis propria rectal tumours.

US for T1/T2 staging MR for T3/T4 staging CT an alternative to MR

CRM, Circumferential resection margins; CT, computed tomography; MR, magnetic resonance;
US, ultrasound.

MRI is recommended to assess response after

neoadjuvant chemoradiotherapy. Current limitations T2w before DWI before
include difficult assessment of pathological complete
response, early identification of non-responders and
lymph nodal restaging.

FDG-PET/CT can be useful for predicting response to

18

neoadjuvant therapy with a promising role in the early

evaluation of response.
Whole body CT and 18FDG-PET/CT are the best T2w after DWI after
methods for patient follow-up.
DWI, Diffusion-weighted imaging; T2w, T2-weighted.

REVISION QUESTIONS
1. What is the most accurate imaging test to select patients for local excision?
2. Which MRI findings are useful for predicting therapy and prognosis of patients with invasive rectal cancer?
3. What is the recommended method to assess response after neoadjuvant therapy?

11
Laghi & Bellini
Pancreatic cancer: Solid and cystic lesions

SCN
Pancreatic cancer is occasionally detected at Serous cystic neoplasm MCN
Mucinous cystic neoplasm
abdominal ultrasound, although its sensitivity is below
70%. Body and tail regions are difficult to explore.

CT is the best-validated imaging modality for diagnosing

Pseudocyst
patients with solid pancreatic cancer; the highest lesion IPMN with debris
conspicuity is achieved during the pancreatic phase of Main duct-type
enhancement.

CT allows locoregional and distant staging of PDAC IPMN

Pancreatic ductal Side branch-type
pancreatic adenocarcinoma. CT is the preferred adenocarcinoma
modality to preoperatively assess patients with
unresectable disease (high positive predictive value).
IPMN, Intraductal papillary mucinous neoplasm.

When CT is contraindicated, contrast-enhanced MRI

Hypoechoic mass, deforming gland
contour with common bile duct (CBD)
and dilatation
Hypoattenuation solid mass due to
desmoplastic fibrotic component
can be used to diagnose and stage pancreatic cancer;
accuracy of MRI is lower than CT.
EUS may provide useful information to evaluate small
peri-ampullary masses, to assess vascular infiltration and
it offers a guide for biopsy. The role of 18FDG-PET/CT in
local staging and in assessing resectability has not yet
been established.
In the case of unresectable pancreatic cancer with
secondary biliary obstruction, either endoscopic
retrograde cholangiopancreatography (ERCP) or
percutaneous transhepatic cholangiography (PTC) can
be used for biliary drainage or stent placement.
FDG-PET/CT is a promising tool to assess response to
18

chemotherapy in locally advanced neoplasia.

MRI represents the imaging modality of choice in the

characterisation of cystic pancreatic neoplasms.

CT or MRI with magnetic resonance

cholangiopancreatography (MRCP) is recommended
to check for “high-risk stigmata” (enhanced solid
component and main pancreatic duct [MPD] >10 mm), Serous Cystic Neoplasm Mucinous Cystic Neoplasm
or “worrisome features” (cyst >3 cm, thickened
enhanced walls, non-enhanced mural nodules, MPD
size of 5–9 mm, abrupt change in the MPD calibre with
distal pancreatic atrophy, and lymphadenopathy).
If no “worrisome features” are present, no further initial
workup is recommended; surveillance is still required. IPMT (Main duct) Pseudopapillary Neoplasm

IPMT, Intraductal papillary mucinous tumour.

REVISION QUESTIONS
1. What is the first imaging exam in patients with suspected pancreatic cancer?
2. What are the typical cross-sectional imaging findings of PDAC?
3. What is the best imaging examination for preoperative evaluation of PDAC?

12
Diagnosis, staging, response assessment and interventional radiology in GI tumours
 Small bowel tumours

Tumours of the small bowel are relatively uncommon with

adenocarcinoma, lymphoma and gastrointestinal stromal
tumour (GIST) accounting for the majority of cases.

A good evaluation of the small bowel requires luminal

distension, which can be obtained by administration
of enteric contrast agent either orally (enterography) or
through a naso-jejunal tube (enteroclysis).

Both MRI and CT have good performance for the

diagnosis of small bowel tumours. The use of an
intravenous contrast medium is mandatory to assess the
bowel wall, lesion enhancement and mesenteric vessels.
PET/CT has a primary role for the evaluation of small
bowel lymphoma.

GIST can affect the whole small bowel and it appears

as a demarcated mass with exophytic extension.
GIST
Lymphoma usually affects the terminal ileum and it
Vascular Reconstruction produces an aneurysmatic dilatation of the bowel loop.
Adenocarcinoma is usually located at the duodenum /
jejunum and it appears as a short annular lesion.

Lymphoma Adenocarcinoma

GIST, Gastrointestinal stromal tumour.

Maximum intensity projection (MIP) vascular Polypoid lesion

(adenocarcinoma)
reconstruction from CT images is useful to assess Small bowel
dilatation
vascularisation.
Intussusception
CT is the best method to assess clinical conditions
(e.g. bowel obstruction) related to tumour masses and
early postsurgical complications. Polypoid lesion
(adenocarcinoma)
CT, and PET/CT for lymphoma, are recommended for
patient follow-up. Polypoid lesion
(adenocarcinoma)

REVISION QUESTIONS
1. What are the best methods to detect small bowel tumours?
2. How do you perform a CT enterography?
3. What is the most accurate method to assess complications?

13
Laghi & Bellini
Summary: Diagnosis, staging, response assessment and interventional
radiology in GI tumours
• Technical aspects:
• CT is currently the imaging modality of first choice in the study of GI tumours
• MR offers a multiparametric approach, but it has some potential limitations and a few absolute contraindications
• 18FDG-PET/CT is an important diagnostic tool at the time of cancer diagnosis and in patient follow-up
• Oesophageal cancer: CT of the chest and abdomen is a recommended test for staging and assessing tumour
resectability
• Gastric cancer: endoscopy with biopsy is the most sensitive and specific test to detect gastric cancer
• Colon cancer: CTC is a valuable alternative diagnostic method to detect colon cancer in both asymptomatic and
symptomatic patients
• Rectal cancer: MR is the recommended technique for staging invasive cancer (≥T3)
• Pancreas:
• CT is the best-validated imaging modality for diagnosing and staging patients with solid pancreatic cancer
• MR is the imaging modality of choice in the characterisation of cystic pancreatic neoplasms
• Small bowel tumours: a good evaluation of the small bowel requires luminal distension by the administration of enteric
contrast agents

Further Reading
Beets-Tan RG, Lambregts DM, Maas M, et al. Magnetic resonance imaging for the clinical management of rectal cancer patients:
recommendations from the 2012 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur
Radiol 2013; 23:2522–2531.
Joye I, Deroose CM, Vandecaveye V, Haustermans K. The role of diffusion-weighted MRI and (18)F-FDG PET/CT in the prediction of
pathologic complete response after radiochemotherapy for rectal cancer: a systematic review. Radiother Oncol 2014; 113:158–165.
Kim TJ, Kim HY, Lee KW, Kim MS. Multimodality assessment of esophageal cancer: preoperative staging and monitoring of response
to therapy. Radiographics 2009; 29:403–421.
Miao F, Wang ML, Tang YH. New progress in CT and MRI examination and diagnosis of small intestinal tumors. World J Gastrointest
Oncol 2010; 2:222–228.
Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT:
a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology 2010; 257:674–684.
Poruk KE, Firpo MA, Adler DG, Mulvihill SJ. Screening for pancreatic cancer: why, how, and who? Ann Surg 2013; 257:17–26.
Spada C, Stoker J, Alarcon O, et al. Clinical indications for computed tomographic colonography: European Society of
Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline.
Endoscopy 2014; 46:897–915.
Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of
the pancreas. Pancreatology 2012; 12:183–197.
Varghese TK Jr, Hofstetter WL, Rizk NP, et al. The society of thoracic surgeons guidelines on the diagnosis and staging of patients with
esophageal cancer. Ann Thorac Surg 2013; 96:346–356.

14
Diagnosis, staging, response assessment and interventional radiology in GI tumours
 3 Oesophageal cancer
Epidemiology, risk factors, prognosis and classification

Oesophageal cancer is the eighth most common 35

cancer worldwide. Incidence rates are twofold higher in Squamous cell cancer
less developed regions. Steep increases in incidence of 30

adenocarcinoma occurred from 1973 and 2001. Today

25
a plateau may have been reached.

Rate per 1,000,000

20
Oesophageal squamous cell cancer (OSCC) comprises
the majority of cases worldwide. In contrast, oesophageal 15
adenocarcinoma (OAC) predominantly occurs in more Adenocarcinoma
developed countries. 10

OSCC carcinogenesis is commonly triggered by 5

exogenous agents. While in the West, alcohol and Others
tobacco abuse are prevalent, in Asia consumption of 0
1975 1980 1985 1990 1995 2000
nitrosamines plays a more dominant role.

Oesophageal metaplasia is a risk factor for OAC.

OAC often develops via metaplasia of the epithelium

Squamous
cell cancer
} • Smoking of the distal oesophagus. Oesophageal metaplasia
(so-called Barrett’s mucosa) is induced by chronic
• Alcohol consumption gastro-oesophageal reflux. Visceral (male) obesity is a
prevalent risk factor.

Adenocarcinoma
} • Obesity While OAC is usually located in the distal oesophagus,
OSCC can be located in the upper, mid or distal
oesophagus. While the median age at diagnosis of OAC is
• Gastro-oesophageal reflux
Barrett’s dysplasia due to 64 years, OSCC is diagnosed at a median age of 56 years.
chronic gastro-oesophageal
reflux disease Lymphatic spread in OAC occurs early, when the
submucosal layer is reached. The prognosis of resected
tumours is critical. In OSCC, lymphatic spread occurs
earlier and is associated with poorer prognosis.

Patients with OSCC often present with comorbid

Adenocarcinoma of the
conditions: malnutrition, chronic obstructive lung disease oesophagogastric junction
and liver cirrhosis have a high prevalence. (AEG Type I-III Siewert) Anatomic cardia

In patients with OAC, obesity, arterial hypertension, Type I

} 5 cm

diabetes and coronary heart disease are common. Type II

} 1 cm
0 cm
} 2 cm
Type III
According to the 7th edition of the TNM classification 5 cm

system, all three types of adenocarcinoma of the

oesophagogastric (OG) junction (AEG Type I-III according
to Siewert) are staged as oesophageal cancers.
J. R. Siewert, Munich 2007

REVISION QUESTIONS
1. How did the incidence of OAC versus OSCC change over recent decades?
2. What are the major risk factors for OAC and for OSCC?
3. What is the typical location of OAC and of OSCC?

15
Lordick et al
Diagnostic workup and staging

Endoscopic ultrasound (EUS) is the most accurate

method to determine the tumour (T) category. The
accuracy is operator dependent and interobserver
variability is significant.

Pooled sensitivity and specificity for T1-T4 staging ranges

are 81.6%–92.4% and 94.4%–99.4%, respectively.
In contrast, the assessment of nodal involvement
(N-category) is more variable with a high sensitivity (up to
91%) but a lower specificity.

In order to exclude distant metastases, high-resolution

and high-quality multidetector computed tomography
(CT) of the thorax, abdomen and pelvis should be
performed.

For proximal tumours, the CT should include the neck

region. Sonography of the neck region can also be
performed to rule out cervical lymphadenopathy.
As for EUS, the accuracy of CT in determining
locoregional nodal involvement is limited. Sensitivity has
been observed to be as low as 50% while specificity
was 83%. Staging laparoscopy should be considered for
junctional cancers, particularly if there is evidence of intra-
abdominal nodal disease.

Positron emission tomography (PET)/CT scanning should

be used in combination with EUS and CT.

Fluorodeoxyglucose (FDG)/PET adds information for

detecting distant metastases. It can thereby help to
avoid futile oesophagectomies.

As for EUS and CT, the accuracy of FDG/PET to

determine locoregional nodal involvement is limited.
Sensitivity has been observed to be as low as 57% while
specificity was 85%.

REVISION QUESTIONS
1. What is the most accurate method to determine the T-category?
2. What is the goal of CT?
3. Does FDG/PET add significant information for determining the T- and N-categories?

16
Oesophageal cancer
 Surgical treatment

Surgery offers a curative potential in localised

oesophageal cancer without distant metastases. There is
a strong relationship between lower hospital mortality and 20.3
20 17.8
increasing surgeon and institutional patient volumes. 16.2
‘Very low’

Mortality (%)
15
Large-volume units consistently report hospital ‘Low’
11.4
‘Medium’
mortalities of less than 5%. This reflects careful 10 8.4 ‘High’
patient selection and focused multidisciplinary team ‘Very high’
management with review and audit of outcome. 5

In very early stages, i.e. in cancers limited to the mucosal 0

layer, endoscopic resection is an accepted alternative to <2 2-4 5-7 8-19 >19

surgery. Due to a 30% rate of lymph node metastases Oesophagectomies / year

in carcinomas infiltrating the submucosa, endoscopic
resection cannot be recommended in cancers infiltrating
beyond the mucosal layer.

Radical oesophagectomy with extended

AEG I AEG II AEG III
lymphadenectomy is the surgical technique
A B C D of choice for resection of intrathoracic
oesophageal cancers.

Transthoracic oesophagectomy has been

compared with the transhiatal approach and,
although there was no overall benefit, there
is an advantage for transthoracic surgery for
node-positive cancers.

AEG, Adenocarcinoma of the oesophagogastric junction.

Despite the optimisation of surgical treatment and the

development of high-volume centres, outcome following Squamous cell carcinoma Adenocarcinoma
oesophageal resection remains unsatisfactory.
100 100
The resection (R) status is one of the strongest 80 80
Survival rate (%)

Survival rate (%)

prognostic factors in oesophageal cancer. Resections 60 60 R0

without clear margins are not curative. 40
R0 40
R1
20 R1 20
The probability of achieving an R0 status is associated R2 R2
0
with the depth of tumour infiltration into the oesophageal 0 6 12 18 24 30 36 42 48 54 60 24 36 48 60
Time after operation (months) Survival time (months)
wall (T-category). It is between only 50%–70% in primarily
resected T3/T4 tumours.

REVISION QUESTIONS
1. On which prognostic factor does post-oesophagectomy mortality particularly depend?
2. What is the recommended resection technique in distal oesophageal adenocarcinoma?
3. What is the probability of an R0 resection in a primarily resected T3/T4 oesophageal carcinoma?

17
Lordick et al
Neoadjuvant treatment

In order to increase the R0 resection rate and improve

survival, neoadjuvant (preoperative) treatment has been
Overall chemotherapy Surgery alone Hazard ratio
(total) (total) (95% CI)

investigated. Neoadjuvant radiotherapy (RT) without Nygaard

Apinop
53
35
25
34
0.76 (0.45-1.28)
0.80 (0.48-1.34)
Le Prise 45 41 0.85 (0.50-1.46)
concurrent chemotherapy (ChT) does not show Urba 50 50 0.74 (0.48-1.12)
Bosset 148 145 0.96 (0.73-1.27)
sufficient efficacy. Walsh (SCC) 29 32 0.74 (0.46-1.18)
Walsh (adenocarcinoma) 58 55 0.58 (0.38-0.88)
Burmeister 128 128 0.94 (0.70-1.26)
Tepper 30 26 0.35 (0.18-0.68)
In contrast, neoadjuvant combined chemoradiation Lv 80 80 0.55 (0.36-0.84)
Lee 51 50 0.88 (0.48-1.62)
(CRT), and also perioperative ChT alone, are effective Mariette
van der Gaast
97
176
98
188
1.09 (0.74-1.59)
0.67 (0.49-0.91)
in locally advanced oesophageal cancer. Total 980
Heterogeneity: χ2=18.04, df=12 (p=0.11), I2=33%
952 0.78 (0.70-0.88)

Test for overall effect: Z=4.28 (P <0.0001) 0.2 0.5 1 2 5

Favours chemotherapy Favours surgery alone

For OSCC, neoadjuvant CRT leads to significantly better

survival, while ChT alone is only marginally effective. For
OAC, both neoadjuvant CRT and ChT lead to significantly
improved survival outcomes.

A small randomised study in OAC and OG junction

Neoadjuvant chemoradiation versus chemotherapy alone
cancer showed a trend towards better survival for
neoadjuvant CRT when compared with ChT.
1.00
Overall survival (probability)

Arm A

0.75
Arm B One meta-analysis came to the conclusion: “A clear
Arm A (chemo alone):
Median survival 21.1 mon, advantage of neoadjuvant chemoradiotherapy over
0.50 3-year survival 27.7%
neoadjuvant ChT has not been established”.
0.25
Arm B (chemoradiation):
Median survival 33.1 mon,
0 12 24 36 48 60 3-year survival 47.7% Some studies showed increased postoperative morbidity
Time (months)
P value = 0.07 (n.s.)
and mortality following combined CRT. This should be
No. of patients at risk
A: 59 41 19 6 5 2 avoidable with optimal interdisciplinary co-ordination and
B: 60 45 30 15 7 1
careful radiation planning.

Current national and international guidelines Staging (endoscopy, EUS, CT, FDG/PET if available)
recommend neoadjuvant treatment for T3 and
resectable T4 oesophageal cancers. Early tumours (T1/2 N0) Locally advanced tumours (T3/4 N+)

The indication for neoadjuvant treatment in T1b/T2 tumours Primary

Multimodal therapy
is debated. Nodal involvement is difficult to assess and resection
therefore is an unreliable criterion for neoadjuvant treatment
outside a randomised controlled trial.
The decision for neoadjuvant CRT followed by surgery in Squamous cell cancer Adenocarcinoma
Neoadjuvant chemoradiation Neoadjuvant chemotherapy
OSCC must be taken together with the informed patient and surgery or neoadjuvant
(“shared decision-making”), as randomised trials did not Alternative: definitive CRT chemoradiation and surgery

show a clear survival advantage for surgery compared

with definitive CRT. CRT, Chemoradiotherapy; CT, computed tomography; EUS, endoscopic ultrasound;
FDG/PET, flurodeoxyglucose/positron emission tomography.

REVISION QUESTIONS
1. Is neoadjuvant treatment an “evidence-based treatment option” in locally advanced oesophageal cancer?
2. Is the effect of neoadjuvant ChT equivalent in OSCC and OAC?
3. Is there a clearly established advantage for neoadjuvant CRT over neoadjuvant ChT in oesophageal cancer?

18
Oesophageal cancer
 Chemoradiation

The randomised Dutch CROSS study reinforced the

value of neoadjuvant CRT in localised oesophageal R Neoadjuvant CRT 41.4 Gy:
Carbo AUC2 + paclitaxel 50 mg/m2 weekly
cancer. RESECTION
N=363
A
The CROSS study included 363 patients, 75% with OAC, Stage II
Stage III N Primary endpoint: Survival
>80% with T3/T4 tumours and >60% with a positive Result: median 49.4 vs 24.0 months
nodal status. OAC D HR: 0.657; 95% CI: 0.495 to 0.871, P = 0.003
OSCC
The experimental arm contained chemoradiation with O
RESECTION
a radiation dose of 41.4 Gy (1.8 Gy per fraction) plus M
concomitant carboplatin AUC2 and paclitaxel 50 mg/m²
given once weekly (x 5).
CI, Confidence interval; CRT, chemoradiotherapy; HR, hazard ratio; OAC, oesophageal
adenocarcinoma; OSCC, oesophageal squamous cell carcinoma.

Survival According to Treatment Group

1.0
0.9
CROSS showed a significant survival advantage in
0.8
favour of neoadjuvant CRT: median survival 49.4
0.7
months versus 24.0 months, hazard ratio (HR): 0.647,
Proportion surviving

0.6
CRT+surgery P=0.003.
0.5
0.4 However, the benefit seemed to be greater for OSCC (HR:
0.453) compared with OAC (HR: 0.732).
0.3 Surgery alone

0.2 Of note, with modern radiation planning and optimised

0.1
interdisciplinary coordination, no increased postoperative
P=0.003
mortality was observed (4% in both arms).
0.0
0 12 24 36 48 60
CRT, Chemoradiotherapy; CT, computed tomography; EUS, endoscopic ultrasound;
Follow-up (mo) FDG/PET flurodeoxyglucose/positron emission tomography.

CRT, Chemoradiotherapy.

1.0 Arm A (surgery)

Arm B (chemoradiation)
0.8
Neoadjuvant CRT followed by surgery was previously
Survival (%)

compared with definitive CRT in OSCC. 0.6

Two randomised studies (one from France [89% OSCC] 0.4

and one from Germany) observed improved local

0.2
tumour control with surgery. But they did not show a
significant survival advantage for surgery.
0 6 12 18 24 30 36 42 48
Therefore, definitive radiation combined with platinum +
ChT/RT Surgery P
5-fluorouracil (FU) ChT remains an alternative option for
Mortality 1% 9% 0.002
patients with locally advanced OSCC. Stent 27% 13% 0.005
Median survival 19.3 months 17.7 months n.s.

ChT, Chemotherapy; RT, radiotherapy.

REVISION QUESTIONS
1. Patients with which histologies and which tumour stages were included into the randomised CROSS study?
2. Did the CROSS study show a significant survival advantage for neoadjuvant CRT?
3. Is definitive CRT equivalent to neoadjuvant CRT followed by oesophagectomy in localised OSCC?

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Lordick et al
Chemotherapy for palliation

Relapses Following Curative Treatment with CRT + Resection

While mediastinal relapses have become rarer in
patients with oesophageal cancer treated with After Resection After CRT + Resection
Relapse HR P-value
neoadjuvant therapies and oesophagectomy and (n=161) (n=213)
lymphadenectomy, haematogenous relapses remain n % n %
a significant problem. Mediastinal 33 20.5% 15 7.0% 0.29 <0.001

Often, oesophageal cancer is diagnosed primarily with Haematogenous 57 35.4% 61 28.5% 0.67 0.03
distant (haematogenous and/or lymphatic) metastases.
CRT, Chemoradiotherapy; HR, hazard ratio.
Therefore, effective ChT is clearly warranted.
Very few trials have been conducted in advanced
oesophageal cancer. The evidence on how to best treat
advanced oesophageal cancer is rather weak.

Many physicians are treating advanced oesophageal

cancer like advanced gastric cancer. But it is not clear
whether this pragmatic approach is justified.

Treatment of advanced OSCC reveals very

poor outcomes. Survival with monotherapy or
5-FU-combined platinum barely exceeds half a year.

“The severe side-effects induced by the combination

n patients response median survival suggest that, currently, no standard chemotherapy can
CDDP/5-FU 34 35% 33 weeks be recommended for patients with advanced squamous
CDDP mono 37 19% 28 weeks cell oesophageal cancer…” (Bleiberg 1997).

5-FU, 5-Fluorouracil; CDDP, cisplatin.

Newly identified molecular targets and targeted therapies

may allow for better and more efficacious treatment in
oesophageal cancer.

HER2, which is expressed in about 20% of patients

with OG junction adenocarcinomas, is an established
drug target. Trastuzumab, an anti-HER2 monoclonal
antibody, improved outcomes in advanced HER2+
gastric and OG junction cancer.

Other targets include epidermal growth factor receptor

(EGFR), which is expressed in the majority of OSCC. c-MET
has been another potentially interesting drug target, but
results of recent trials in advanced gastric and OG junction
cancer have not shown improved survival rates for patients
treated with MET inhibitors. HR, Hazard ratio.

REVISION QUESTIONS
1. Is locoregional or haematogenous relapse the bigger problem after trimodality therapy of oesophageal cancer?
2. Is there a recommended standard ChT regimen in advanced oesophageal cancer?
3. What are potentially interesting drug targets currently identified in oesophageal cancer?

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Oesophageal cancer
 Summary: Oesophageal cancer
• While the incidence of OSCC has decreased in parts of the Western world, the incidence of OAC has increased
dramatically over the past 4 decades
• Treatment of oesophageal cancer is stage-dependent
• Diagnostic workup should comprise of endoscopy and endoscopic ultrasound (for T-categorisation), CT and, if
available, FDG/PET (for exclusion of distant metastases). Nodal staging is inaccurate
• Neoadjuvant treatment has a proven benefit in the locally advanced stages of oesophageal cancer, especially for T3
and resectable T4 cancers
• In OAC, both neoadjuvant ChT or neoadjuvant CRT can be recommended before surgery
• In OSCC, neoadjuvant CRT followed by surgery produces similar results to definitive CRT. Surgery after definitive CRT
should be considered for those with residual disease or local relapse, but will also be determined by patient factors
• There is no standard ChT regimen for the treatment of advanced oesophageal cancer. Pragmatically, many physicians
treat advanced oesophageal cancer like advanced gastric cancer

Further Reading
Allum WH, Blazeby JM, Griffin SM, et al; Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, the British Society
of Gastroenterology and the British Association of Surgical Oncology. Guidelines for the management of oesophageal and gastric
cancer. Gut 2011; 60:1449–1472.
Carneiro F, Chaves P. Pathologic risk factors of adenocarcinoma of the gastric cardia and gastroesophageal junction. Surg Oncol Clin N
Am 2006; 15:697–714.
Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with
cancer of the esophagus. N Engl J Med 1992; 326:1593–1598.
Lordick F, Hölscher AH, Haustermans K, Wittekind C. Multimodal treatment of esophageal cancer. Langenbecks Arch Surg 2013;
398:177–187.
Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the
oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007; 8:797–805.
Minsky B, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy
for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002; 20:1167–1174.
Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998; 85:1457–1459.
Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable
oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011; 12:681–692.
Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell
carcinoma of the esophagus. J Clin Oncol 2005; 23:2310–2317.
van Hagen P, Hulshof MC, van Lanschot JJ, et al; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer.
N Engl J Med 2012; 366:2074–2084.

21
Lordick et al
Gastric cancer 4
Epidemiology and clinical presentation

Gastric cancer is the second most prevalent

tumour worldwide. However, its incidence in
Western countries, particularly in the corpus/
antral location, is decreasing.

Gastric cancer with corpus and antral

location is related to Helicobacter pylori (Hp)
infection as a causative agent.

In Western countries, tumours located around

the gastro-oesophageal junction are increasing
in prevalence, mainly in men, smokers and the
overweight.

Gastric cancer, according to the Lauren classification, can be

defined as intestinal (A) or diffuse (B).

The WHO classification recognises four major histological patterns:

tubular, papillary, mucinous and poorly cohesive (including signet ring
cell carcinoma), plus uncommon histological variants.
<10% of gastric cancers are hereditary. Mutations in p53 (Li–Fraumeni),
STK1 (Peutz–Jeghers), APC (familial adenomatous polyposis) or
mismatch repair genes (Lynch) are the most common. Hereditary
diffuse gastric cancer is related to CDH1 mutations.

Gastric cancer can cause vague symptoms until an

advanced stage. Abdominal pain, weight loss, dysphagia,
dyspepsia, vomiting, bleeding, early satiety and/or iron-
deficiency anaemia may be observed.
Palpable epigastric mass, jaundice, periumbilical masses,
left supraclavicular nodes and acanthosis nigricans are
generally late events indicating metastatic disease.

Diagnosis should be made from a gastroscopic or

surgical biopsy, that is reviewed by an experienced
pathologist. Histology should be reported according to
the WHO criteria and the Lauren classification.

REVISION QUESTIONS
1. What is the role of Hp in gastric cancer carcinogenesis?
2. What are the main subtypes of gastric cancer according to the Lauren classification?
3. Which subtype is related to CDH1 mutations?

22
Gastric cancer