Introduction
The WHO classification of digestive system tumours presented in the first volume of
the WHO classification of tumours series, 5th edition, reflects important advancements
in our understanding of tumours of the digestive system (Table 1). For the first time,
certain tumour types are defined as much by their molecular phenotype as their histological
characteristics; however, in most instances histopathological classification remains
the gold standard for diagnosis. The WHO classification of tumours series is designed
to be used worldwide, including those settings where a lack of tissue samples or of
specific technical facilities limits the pathologist's ability to rely on molecular
testing.
Table 1
Selected changes within the new classification of tumours of the digestive system
Type
Subject
Change in 2019 classification
Oesophageal adenocarcinoma
Aetiology and epidemiology
The epidemiology has been updated: 7% of cases are thought to be familial, and the
risk factors involved in sporadic cases have been updated. The role of gastro‐oesophageal
reflux in the inflammation–metaplasia–dysplasia adenocarcinoma model has been emphasised
Oesophageal adenocarcinoma
Prognosis and prediction
The use of antibodies targeting ERBB2 (HER2) in patients overexpressing this molecule
is included, and the need for testing
Oesophageal squamous carcinoma and oesophageal squamous dysplasia
Aetiology and pathogenesis
The potential role of HPV remains uncertain. Other environmental factors, including
tobacco and alcohol consumption appear to be more important. The importance of TP53
mutation is now clear, and studies have identified alterations in genes that regulate
cell cycle, cell differentiation (especially NOTCH pathway) and EGFR (HER1) signalling
as key genetic abnormalities
Gastric adenocarcinoma
Aetiology and pathogenesis
Most sporadic gastric cancers are now considered to be inflammation‐driven, and their
aetiology is characteristically environmental – usually related to Helicobacter pylori
infection. Up to 10% of gastric cancers are familial. Other factors include tobacco
smoking, irradiation and diet. Molecular subtypes as proposed by two consortia are
described, although clinical application is limited
Gastric adenocarcinoma
Classification
Heterogeneity of poorly cohesive carcinoma (PCC) is discussed, including signet‐ring
cell carcinoma and PCC‐NOS. Rare subtypes are described, such as gastric adenocarcinoma
of fundic‐gland type
Gastric adenocarcinoma
Prognosis and prediction
ERBB2 testing is used to predict potential response to anti‐ERBB2 therapy. MSI‐H and
EBV positivity are markers of good prognosis with potential therapeutic importance,
namely for immunotherapy targeting the PD‐1/PD‐L1 axis (under investigation in clinical
trials). A large number of other reported markers are described, but not yet in practice
Small intestinal and ampullary carcinomas
Pathogenesis
These are split into ampullary and non‐ampullary types, on the basis of anatomy. Pathogenesis
seems similar to colorectal carcinoma, though more information is required
Goblet cell adenocarcinoma of the appendix
Classification
This is a change from goblet cell carcinoid/carcinoma as it is now recognised to have
a minor neuroendocrine component
Serrated lesions of the colon, rectum and appendix
Classification and pathogenesis
The preferred name is serrated lesion, as these may be flat rather than polypoid,
and the association with BRAF or KRAS mutation delineates two separate neoplastic
pathways
Anal squamous dysplasia
Diagnostic molecular pathology
P16 and HPV testing is recommended
Neuroendocrine neoplasms (NEN)
Classification and molecular pathology
The general principles of the new classification of neuroendocrine tumours (NET) will
be applied to the entire 5th series, based on a consensus meeting in Lyon (1), dividing
NEN into NET and neuroendocrine carcinomas (NEC) based on their molecular differences.
Mutations in MEN1, DAXX and ATRX are entity‐defining for well‐differentiated NETs,
while NECs usually have TP53 or RB1 mutations
Precursor lesions
Classification
The term ‘dysplasia’ is preferred for lesions in the tubal gut, whereas ‘intra‐epithelial
neoplasia’ is preferred for those in the pancreas, gallbladder and biliary tree. Use
of the term ‘carcinoma in situ’ is not recommended
Hepatocellular tumours
Classification
Revision based on molecular profiling studies. Fibrolamellar carcinoma defined by
DNAJB1–PRKACA translocation
Intrahepatic cholangiocarcinoma
Classification
Two main subtypes: a large duct type, which resembles extrahepatic cholangiocarcinoma,
and a small duct type, which shares aetiological, pathogenetic and imaging characteristics
with hepatocellular carcinoma
Pancreatic intraductal neoplasms
Classification
Intraductal oncocytic papillary and intraductal tubulopapillary neoplasms are distinguished
from intraductal papillary mucinous neoplasms and ductal adenocarcinoma by the absence
of KRAS in these lesions
Acinar cystic transformation of the pancreas
Classification
Previously called acinar cell cystadenoma, but now demonstrated to be non‐neoplastic
by molecular clonality analysis
Haematolymphoid tumours and mesenchymal tumours
Classification
Grouped together in separate chapters, to ensure consistency and avoid duplication
EBV‐positive inflammatory follicular dendritic cell sarcoma of the digestive tract
Classification
This name change is necessary due to new information on the EBV relationship of this
tumour type, previously known as ‘inflammatory pseudotumour‐like fibroblastic/follicular
dendritic cell tumour’
Genetic tumour syndromes of the digestive system
Classification, pathogenesis and diagnostic molecular pathology
Common syndromes are updated. A new section on GAPPS (gastric adenocarcinoma and proximal
polyposis of the stomach) syndrome is presented. Tumour predisposition syndromes that
confer a raised risk of various gastrointestinal tumours are described
EBV, Epstein–Barr virus; HPV, Human papillomavirus; PD‐1, Programmed death 1; PD‐L1,
Programmed death ligand; NOS, Not otherwise specified; EGFR, Epidermal growth factor
receptor; HER1, Human epidermal growth factor receptor 1.
Rindi et al.
3
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Since the publication of the 4th‐edition digestive system tumours volume in 2010,1
there have been important developments in our understanding of the aetiology and pathogenesis
of many tumours. However, the extent to which this new information has altered clinical
practice has been quite variable. For some of the tumours described in this volume
there is little molecular pathology in clinical use, despite the fact that we now
have a more detailed understanding of their molecular pathogenesis. A tumour's molecular
pathology, as defined for the purposes of this publication, concerns the molecular
markers that are relevant to the tumour's diagnosis, biological behaviour, outcome
and treatment, rather than its molecular pathogenesis. However, the role of molecular
pathology is expanding; for some tumour entities, molecular analysis is now essential
for establishing an accurate diagnosis. Some of these analyses require investigation
of somatic (acquired) genetic alterations, gene or protein expression, or even circulating
tumour markers. For certain tumour types, specific analytical tests are needed to
predict prognosis or tumour progression, and these tests are carefully outlined in
this volume. In the following paragraphs, we have summarised some of the more notable
changes since the 4th edition. In instances where the new WHO classification of tumours
editorial board determined that there was insufficient evidence of the diagnostic
or clinical relevance of new information about a particular tumour entity, the position
held in the 4th edition has been maintained as the standard in the new volume.
Oesophageal and gastric tumours
There has been substantial progress in our understanding of the development of glandular
oesophageal neoplasia and the sequential neoplastic progression from inflammation
to metaplasia (Barrett's oesophagus), dysplasia and, ultimately, adenocarcinoma. This
process is initially driven by gastro‐oesophageal reflux disease, which leads to reprogramming
of cell differentiation and proliferation in the oesophagus. There is evidence that
TP53 mutation in proliferating epithelium leads to high‐grade dysplasia, while SMAD4
mutation precedes the development of invasive carcinoma. While demonstration of these
mutations is not required clinically, testing oesophageal and gastric adenocarcinomas
for ERBB2 [human epidermal growth factor receptor 2 (HER2)] is recommended, as this
influences treatment decisions.
The pathogenesis of precursor lesions is less clear in oesophageal squamous carcinogenesis
than in gastric carcinogenesis. Environmental factors are believed to play an important
role, but the mechanisms of neoplastic change as a result of specific factors, such
as tobacco use and alcohol consumption, are poorly understood. For example, human
papillomavirus (HPV) infection was initially believed to play a key role in squamous
carcinogenesis, but recent evidence suggests that there is no such association in
most cases of oesophageal squamous cell carcinoma.
The molecular pathway of cancer progression in the stomach is less clear. Most epidemic
gastric cancers are now considered inflammation‐driven, and their aetiology is characteristically
environmental – usually related to Helicobacter pylori infection. It is because of
this infectious aetiology that gastric cancer is included among the limited number
of highly lethal, but preventable, cancers. Chronic gastric inflammation leads to
changes in the microenvironment (including the microbiome) that results in mucosal
atrophy/metaplasia, which may then progress to neoplasia after further molecular alterations.
Metaplastic changes in the upper gastrointestinal tract are well‐recognised as early
cancer precursors, but their precise molecular mechanisms and the exact role of progenitor
cells in the oncogenic cascade remain a subject of intense investigation. For some
rare tumours, distinctive driver mutations have been identified; for example, the
characteristic MALAT1–GLI1 fusion gene in gastroblastoma and EWSR1 fusions in gastrointestinal
clear cell sarcoma and malignant gastrointestinal neuroectodermal tumour. In both
examples, demonstration of the fusion gene is now required for the diagnosis.
Tumours of the anus, small and large intestines
The pathogenesis of adenocarcinomas of the intestines (the small and large bowel and
the appendix) is now much better delineated than it was a decade ago. The introduction
of population‐based screening for colorectal cancer has laid the foundation for a
better understanding of neoplastic precursor lesions and the molecular pathways associated
with each type of tumour. For example, our knowledge of the molecular pathways and
biological behaviour of conventional adenomas and serrated precursor lesions, including
the recently renamed sessile serrated lesion (formerly called sessile serrated polyp/adenoma),
has grown rapidly in the past decade, and this has enabled clinicians to provide tailored,
evidence‐driven screening and surveillance programmes. Colorectal cancers, in which
it will make a difference to patient treatment, should undergo molecular testing for
microsatellite instability and extended RAS testing for mutations in KRAS, NRAS and
BRAF. Our understanding of appendiceal tumours has also improved. For example, we
now know that many tumours of the appendix develop via neoplastic precursor lesions
similar to those in the small and large intestines, and the biological potential and
molecular pathways of appendiceal tumours are therefore much better appreciated. The
recently renamed goblet cell adenocarcinoma (formerly called goblet cell carcinoid/carcinoma)
of the appendix is a prime example of a tumour whose biological potential and histological
characteristics have been better described, resulting in improvements in the pathological
approach to these tumours. Studies of the aetiology and pathogenesis of anal squamous
lesions suggests that HPV infection plays an important aetiological role, driving
genetic alterations similar to those in cervical cancer. p16 and HPV testing are recommended
for such lesions.
Neuroendocrine neoplasms
One particularly important change in the 5th edition is in the classification of neuroendocrine
neoplasms (NENs), which occur in multiple sites throughout the body. In this volume,
NENs are covered within each organ‐specific chapter, including the chapter on tumours
of the pancreas, where detailed sections describing each functioning and non‐functioning
subtype are provided. Previously, these neoplasms were covered only in the volume
on tumours of endocrine organs.2 The general principles guiding the classification
of all NENs are presented in a separate introduction to this topic (Table 2). To consolidate
our increased understanding of the genetics of these neoplasms, a group of experts
met for a consensus conference at the International Agency for Research on Cancer
(IARC) in November 2017 and subsequently published a paper in which they proposed
distinguishing between well‐differentiated neuroendocrine tumours (NETs) and poorly
differentiated neuroendocrine carcinomas (NECs) in all sites where these neoplasms
arise.3 NEN are divided into NET and NECs, based on their molecular differences. Mutations
in MEN1, DAXX and ATRX are entity‐defining for well‐differentiated NETs, whereas NECs
usually have TP53 or RB1 mutations. In some cases, these mutations can be of diagnostic
benefit. Genomic data have also led to a change in the classification of mixed NENs,
which are now grouped into the conceptual category of ‘mixed neuroendocrine–non‐neuroendocrine
neoplasms (MiNENs)’. Mixed adenoneuroendocrine carcinomas (MANECs), which show genomic
alterations similar to those of adenocarcinomas or NECs rather than NETs, probably
reflect clonal evolution within the tumours, which is a rapidly growing area of interest.
The study of these mixed carcinomas may also lead to an improved understanding of
other facets of clonality in tumours of the digestive system and other parts of the
body.
Table 2
Classification and grading criteria for neuroendocrine neoplasms (NENs) of the GI
tract and hepatopancreatobiliary organs
Terminology
Differentiation
Grade
Mitotic rate* (mitoses/2 mm2)
Ki‐67 index*
NET, G1
Well differentiated
Low
<2
<3%
NET, G2
Intermediate
2–20
3–20%
NET, G3
High
>20
>20%
NEC, small‐cell type (SCNEC)
Poorly differentiated
High†
>20
>20%
NEC, large‐cell type (LCNEC)
>20
>20%
MiNEN
Well or poorly differentiated‡
Variable‡
Variable‡
Variable‡
LCNEC, Large‐cell neuroendocrine carcinoma; MiNEN, Mixed neuroendocrine–non‐neuroendocrine
neoplasm; NEC, Neuroendocrine carcinoma; NET, Neuroendocrine tumour; SCNEC, Small‐cell
neuroendocrine carcinoma.
*
Mitotic rates are to be expressed as the number of mitoses/2 mm2 as determined by
counting in 50 fields of 0.2 mm2 (i.e. in a total area of 10 mm2); the Ki‐67 proliferation
index value is determined by counting at least 500 cells in the regions of highest
labelling (hot‐spots), which are identified at scanning magnification; the final grade
is based on whichever of the two proliferation indexes places the neoplasm in the
higher‐grade category.
†
Poorly differentiated NECs are not formally graded, but are considered high‐grade
by definition.
‡
In most MiNENs, both the neuroendocrine and non‐neuroendocrine components are poorly
differentiated, and the neuroendocrine component has proliferation indices in the
same range as other NECs, but this conceptual category allows for the possibility
that one or both components may be well differentiated; when feasible, each component
should therefore be graded separately.
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Another important change concerns the recognition that well‐differentiated NETs may
be high grade (G3 in the WHO grading system, defined as having a mitotic rate >20 per
2 mm2 or Ki67 >20%), but these neoplasms remain well‐differentiated genetically and
distinct from poorly differentiated NECs. G3 NETs were first recognised and are most
common in the pancreas, but they can occur throughout the GI tract. Thus, the current
WHO classification includes three grades (G1, G2 and G3) for NETs. NECs are no longer
graded, as they are recognised to be uniformly high grade by definition, but continue
to be separated into small‐and large‐cell types.
Precursor lesions
There are certain terms in current day‐to‐day use about which many pathologists continue
to disagree. The editorial board carefully considered our current understanding of
carcinogenetic pathways when considering the use of specific terms and definitions.
In general, the overall consensus was that established terms, definitions and criteria
should not be changed unless there was strong evidence to support doing so and the
proposed changes had clinical relevance. For some tumours, our understanding of the
progression from normal epithelium to metastatic carcinoma remains inadequate. For
example, in certain tumours the line between benign and malignant can be ambiguous,
and in some cases the distinction is more definitional than biological. These are
some of the many areas of tumour biology that need to be more fully investigated in
the future.
In the 5th edition, the terminology for precursors to invasive carcinoma in the digestive
system has been standardised somewhat, although the terms ‘dysplasia’ and ‘intra‐epithelial
neoplasia’ are both still considered acceptable for lesions in certain anatomical
locations, in acknowledgement of their ongoing clinical acceptance. For example, the
term ‘dysplasia’ is preferred for lesions in the tubular gut, whereas ‘intra‐epithelial
neoplasia’ is preferred for those in the pancreas, gallbladder and biliary tree. For
all anatomical sites, however, a two‐tiered system (low‐ versus high‐grade) is considered
the standard grading system for neoplastic precursor lesions. This has replaced the
three‐tiered grading scheme previously used for lesions in the pancreatobiliary system.4
The term ‘carcinoma in situ’ continues to be strongly discouraged in clinical practice
for a variety of reasons, most notably its clinical ambiguity. This term is encompassed
by the category of high‐grade dysplasia/intraepithelial neoplasia.
Liver tumours
Many refinements of the 4th‐edition classification have been made concerning liver
tumours, supported by novel molecular findings. For example, a comprehensive picture
of the molecular changes that occur in common hepatocellular carcinoma has recently
emerged from large‐scale molecular profiling studies. Meanwhile, several rarer hepatocellular
carcinoma subtypes, which together may account for 20–30% of cases, have been defined
by consistent morphomolecular and clinical features, with fibrolamellar carcinoma
and its diagnostic DNAJB1–PRKACA translocation being one prime example. Intrahepatic
cholangiocarcinoma is now understood to be an anatomically defined entity with two
different major subtypes: a large duct type, which resembles extrahepatic cholangiocarcinoma,
and a small duct type, which shares significant aetiological, pathogenetic and imaging
characteristics with hepatocellular carcinoma. The two subtypes have very different
aetiologies, molecular alterations, growth patterns and clinical behaviours, exemplifying
the conflict between anatomically and histogenetically/pathogenetically based classifications.
Clinical research and study protocols will need to incorporate these findings in the
near future. Also supported by molecular findings, the definition of combined hepatocellular–cholangiocarcinoma
and its distinction from other entities has recently become clearer. Cholangiolocellular
carcinoma is no longer considered a subtype of combined hepatocellular–cholangiocarcinoma,
but rather a subtype of small duct intrahepatic cholangiocarcinoma, renamed cholangiolocarcinoma,
meaning that all intrahepatic carcinomas with a ductal or tubular phenotype are now
included within the category of intrahepatic cholangiocarcinoma. A classic example
of morphology‐based molecular profiling leading to a new classification based on a
combination of biological and molecular factors is the classification of hepatocellular
adenomas, which has gained a high degree of clinical relevance and has fuelled the
implementation of refined morphological criteria and molecular testing in routine
diagnostics.
Tumours of the pancreas
Most of the classification of pancreatic neoplasms in the 5th edition remains unchanged
from the last volume. As highlighted above, precursor lesions including pancreatic
intraepithelial neoplasia, intraductal papillary mucinous neoplasms and mucinous cystic
neoplasms are now classified into two tiers of dysplasia, based on the highest grade
of dysplasia detected, rather than the three‐tier system used in the last edition
of the WHO classification. Intraductal oncocytic papillary neoplasm and intraductal
tubulopapillary neoplasms are now separated from the other subtypes of intraductal
papillary mucinous neoplasm based on their distinct genomic and morphological features.
The prior entity of acinar cell cystadenoma, which has recently been demonstrated
to be non‐neoplastic by molecular clonality analysis, is now termed ‘acinar cystic
transformation of the pancreas’. Also, the entire spectrum of pancreatic neuroendocrine
neoplasms is now included in this volume; previously, details concerning the individual
functional types were presented in the WHO classification of tumours of the endocrine
organs.
Mixed tumours
Mixed tumours in several anatomical sites (e.g. oesophageal adenosquamous carcinoma
and mucoepidermoid carcinoma, as well as hepatic carcinomas with mixed hepatocellular
and cholangiocellular differentiation), remain subjects of some uncertainty. The relative
importance of the various lineages of differentiation within these neoplasms remains
unknown. It is also uncertain how these neoplasms develop and how they should be treated.
These issues are a matter of debate because hard evidence is lacking, but there are
improvements in the pathological criteria and classification of these neoplasms that
should help to standardise the diagnostic approach and facilitate better clinical
and genomic research.
Haematolymphoid tumours and mesenchymal tumours
Each of these tumour types is grouped together in separate chapters. This ensures
consistency and avoids duplication. The term ‘EBV positive inflammatory follicular
dendritic cell sarcoma of the digestive tract’ has been adopted to replace the entity
previously known as ‘inflammatory pseudotumour‐like fibroblastic/follicular dendritic
cell tumour’.
Genetic tumour syndromes
New in this book is the chapter on genetic tumour syndromes of the digestive system,
the introduction to which contains a table that lists each of the major syndromes
and summarises key information about the disease/phenotype, pattern of inheritance,
causative gene(s) and normal function of the encoded protein(s). Common syndromes,
including Lynch syndrome and familial adenomatous polyposis 1 (FAP), are covered in
detail, as well as several other adenomatous polyposes defined since the last volume
and the GAPPS (gastric adenocarcinoma and proximal polyposis of the stomach) syndrome,
now recognised as a FAP variant, with a unique phenotype. A number of other genetic
tumour predisposition syndromes that confer a raised risk of various gastrointestinal
tumours are also described, including Li–Fraumeni syndrome, hereditary haemorrhagic
telangiectasia, syndromes associated with gastroenteropancreatic NETs and multilocus
inherited neoplasia alleles syndrome. This should be helpful to many involved in the
diagnosis of such syndromes, as well as those researching the mechanisms involved.
Format changes
The format of the books has been updated to reflect the new edition of the classification:
the move from three to two columns has allowed larger illustrations, and the use of
set headings for each tumour type show very clearly where evidence is lacking.
Conflict of interest
I.D.N. reports that her institute benefits from research funding from the Dutch Cancer
Society (KWF) and the Dutch Digestive Foundation (MLDS). No other authors report any
conflicts of interest to IARC that would affect their participation in forming the
classification.