world cancer report - iarc

Fig. 5.76 A radiographic view of an oesophageal
cancer taken following a barium swallow. Arrows
indicate a filling defect caused by obstruction by
the tumour.
atypical squamous cells which infiltrate
the underlying normal tissue and contain
keratin pearl formation and intercellular
bridges [9].
The sequence of genetic events leading
to squamous cell carcinoma is only partially
understood (Fig. 5.78). Mutation of
the p53 gene is an early event, detected
Normal oesophagus
p53 mutations
Oesophagitis
in 35-70% of tumours, depending on geographic
origin. Tumours from high-incidence
areas of Western Europe show a
high proportion of mutations at A:T base
pairs. These mutations may reflect a contribution
of metabolites of alcohol. In
East Asia, mutations at A:T base pairs are
less common, but transversions at G:C
base pairs occur at a higher rate than in
Western Europe [10]. Mutations in p53
have been observed in dysplasia, and in
normal mucosa adjacent to cancer
lesions [11].
In squamous cell carcinoma, other commonly
mutated genes are those encoding
proteins involved in the control of the
G1/S cell-cycle checkpoint, such as
cyclin D1 and p16 INK4A (Cell cycle, p104).
Amplification of the cyclin D1 gene
CCDN1 (11q13) occurs in 20-40% of
tumours. The gene encoding p16 INK4A is
often subject to hypermethylation of the
promoter region, resulting in down-regulation
of expression. Amplification of a
number of proto-oncogenes (HST-1, HST-
2, EGFR, MYC) has also been reported
[12]. In the Japanese population, a polymorphism
in the gene encoding aldehyde
dehydrogenase 2 (ALDH2), which plays a
role in ethanol metabolism, is significantly
associated with squamous cell carcinoma
[13].
Adenocarcinoma of the oesophagus
mostly occurs within the distal third of
the oesophagus and is preceded by a
Overexpression of CYCLIN D1
LOH at 3p21; LOH at 9p31
LOH 3p14 (FHIT); LOH 17q25 (TOC)
Low-grade
intraepithelial neoplasia
Fig. 5.77 Moderately differentiated squamous cell
carcinoma of the oesophagus, ulcerated, deeply
invasive and extending below the normal squamous
epithelium (SE).
well-defined preneoplastic lesion called
Barrett mucosa (or Barrett oesophagus)
(Fig. 5.79). Barrett mucosa is a glandular,
metaplastic mucosa of the normal squamous
epithelium. It is often associated
with chronic gastro-oesophageal acid
reflux. However, it also occurs in the context
of chronic biliary alkaline reflux, as
well as, in some cases, the absence of a
detectable reflux. Men are seven times
more commonly affected than women
[14].
The estimated risk of developing an adenocarcinoma
for patients with Barrett
mucosa is 30-125 times greater than in
the general population. There are three
subtypes: fundic (base of oesophagus),
cardiac (the region between the oesophagus
and the stomach), and intestinal.
Multiple loss of heterozygosity (LOH)
Amplification of C-MYC, EGFR, CYCLIN D1, HST1...
High-grade
intraepithelial neoplasia
Fig. 5.78 Sequence of genetic alterations in the development of squamous cell carcinoma of the oesophagus.
SE
SE
SE
SE
Invasive squamous
cell carcinoma
Oesophageal cancer
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