world cancer report - iarc

Fig. 5.62 Five-year relative survival rates after
diagnosis of cervical cancer.
Advanced carcinoma is suggested by backpain,
oedema of the lower extremity, a nonfunctioning
kidney (due to ureteral obstruction),
invasion of sacral nerve branches or
extranodal extension and encroachment of
the pelvic wall veins and lymphatics [6].
In the event of invasive disease, investigations
are undertaken to determine whether
metastatic disease is present, i.e. chest
radiography, blood cell count and serum
chemistry. Intravenous pyelography is used
to investigate the possibility of uretic
obstruction; abdominal CT and MRI are
used to indicate spread and to take tumour
measurements, respectively. Cytoscopy
and sigmoidoscopy are necessary in the
event of anterior or posterior spread.
Pathology and genetics
Precursor lesions of the cervix are commonly
classified using terminology for histological
diagnosis, thus mild dysplasia is
categorized as cervical intraepithelial neoplasia
CIN I, moderate dysplasia is CIN II,
and severe dysplasia, CIN III. However,
newer terminology for precursor lesions of
the cervix classifies them as squamous
intraepithelial lesions, which are graded
from low (mild dysplasia, usually diploid or
polyploid, associated with various HPV
types) to high (associated with intermediate
or high-risk HPV type, typically aneu-
ploid, moderate or severe dysplasia or carcinoma
in situ) [6]. One of the precursors
of invasive adenocarcinoma is recognized
as adenocarcinoma in situ. This is sometimes
difficult to diagnose, often not being
detected by Pap smear [8].
Squamous cell carcinomas may be either
large cell non-keratinizing or large cell keratinizing,
or a less common variant, such
as the well-differentiated verrucous carcinoma.
The worldwide prevalence of adenocarcinomas
of the cervix has increased
from 5% in 1950-60 to 20-25% of all cervical
tumours [6]. The most common type is
mucinous adenocarcinoma, which may be
intestinal, endocervical or signet-ring, followed
by endometrioid adenocarcinoma.
Another epithelial tumour type consists of
a mixture of squamous cell carcinomas
and adenocarcinomas.
Subsequent to infection, the HPV genome
of high-risk types becomes stably integrated
into the host DNA, commonly near cellular
oncogenes such as C-MYC and N-
MYC, or into regulatory sequences, such
as the genes encoding transcription factors
Erg and Ets-2 [9]. The observation that
low frequencies of p53 gene mutations are
found in tumours associated with HPV is
probably a reflection of the fact that the
viral protein E6 is able to functionally inactivate
p53 protein. A variety of molecular
markers for cervical cancer are under preliminary
investigation, including telomerase
(Box: Telomeres and Telomerase,
p108), which appears to be expressed in
most cervical epithelial neoplasias and
KRAS (mutations having been detected in
DNA extracted from cervical aspirates)
[10]. Loss of heterozygosity on chromosome
3p has been observed in invasive
and pre-invasive lesions [11] suggesting
the presence of a tumour suppressor gene;
the FHIT gene (fragile histidine triad) has
been mapped to 3p14.2 (a suspected HPV
integration site which is commonly altered
in cervical cancer).
Management
Cervical intraepithelial neoplasms may be
treated by local excision (wire loop electrode,
conisation with laser or scalpel) or
destruction (laser vapourisation, radical
diathermy or cryocautery). Methods which
do not produce a tissue specimen for histology
may ablate an undetected adenocarcinoma
in situ or microinvasive carcinoma
[12]. Recurrences or persistent residual
disease may occur.
For early stage invasive carcinoma, where
the cancer is confined to the cervix or
spread to the upper vagina, surgery and
radiotherapy are the primary treatment
options. Radiotherapy is usually employed
for patients with advanced disease and
external beam therapy is used initially for
patients with bulky tumours. The use of an
intracavity radium source is being replaced
with caesium-137, which is considered
safer. Radiotherapy may be given postoperatively
to patients at a high risk of
recurrence (although benefits are not
proven) [13].
Unresectable lymph node metastases are
a risk factor for persistent disease.
Invasive carcinoma of the cervix may follow
a more rapidly progressive course in
HIV-positive women. Despite initial treatment
and even hysterectomy, cervical
intraepithelial neoplasia and even invasive
cancer may still recur, or residual disease
may persist. Common sites of recurrence
are the paraortic lymph nodes, liver, lungs,
abdomen, bones, the central nervous system
and supraclavicular lymph nodes.
Recent treatment advances include high
dose rate brachytherapy, refinement of
treatment dose to minimize failure rate,
and addition of chemotherapy concurrently
with radiotherapy to minimize local and
distant failures. Palliative treatment of
those with advanced or metastatic disease
may consist of combination platinumbased
chemotherapy [14].
Survival from cancer of the cervix depends
on stage of disease, with 70-85% of localized
cancer cases surviving five years compared
to less than 10% of cases with distant
spread. Important differences are present
in relation to age and ethnic or socioeconomic
characteristics, probably as a consequence
of differential access to medical
care. Survival rates for all stages also vary
between regions; even in developing countries,
where many cases present at relatively
advanced stage, survival rates reach
49% on average (Fig. 5.62). The poorest
survival is estimated for Eastern Europe.
Cancers of the female reproductive tract
217