In August 2008, the UK reality TV star Jade Goody was diagnosed with
cervical cancer, due to which she passed away in March 2009. Her illness
propelled the public consciousness on the issue of cervical cancer in
headlines. The honest revelation of her illness was shared with the
public, leading to what we now know as the Jade Goody Effect.
It described the huge surge in number of cervical cancer screenings
among women in UK after her diagnosis and untimely death.
It reported 12% increase in the number of cervical cytology
samples and a 10% increase in referrals to colposcopy following
Goody's diagnosis and death in year 2008/2009. Thus, it necessitates
the consideration of the current screening and diagnosing strategies,
their possible impact on Human Papillomavirus (HPV) testing and the
potential long-term effects of the current changes to cervical cancer
prevention.
Cervical Cancer Screening: Only Way To Prevent It!
The mortality due to uterine cervix cancer has fallen dramatically in
developed countries since the advent and widespread application of
cytology-based screening with Pap smear test, developed by George
Papanicolaou in the 1950s. Despite existence of national guidelines,
the screening reportage in India is appallingly low. Hence, a large
proportion of these cancer cases are present in advanced stages at
the time of diagnosis, when it is difficult to reverse.
Screening Strategies: Right Approach at Right time!
1. Pap Smear Test
The Papanicolaou smear (Pap) test, involves examining the morphology
of exfoliated cervical cells under a microscope and it generally has a low
sensitivity (53-55.4%) and high specificity (84.2-94.5%).
The Pap test has been the method of choice for cervical cancer screening
since the 1950s, proving valuable for mass screening and enabling
detection of lesions early enough for effective treatment. There are
two acceptable techniques for collecting the Pap Smear, Conventional
and Liquid-based.
Conventional method.
The clinician places a Speculum into the woman's vagina and scrapes off
mucous membrane cells from the transformation zone of the cervix using
a small spatula. The cells from the spatula are transferred to a slide and
fixed with a preservative. These smears can have false negative and
false-positive results because of inadequate sampling and slide preparation,
and errors in laboratory detection and interpretation.
Liquid-based cervical cytology
This method was developed to improve the diagnostic reliability of Pap
smears. The cervical cells are rinsed in preservatives so that blood and
other potentially obscuring material can be separated. This cytological
method uses two different smearing techniques. ThinPrep
(uses filtration and transfer of cells on slide) and SurePath
(uses gradient centrifugation). Both the techniques provide improved single
collection. Theoretically, it has the advantages of easier interpretation,
fewer unsatisfactory results and of blood and debris. The sample can
be preserved, for further HPV test at the same time.
The main advantage of the above cytological screening is that it allows
detection in its pre-invasive phase which can be easily treated.
Cytological screening has been found to reduce the incidence of cervical cancer by 80%.
2. Colposcopy
The main objective is to check the cervix for abnormal areas or for an
abnormal pap smear. It involves the use of a colposcope to examine
the cervix. The subepithelial vascular distribution is also closely examined
as it may be abnormal in the presence of Cervical Intraepithelial Neoplasia
(CIN). The methods such as Visual Inspection with Acetic acid (VIA) with
the naked eye or magnification and use of Lugol's lodine (VILI) are used
for early cervical lesions.
VIA
It is a visual examination of the uterine cervix after applying 3-5% acetic
acid. If the cervical epithelium contains an abnormal load of cellular proteins,
the acetic acid coagulates the proteins presenting an opaque and white aspect
of the concerned area. A precancerous lesion has higher Protein content as
compared to normal epithelium. As a consequence, it becomes white
(acetowhite) and it is considered to be "VIA positive." For practical
consideration, the expected rate of CIN grade 2 (CIN2 + ) or worse in
an unscreened or poorly screened population, is between 2-4%.
VILI- It is a visual examination performed generally after VIA test
and requires the Lugol's lodine application, a compound that reacts
with glycogen resulting in a brown or black coloration. Normal mature
squamous epithelium contains glycogen. So, when in contact with Lugol's
iodine, it becomes black, whereas precancerous lesions and Cancer
contain little or no glycogen, thus turning yellow after Lugol application.
Such a reaction is considered to be "VILI positive."
The main advantage of this assessment is the immediate availability of
the results which permits diagnosis and/or treatment to be performed
in the same sitting. Screening is not beneficial in women older than
65 years if they have had a recent history of negative test results.
3. Histopathologic Examination Of Biopsied Specimens
A long-recognized, pathognomonic feature of HPV infection is the
appearance of halo or koilocytotic cells in the differentiated layers
of the squamous epithelium. these koilocytes are squamous epithelial
cells containing an acentric, hyperchromatic nucleus, displaced by a
large perinuclear vacuole. In clinical biopsies, koilocytosis is observed
in both low-and highrisk HPV infections. In this process, the biopsied
epithelium of the cervix is examined by a pathologist and classified
according to the fraction of the epithelial layer that displays abnormal
cellular morphology. For squamous epithelium, score of CIN1 or
Low-grade
Squamous Intraepithelial Neoplasia (LSIL) is given when a third or less
of the epithelium has undergone cellular changes CIN2 and 3 or High-grade
Squamous Intraepithelial Neoplasia (HSIL), when greater than one-third
of the squamous epithelium displays abnormal cellular morphology.
Cancer is diagnosed when invasion is noted in the squamous epithelium
(squamous cell carcinoma) or glandular epithelium (adenocarcinoma).
If left untreated, CIN2 or more severe diagnoses, referred to as CIN2+
diagnoses, can progress to invasive cancer and therefore are commonly
treated by ablation or excision to prevent progression.
4. HPV-DNA Genotyping
Nucleic acid (DNA) testing by PCR has become a standard, non-invasive
method for determining the presence of a cervical HPV infection. Proper
implementation of nucleic acid testing for HPV may increase the sensitivity
of cervical cancer screening programs by detecting high-risk lesions earlier
in women 30 years and older with normal cytology and reduce the need
for unnecessary colposcopy and treatment in patients under 21 years and
older with cytology results showing Atypical Squamous Cells of
Undetermined Significance (ASC-US). The most commonly used in clinical
practice is Hybrid Capture II, which is a batch test based on hybridization.
It tests for the presence of 1 risk HPV types above a certain threshold
(HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) with
direct genomic detection or by amplification of a viral DNA fragment.
HPV genotyping identifies specific viral types usually HPV 16 and 18.
Their major disadvantages are that they are expensive, time-consuming
and laborious; hence, they are used more in research settings. HPV as a
screening test has a very good sensitivity and a high negative predictive
value, thus allowing lengthening of the screening intervals. HPV testing
can not differentiate between persistent and transient infe
ion, therefore
it has 3-4% lower specificity than cytology.
Staging of Carcinoma
When a diagnosis of invasive cervical carcinoma is histogically confirmed,
the disease should be staged prior to the initiation of treatment. The most
widely used staging system is the one developed by the International
Federation of Gynecology and Obstetrics (FIGO)- FIGO Staging of
Carcinoma of the Cervix Uteri.
- Stage I
Carcinoma is strictly confined to the cervix uteri IA-Diagnosed only by
microscopy, with maximum depth of invasion <5 mm
- IA1 Invasion <3 mm in depth IB-Invasion 25 mm, lesion limited to the
cervix uteri
- IB1 Invasive carcinoma 25 mm depth of invasion and <2 cm in greatest
dimension
- IB2 Invasive carcinoma 2 cm and <4 cm in greatest dimension
- IB3 Invasive carcinoma 24 cm in greatest dimension
-
Stage II
Carcinoma invades beyond the uterus, but not up to the lower third of the
vagina or pelvic wall
- IIA- Involvement limited to the upper two-thirds of
the vagina without parametrial involvement
- IIA1 Invasive carcinoma <4 cm in greatest dimension
- IIA2 Invasive carcinoma 24 cm in greatest dimension
- IIB- With parametrial involvement but not up to the pelvic wall
-
Stage III
Carcinoma involves the lower third of the vagina, extending to the pelvic
wall and/or non functioning kidney and/or para-aortic lymph nodes
TIA-Carcinoma involves the lower third of the vagina, with no extension
to the pelvic wall
- IIIB Extension to the pelvic wall or non-functioning kidney
- IIIC Involvement of pelvic and/or para-aortic lymph nodes, irrespective
of tumor size and extent
- IIIC1 Pelvic lymph node metastasis only
- IIIC2 Para-aortic lymph node metastasis
-
Stage IV Carcinoma extended beyond true pelvis or has involved mucosa
of bladder or rectum IVA-Spread of growth to adjacent organs IVB-Spread
to distant organs
Interventions
The results of other diagnostic examinations, together with the operative
findings, may be used to plan treatment; however, they should not be used
to assign the clinical stage. These diagnostic examinations include
Computerized Tomography (CT) scanning, Magnetic Resonance Imaging
(MRI), Lymphangiography and Laparoscopy.
Interventions such as immunizations against high-risk HPV types may
have a future role in the prevention of cervical neoplasia. Although
surgery and radiation therapies have been very successful in the treatment
of early-stage cervical carcinoma, the prognosis for advanced and recurrent
disease remains poor, mainly because there is no effective systemic therapy.
Cervical cytologic screening must be promoted.
