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Gynaecological Oncology
Therefore, it would seem reasonable to follow up post-treatment dependant on good compliance of the patients, who need to make
women with an HPV test at six months, with reflex cytology reserved multiple follow-up visits. HPV testing is accepted and reimbursed as a
for those with positive HPV DNA. However, this needs further standard reflex test for borderline abnormalities or ASCUS pap smears
validation with larger multicentre studies. Recently, the EU Quality in virtually all European countries, and is included in the EU Guidelines
Assurance guidelines for cervical cancer screening
13
stated that HPV for Cervical Cancer Screening
14
as the best strategy. The discussion
testing is recommended for follow-up and triage indications. about the optimal strategy and time-points of incorporating HPV
testing into the triage of women with ASCUS (or borderline nuclear
Human Papillomavirus Testing to abnormality) smears is still ongoing in the UK, where HPV testing has
Triage Minor Cytological Lesions not been included in the cervical screening programme.
Atypical squamous cells of undetermined significance (ASCUS) remain
a common cytological diagnosis and are detected in 4–7% of screened Role of Type-specific
women. In several countries, it is currently recommended to follow up Human Papillomavirus Tests
these women with conventional (Pap) smear or with liquid-based Although cervical cancer is induced by HPV, the different HPV types
cytology (LBC) at six-monthly intervals until three negative smears are are not equally carcinogenic. Thirteen oncogenic or high-risk strains
obtained. Women with two or more ASCUS results are referred for a are involved in cervical carcinogenesis. Of these high-risk types, HPV
colposcopy. In The Netherlands, about one-third of women with ASCUS 16 and, to a lesser extent, HPV 18 and HPV 45 carry a higher risk than
in primary screening smears are eventually referred for colposcopy. It the others. HPV 16 and HPV 18 are aetiologically associated with CIN3
is now accepted practice in many countries for reflex HPV DNA testing and invasive cervical carcinomas being found in 60% and 70% of
to be performed directly from the LBC media in those women specimens, respectively.
15
Extraordinarily high odds ratios for having
presenting with ASCUS smears, therefore obviating the need for invasive cervical cancer are associated with infection with high-risk
women to return for a repeat cytology test. The NPV is 98%, providing types of HPV: for HPV 16, the odds ratio of having cervical cancer if
reassurance of the absence of underlying disease.
6
infected are 434; for HPV 18, the odds ratio of having cancer is 248.
Khan et al. suggested using combined cytology and HPV DNA testing
Human papillomavirus testing is
as a primary screening tool. Women with a normal cytology test and
a positive HPV test could be further triaged using a type-specific test
accepted and reimbursed as a standard
to identify HPV 16. Women found to be positive for HPV 16 would be
reflex test for borderline abnormalities
referred to colposcopy; those found to be negative for HPV 16 could
be re-tested with LBC or Pap smear and HPV after a year. This will
or atypical squamous cells of
improve the sensitivity of the test and reduce unnecessary referral
undetermined significance pap smears
for colposcopy.
16
in virtually all European countries.
Approximately 50% of ASCUS specimens demonstrate high-risk
HPV infections. The ASCUS LSIL Triage Study Group reported that
the two-year cumulative absolute risk of CIN3+ is 32.5% for
The poor cytological reproducibility of the ASCUS diagnosis remains HPV-16-positive ASCUS specimens. This study also showed
a problem, since 5–17% of these cases are subsequently diagnosed, that HPV-16-infected women with an initially equivocal or mildly
at the next biopsy, as having CIN2 or CIN3. This creates significant abnormal cytology had a 51.6% risk of developing a CIN2 or worse
clinical management issues. These cases require further evaluation lesion (biopsy-confirmed) within two years.
17
to identify those women with high-grade disease (CIN2+).
Colposcopy and colposcopy-directed biopsy have historically been Moreover, the persistence of HPV infection is most often associated
considered the gold standard, although this approach requires with HPV 16 and HPV 18, suggesting that the identification of these
highly-skilled colposcopists, is invasive and expensive and can miss two HPV types may play an important role in the risk-stratification of
up to one-third of high-grade lesions because of sampling and patients with ASCUS.
diagnostic errors. Therefore, it can be difficult to identify high-grade
lesions because of false-positive cytology results and false-negative There is no diagnostic value of HPV typing of CIN3 or cervical cancer.
biopsy results. The burden on women and the healthcare systems However, HPV typing may have some prognostic role. Demonstrating
would be reduced if the subgroup of women with high-grade lesions the same HPV type in the post-treatment specimen as in the treated
could be identified. CIN3 lesion may indicate recurrent HPV infection, which indicates that
the woman may be unable to cope with this particular HPV type and
HPV testing can be used for risk-stratification of women with may thus require more intense follow-up. Clinical algorithms still need
low-grade abnormal smears (ASCUS and low-grade squamous to be developed by experts to help guide clinicians on the use and
intra-epithelial lesions [LSIL]). Because no histological progression is role of a genotyping test in their clinical practice.
seen in women who spontaneously clear the HPV infection,
13
women
without detectable HPV infection do not need further follow-up. This Persistent Human Papillomavirus Infection
could be the case in 40–60% of women with negative HPV DNA and Persistent HPV oncogene expression is essential for the maintenance
persistent ASCUS smears. The updated meta-analysis found HPV triage and progression of cervical neoplasia.
18
Detection of the same
of ASCUS cases to have better sensitivity for detection of high-grade high-risk HPV type over a prolonged period is associated with
CIN compared with repeat cytology.
2
HPV triage is not very specific carcinogenesis. The median time for clearance of HPV infections
(63%), but neither is cytology triage (62%). Moreover, cytology triage is detected during screening studies is six to 18 months.
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