8
Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
Fig. 8.48 Koilocytotic atypia.
Cervical smears with LSIL, showing cells with vacuolization of the cytoplasm and slight atypia of the nuclei (Papanicolaou x MP).
the host cell takes place does its disadvantageous effects pop
up being the result of blocking of p53 (the "guardian" of the
genome) as well as blocking of pRb (the "brake" of the cell cycle).
Both effects of HPV, DNA instability and hyperproliferation, may
finally lead to invasive carcinoma of the cervix.
The presence of high-risk (hr)-HPV genotypes rises with
increasing severity of the CIN lesion and depends on the
method of detection. Two popular and widely used HPV
detection techniques are PCR, which uses very sensitive prim-
ers (MY09/11 and GP5/6) by which the HPV target is amplified,
and hybrid capture (HC) assays. The latter system has recently
been approved by the US FDA and has now a second-generation
(HC2) that allows for the detection of 13 hr-HPV types (16, 18,
31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). It works with a
reaction tube in which cervical cells become destroyed in order
to release HPV DNA that is hybridized with complementary
chemical RNA probes, after which the hybridized product is
visualized with a staining procedure on a micro titration plate.
HC2 is more automated but somewhat less sensitive than PCR
and its advantage over PCR is that it is less prone to cross-
specimen contamination as PCR is able to produce millions of
copies from a single set of DNA base pairs.
With sensitive primers as MY09/11 and GP5/6 in the PCR it
appeared that more than 99% of cervical cancers are HPV DNA
positive.50 CIN lesions that are hr-HPV positive are more likely
to progress than those that are negative.53 Further, it appeared
that hr-HPV infections lead to a 100- to 300-fold increased risk
for patients with persistent hr-HPV infections to getting a CIN 3
lesion.54,55 All these studies assume that (persistent) hr-HPV is
associated with progression of CIN. However, it was also shown
that young women often have transient infections and more
than 80% of hr-HPVs do become cleared.56
Recently, many studies have investigated the value of HPV
detection in addition to conventional cytology in order to
increase sensitivity and specificity of cervical cancer screening.
The summary of meta-analysis of Arbyn et al. gives a good over-
view of these studies.57 Their study concludes that HPV triage
with the HC2 assay is slightly more accurate than repeat cytology
in women with "equivocal" (ASCUS) Pap smear results. Triaging
women with low-grade squamous intraepithelial lesions (LSIL)
(or more) does not show a significant higher sensitivity, but
even a significant lower specificity if it is compared to repeat
Pap smear testing. Partly based on this knowledge, the United
States recently started to combine cytology and HC2 primary
screening in women older than 30 years. In Europe, primary
screening with the Pap smear alone still remains the standard.
Several large randomized controlled trials that test the role of
HPV in primary cervical screening are now underway. These
trials are near to completion (Sweden 2006; The Netherlands
2007; UK 2007, Italy 2007, and Finland 2009).58
One of the disadvantages of HPV testing with PCR or HC2 is
that the cost of a single test is rather high and its technology is
not as widely available as is the Pap smear. Another unresolved
problem with HPV testing is how to communicate the test results
when a tested woman is "HPV-positive." This woman must be
told that she harbors a sexually transmitted viral infection that
eventually may cause cervical carcinoma. Must she change her
sexual habits? What about the legal complications? Thirdly,
suppliers of an HPV test can guarantee high-quality standards
for the test. What will happen when more tests become avail-
able? An HPV test harbors many variables that a simple Pap test
does not have.59 Moreover, it is remarkable that despite the tre-
mendous amount of research on HPV (with PCR and/or HC2),
there are just a few in situ hybridization studies dealing with the
physical state (episomal or integrated) of HPV in the infected
cell. Studies with PCR or HC2 only give information regarding
the mere presence of HPV in cervical swabs or brushes and do
not inform us about the physical state of the HPV, where it is
located and what it is doing in the cervix.
.60,61
Condylomatous Lesions and Epithelial Abnormalities
Intraepithelial neoplastic lesions of the human cervix, first
defined as koilocytotic warty atypia by Koss and Durfee,44 would
now be diagnosed as condylomatous lesions, caused by an
infection with HPV. In particular the subspecies 6 and 11 were
known as causative agents in warty condyloma acuminatum of
the vulva and vagina and were thought to be important sexually
transmitted factors in the genesis of cervical cancer.62 Condy-
loma acuminatum is found in younger age groups than is dys-
plasia and is common in sexually active teenagers.63
Types 6 and 11 are most commonly associated with condyloma
acuminatum of the cervix and with CIN lesions of mild severity.
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