Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
hyperproliferation (Mib1 positive) and p16 over-
expression in both types of epithelium (Fig. 8.130).
As enhanced expression of p16 is highly associated
with dysplastic and neoplastic changes of the cervical
epithelium, it has been demonstrated that p16 makes
it easier to recognize dysplastic cells on a cytological
slide.248,249 Positive nuclear and cytoplasmic staining
in liquid-based cervical specimens had a sensitivity
for HSIL or worse of about 90-100% .249-251 Specificity,
however, is much lower since individual normal
squamous metaplastic, endometrial, and tubal meta-
plastic cells in a cytological specimen sometimes may
show some slight staining.249,252
In conclusion, in histology as well as cytology, Mib1 and p16
are sensitive markers for dysplastic squamous and atypical glan-
dular cells of the cervix. However, up till now the studies with
Mib1 and p16 are performed on rather small and very selective
series and are clearly not representative for screening situations.
Before these markers can be used in (automated) mass screen-
ing, criteria regarding the extent of positivity and staining inten-
sity that define real "positive" cases must be set up. It may even
turn out that a combination of these two markers is better suited
to triage indistinct cervical abnormalities than high-risk HPV
testing such as now being performed. Moreover, if cytological
slides contain positive cells with these two markers, it is always
possible to simultaneously judge the morphology of doubtful
Efficacy of Cervical Cytology in the Detection
of Cervical Abnormalities
Mortality due to cervical cancer has declined significantly during
the past decades because of the widespread use of preventive
cervical cytologic screening. Readers are referred to Chapter 3,
Cytologic Screening Programs, for additional information.
For the detection of cervical cancer, cytologic testing is most
appropriate. Squamous cell carcinoma is highly vulnerable to
detection technology and therefore secondary prevention. High-
risk groups have been defined, and cancer precursors (i.e. dyspla-
sia of the cervix and carcinoma in situ) have been described.253
Criteria that define the suitability of cervical cancer for routine
screening are detectability by a reliable test that is easy to per-
form and acceptable to patients, a prolonged preclinical phase,
and the availability of effective therapy that is more efficient and
less of a burden to patients than treatment for a clinical cancer.
The purpose of screening cytologic samples is to identify
amidst a multitude of normal cells those cells consistent with
a premalignant or malignant change. The samples may also dis-
close functional characteristics of the cells or important findings
such as infections and infestations.
The detection system of a cytologic cervical smear examina-
tion leading to the discovery and treatment of precancerous
lesions and early cancer of the cervix has been shown to be
effective in reducing the rate of morbidity and mortality from
high-stage invasive cervical cancer in appropriately screened
populations.127 Ample evidence shows that the cervical smear
has contributed in a remarkable fashion to the prevention of
invasive carcinomas of the uterine cervix.118
After the implementation of well-organized screening pro-
grams, remarkable reductions in the incidence and mortality
rates were documented.76,145,183,253-255 However, there is no evi-
dence that the Papanicolaou test has succeeded in the com-
plete eradication of this theoretically preventable disease, thus
emphasizing the importance of identifying the potential fail-
ures of this detection system and of analyzing the reasons for
them.118,122,128 Cytologic case finding may fail because of inade-
quate samples, insufficient training, insufficient time devoted to
screening (excessive workload), inadequate clinical information,
inadequate supervision of laboratory procedures, relatively high
intraobserver and interobserver variability of cytologic diag-
noses, and inadequate follow-up procedures.127,256
The cervical smear is a safe, easy, and inexpensive method
for screening large numbers of sexually active women. When
a cervical cytologic report states the presence of an epithelial
abnormality, it has a high rate of accuracy. "The cytologic screen-
ing of cervical specimens is a complex matter and, regardless of
its problems, has contributed in a tangible and statistically sig-
nificant way to the reduction of morbidity and mortality from
carcinoma of the uterine cervix."257 It can be stated that the cervi-
cal smear test is perhaps the only effective screening test known
today. To reduce the problem of false-negative diagnoses, quality
control of the taking of the cytologic sample and the cytologic
diagnostic procedure is important.122, 124,128,258 To reduce the con-
sequences of false-negative results, it may be advisable to make
a repeat smear 1 year after the initial smear. After two negative
smears, a longer interval of 3 years or even 5 years seems jus-
tified.145,183 The number of preclinical asymptomatic invasive
cancers and preinvasive cancers diagnosed depends largely on
the prevalence of these abnormalities in the population under
study, the sensitivity and specificity of the cytologic test, and the
efficacy of follow-up procedures.122,123,128
Liquid-Based cervical cytology
The conventional cervical Pap smear has several disadvantages.
Though successful in reducing the incidence of and mortality
from cervical carcinoma, the diagnostic accuracy of screening
with conventional Pap smears is hampered by the occurrence of
both false-negative and false-positive results. These erroneous
results are mainly caused by diagnostic errors and poorly stand-
ardized sample taking and preparation.259,260 In the conventional
Pap smear, the cells are unevenly distributed and cell overlapping
makes interpretation difficult. Cells can be obscured by mucus,
blood, and inflammatory cells and cell fixation is often insuf-
ficient. The liquid-based cytology (LBC) or thin layer technique
does not have these disadvantages. The physician samples the
cells with a traditional device or cervical brush and the cell mate-
rial is rinsed into a vial with preservation solution rather than
smeared on a slide. In the laboratory, a representative sample
from the cell material in the vial is obtained and subsequently
transferred to a slide, resulting in a thin layer of well-preserved
non-obscured cells (Fig. 8.131). Despite the considerably higher
costs of liquid-based techniques, these advanced methods of cell
preparation may turn out to be cost-effective when the stand-
ardized cell preparations result in a higher diagnostic accuracy.
Claims have been made that screening time is reduced due to
better recognition and preservation of the cells and reduction
of the total area to be screened. Cytotechnicians favor to look
at thin-layer specimens as the clean and less obscured pictures
are much less stressing and laborious than conventional smears.
Also, additional diagnostic procedures such as HPV testing,
DNA- and RNA-based analyses, and immunocytochemistry can
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