2011, Volume 27, Number 2, Page(s) 144-148
Histopathological Correlation of Squamous Cell Abnormalities Detected on Cervical Cytology
Remzi ABALI1, Besim Haluk BACANAKGİL2, Serdar ÇELİK2, Özlem ARAS2, Pelin KOCA2, Birtan BORAN2, Nevra DURSUN3
1Department of Obstetrics and Gynaecology Namık Kemal University, Faculty of Medicine, TEKİRDAĞ, TURKEY
2Department of Obstetrics and Gynaecology, M.H. İstanbul Education and Research Hospital, İSTANBUL, TURKEY
3Department of Pathology, M.H. İstanbul Education and Research Hospital, İSTANBUL, TURKEY
Keywords: Cytology, Cervical smears, Papanicolaou test, Pathology
To investigate the correlation between cytology and
cervical biopsy in patients with squamous cell abnormality on
Material and Method: The cervical smears diagnosed in our clinic
between 2005-2008 were reviewed retrospectively. Cases which
exhibited squamous cell abnormality (n: 374) were evaluated.
Results: The mean age was 45.15±10.78. In the cytopathological
results, 256 (68.4%) ASC-US, 21 (5.6%) ASC-H, 31 (8.2%) LSIL, 48
(12.8%) HSIL, and 8 (4.8%) invasive carcinomas were diagnosed.
Histopathological results were 213 (57%) nonneoplastic, 85 (22.7%)
CIN I, 14 (3.7%) CIN II, 34(9.0%) CIN III and 28 (7.5%) invasive
squamous cell carcinomas. Including all squamous cell abnormalities,
the sensitivity of the smear test in CIN I and higher grade lesions
was 56.95% and the false positivity was 43.04%. Excluding ASC-US
and ASC-H lesions, the sensitivity of the smear test was 77.31%
and the false positivity was 22.68%. After evaluating cervical cytohistopathological
correlation, the positive predictive value was found
to be 100% in invasive carcinoma, 62% in HSIL and 38% in LSIL.
Conclusion: As the grade of cytopathological result increases, the
correlation between biopsy and the smear test also increases. The
high sensitivity of the cervical smear test for high-grade lesions shows
that it is an effective screening test.
Cervical cancer is the second most common cancer in
females globally. It is possible to diagnose earlier and
manage better compared to past years with the development
of methods for early diagnosis and treatment. However,
it continues to be an important cause of morbidity and
mortality in women. There are approximately 500.000 new
cases and 280.000 deaths every year and 83% of these cases
are from developing countries, making up 15% of female
A significant decrease in the incidence and mortality
of cervical cancer can be realized with effective cervical
cytology screening programs2. However, there is also an
increase in the diagnosis of precancerous cervix lesions.
The aim of the Papanicolaou (Pap) smear test is to detect
precancerous cervix lesions before they become invasive
cancer. The accuracy of the Pap smear test is evaluated
using sensitivity, specificity and predictive value. Evaluating
the correlation between cervical cytology and biopsy is the
best method of determining the Pap smear test accuracy.
However, it is not a perfect method due to the potential
sampling and interpretation errors3.
We retrospectively evaluated the correlation with
histopathology results in patients who had been
cytopathologically found to have squamous cell abnormality
with the cervical smear method.
The conventional Pap smears obtained from women
presenting at the İstanbul Training and Research Hospital
Department of Obstetrics and Gynecology between 2005
and 2008 were evaluated retrospectively. Patients with
squamous cell abnormalities in the smear results were
included in the study. Information related to the patients
was obtained from the patient files, cytopathology and
histopathology reports and patient follow-up forms.
The smears were taken with a CerviBrush® and put on a
slide. They were then fixed by using a spray from 25-30
cm and evaluated at our hospital's pathology laboratory.
Conventional Pap smear results were classified according
to the 2001 Bethesda system. A total of 374 patients with
ASC-US (atypical squamous cells - unknown significance),
ASC-H (atypical squamous cells where a high-grade
lesion cannot be eliminated), LSIL (low-grade squamous
intraepithelial lesion), HSIL (high-grade squamous
intraepithelial lesion) or invasive carcinoma underwent
colposcopic cervical biopsy after 4-6 weeks. Biopsy results
were evaluated with the cervical intraepithelial neoplasm classification and the correlation with Pap smear results was
Biopsy results were divided into 4 groups as nonneoplastic
(chronic cervicitis and inflammation-related regenerative
changes), LSIL (CIN I/mild dysplasia), HSIL (CIN II
and CIN III/moderate and severe dysplasia) and invasive
The SPSS (Statistical Package for the Social Sciences)
software was used for statistical calculations. A p value
<0.05 was considered significant for statistical evaluation.
The Spearman correlation test, Tukey HSD for two-way
comparisons, one-way variance analysis, the Tamhane
test and anova test were used for statistical evaluations.
Two-way comparisons were used to create 2x2 tables and
calculate the positive predictive values.
A total of 374 patients were included in the study. The mean
age was 45.15 ± 10.78 (range 23-78). The cases ages of the
cytology categories were compared and the difference was
found to be significant (p=0.001). A significant difference
was found between the ages of ASC-US and invasive cancer
cases (p<0.02). There was also a significant difference
between the ages of LSIL and HSIL patients (p<0.02) (Table I
Click Here to Zoom
|Table I: Distribution of mean ages of cases where a
cytopathological epithelial cell abnormality was found
Cytopathologically, there were 256 (68.4%) ASC-US, 21
(5.6%) ASC-H, 31 (8.2%) LSIL, 48 (12.8%) HSIL, 18 (4.8%)
invasive carcinoma cases.
We found a significant difference between the ages of the
nonneoplastic group and CIN I patients (p=0.001). There
was also a significant difference between the ages of CIN I
and squamous cell carcinoma patients (p=0.002) (Table II).
Click Here to Zoom
|Table II: Distribution of mean ages of histopathological
Histopathologically, there were 213 (57%) nonneoplastic
lesions, 85 (22.7%) CIN I cases, 14 (3.7%) CIN II cases, 34
(9.0%) CIN III cases, and 28 (7.5%) invasive squamous cell
carcinomas (Table III).
Click Here to Zoom
|Table III: Histopathological evaluation results of cases where epithelial cell abnormalities were found
The relationship between cytopathological and
histopathological results was significant (r=0.58,
p=0.0001). When all the squamous cell abnormalities in the
cervicovaginal cytology was included, the sensitivity of the
smear test for CIN I and higher grade lesions was 56.95%
(213/374) while false positivity was 43.04% (161/374).
When ASC-US and ASC-H were excluded, the sensitivity
was 77.31% (75/97) and false positivity 22.68% (22/97).
We were unable to calculate sensitivity, specificity and
negative predictive value for the patient groups as there were
no real negative or false negative groups. The correlation was calculated using the positive predictive values (PPV)
according to our study data.
The cyto-histopathological correlation increased in parallel
to the grade of PPV and was 100%, 62% and 38% for invasive
carcinoma, HSIL and LSIL, respectively (Table IV).
Click Here to Zoom
|Table IV: Positive Predictive Values of cyto-histopathological
The cyto-histopathological comparison for cervical
intraepithelial lesions (CIN I-II-III) and invasive carcinoma
revealed that the smear test predictive value increased as
the epithelial abnormality of the lesion increased and was
30% for ASCUS, 48% for LSIL, 87% for HSIL and 59% for
HSIL+LSIL (Table V).
A cervical intraepithelial lesion (CIN II-III) was found in
3-5% of the total ASCUS cases. Comparison of the cervical invasive disease correlation of ASCUS and ASC-H cases
showed a higher correlation value for ASC-H than ASCUS.
The aim of using the cervical smear test is screening sexually
active women to enable early detection and treatment of
precancerous lesions and prevent mortality due to cervical
cancer. There is a relationship between the widespread
use of the cervical smear test and decreased mortality due
to invasive squamous cancer. Screening programs have
therefore been developed all over the world. Cases where a
cytological abnormality has been detected undergo biopsy
from the suspect lesions under colposcopy for a definite
It is recommended that screening should be started in
developed countries as soon as the patient becomes sexually
active. The screening interval varies between 1 and 5 years
by country. Many associations in Turkey suggest sexually
active women over the age of 18 to undergo a smear test
once a year for the first 3 years and then to be repeated
every 3-5 years if the first 3 tests are negative5. Additional
methods such as cervicography and HPV DNA typing are
also used for diagnosis.
It is difficult to definitely establish PPV of the Pap smear
test for preinvasive lesions. The literature figures are 50-90%
for sensitivity and 31-90% for specificity6. The PPV is
17-89% for preinvasive or microinvasive lesions and almost
100% for squamous cell carcinoma7-10. This wide range
for sensitivity indicates that all abnormal smear results
should be evaluated.
The February 1999 AHCPR (Agency for Health Care Policy
and Research) report has stated that conventional Pap
smear sensitivity is not as high as previously reported11.
The conventional Pap smear sensitivity was mentioned as
51% and the specificity as 98% in this report. It was also
reported that cervical cytology detected high risk lesions
more accurately when the threshold value was high while a
low threshold value (LSIL/ASCUS) led to lower possibility
of finding low-risk or high-risk dysplasia11.
A study where the cyto-histopathological correlation of 283
cases was analyzed showed full match between the cytology
and biopsy in 51% of the cases while this rate was 63.9% and
74.6% for low-grade and high-grade lesions, respectively.
Cervical cytology sensitivity was 91.7%12.
We found increased cyto-histopathological correlation with
the cervical intraepithelial lesion as the degree of epithelial
cell abnormality increased. The PPV was 30% for ASCUS,
48% for LSIL, 87% for HSIL, and 59% for HSIL+LSIL. We
evaluated the cervical cytology and biopsy correlation again
after matching the Bethesda terminology counterpart of the
smear results with the CIN terminology result of the biopsy
results. The PPV again showed an increase with the lesion
degree and was 38%, 62% and 100% for LSIL, HSIL and
invasive carcinoma cases, respectively.
Cervical precancerous lesions can be detected approximately
10 years before they become cancerous with the Pap
smear screening. Comparison of the ages of our patients
revealed a significant difference between CIN I and invasive
carcinoma. The mean age for the CIN I group was 40.14
while the squamous cell carcinoma group had a mean age of
51.21 with a difference of over 10 years. This indicates that
a period where lesions can be detected and treated before
they become cancerous exists.
The clinical results of patients diagnosed as ASC-US and
ASC-H by cervical smear can show great variety, from
clearly benign lesions to potentially serious lesions and it
is therefore not possible to provide a definite classification.
Various laboratories report a cervical intraepithelial lesion
rate of 15-43% among ASC-US cases13-15. We found
nonneoplastic changes in 179 (69.9%), CIN I in 68 (26.6%),
CIN II in 6 (2.3%) and CIN III in 3 (1.2%) ASC-UC cases.
The total rate of cervical intraepithelial lesions among cases
with an ASC-US smear result was 30%. The 21 cases with
an ASC-H diagnosis were diagnosed as nonneoplastic in 12
(57.1%), CIN I in 3 (14.2%), CIN II in 3 (14.2%) and CIN
III in 3 (14.2%). The total rate of cervical intraepithelial
lesion in ASC-H cases was 42.8%. The higher CIN II and
CIN III rates in cases reported as ASC-H indicates a need
for closer follow-up of these patients.
The false positive cases' follow up in this study showed
regenerative changes due to chronic cervicitis or
inflammation. The mean age of cases having a smear
performed was also quite high (mean age=45.16). The
decreased estrogen in the postmenopausal period leads
to larger squamous cell nuclei and smaller cytoplasm
size (atrophy). The addition of inflammation-related
regenerative changes to these aging-related physiological
changes makes differentiation from neoplastic lesions
difficult16. This increases the rate of smears reported
as ASC-US. Most cases at our hospital present symptoms
related to menopause or an infection and there are almost
no patients who had smear tests for screening.
Another reason for the false high positivity rate may be
the lack of a specialized histopathologist in our hospital.
Cytotechnicians evaluate the cervicovaginal smear test
in developed countries such as the U.S.A. and a second
evaluation is by a specialized cytopathologist is suggested if
abnormal changes are noticed16. Cervicovaginal smears
are usually obtained from patients presenting at the hospital
for infection or menopause in our country and almost all
these preparations contain regenerative cytopathological
changes. The most common finding in false positive cases
is also regenerative changes and their evaluation therefore
becomes more important. It is suggested that regenerative
changes can be divided into typical and atypical and the
atypical regeneration group in particular be added to the
ASC-US group.17. The low number of pathologists in our
county also makes it difficult for cases presenting difficulties
with the differentiation between ASCUS and regenerative
lesion to be evaluated by a second pathologist.
Differentiation of regenerative changes from neoplastic
lesions in the smear test requires taking a biopsy after 3 positive results in cases where ASCUS is found. However,
hospitals like ours where patient follow-up is not possible
due to the low socioeconomic level of the patient
population usually proceed to endo-ectocervical biopsy
with colposcopy even after a single positive result. This
leads to an increased false positivity rate.
Other studies have demonstrated a relatively low level of
false positivity in university hospitals in our country18.
However the mean age of the patient population is lower
and the socioeconomic level is higher in these studies. This
leads to a lower rate of regenerative changes and atrophic
cells that were seen in our study and created difficulties in
the differential diagnosis with ASCUS. These hospitals also
have specialized cytopathologists18. It is possible for the
specialized cytopathologist to review cases where there are
diagnostic difficulties between ASCUS and regenerative
A study has found 79.09% cyto-histopathological correlation
in cases with a positive diagnosis regarding epithelial
abnormality and cervicitis and regenerative changes were
the pathologies found most commonly in false positive cases15. Another study on cyto-histopathological correlation
found a false negativity rate of 5.3% and false positivity rate
of 3.5%. The most common cause of false negativity was
In conclusion, increased degree of neoplasia in cervical
lesions increases the correlation between Pap smear
and biopsy. The high sensitivity of the Pap smear test for
high-grade neoplastic lesions shows that it is an effective
screening test for cervical cancer and precursor lesions if
used at suitable intervals. However, the cervical smear test
is still not used at adequate levels as a screening test in our
country. Most cases undergoing the cervical smear test
have presented at the hospital for menopause or infection.
This increases the risk of false positivity. Our country
therefore needs programs that will increase the use of the
cervicovaginal smear test as a screening test and decrease
the mean age of the screening group.
1) Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics,
2002. CA Cancer J Clin 2005, 55:74-108 [ PubMed ]
2) Sankaranarayanan R, Gaffikin L, Jacob M, Sellors J, Robles S:
A critical assessment of screening methods for cervical neoplasia.
Int J Gynaecol Obstet 2005, 89:4-12 [ PubMed ]
3) Rohr LR: Quality assurance in gynecologic cytology. What is
practical? Am J Clin Pathol 1990, 94:754-758 [ PubMed ]
4) Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ:
ASCCP-Sponsored Consensus 2001 Consensus Guidelines for the
management of women with cervical cytological abnormalities.
JAMA 2002, 287:2120-2129 [ PubMed ]
5) Fink DJ: Change in American Cancer Society Checkup Guidelines
for detection of cervical cancer. CA Cancer J Clin 1988,
38:127-128 [ PubMed ]
6) Uyar DS, Eltabbakh GH, Mount SL: Positive predictive value
of liquid-based and conventional cervical Papanicolaou smears
reported as malignant. Gynecol Oncol 2003, 89:227-232 [ PubMed ]
7) Soost HJ, Lange HJ, Lehmacher W, Ruffing-Kullmann B:
The validation of cervical cytology: sensitivity, specificity and
predictive values. Acta Cytol 1991, 35:8-14 [ PubMed ]
8) Johnson SJ, Wadehra V: How predictive is a cervical smear
suggesting invasive squamous cell carcinoma? Cytopathology
2001, 12:144–150 [ PubMed ]
9) Clark SB, Dawson AE: Invasive squamous-cell carcinoma in
ThinPrep specimens: diagnostic clues in the cellular pattern.
Diagn Cytopathol 2002, 26:1–4 [ PubMed ]
10) Mitchell H, Medley G, Drake M: Quality control measures for
cervical cytology laboratories. Acta Cytol 1988, 32:288-292 [ PubMed ]
11) McCrory DC, Matchar DB, Bastian L, Datta S, Hasselblad V,
Hickey J, Myers E, Nanda K: Evaluation of cervical cytology. Evid
Rep Technol Assess (Summ) 1999, 5:1-6 [ PubMed ]
12) Yeoh GP, Chan KW: The accuracy of Papanicolaou smear
predictions: cytohistological correlation of 283 cases. Hong Kong
Med J 1997, 3:373-376 [ PubMed ]
13) Eltabbakh GH, Lipman JN, Mount SL, Morgan A: Significance
of atypical squamous cells of undetermined significance on
ThinPrep papanicolaou smears. Gynecol Oncol 2000, 79:44-49 [ PubMed ]
14) Aydın F, Tuncer ZÇ, Kuzey GM, Başaran M: Servikovaginal
sitoloji ile ASCUS ve AGUS tanısı alan olguların değerlendirilmesi.
T Klin J Gynecol Obst 2002, 12:148-154
15) Kaufman RH: Atypical squamous cells of undetermined
significance and low-grade squamous intraepithelial lesion:
diagnostic criteria and management. Am J Obstet Gynecol 1996,
175:1120-1128 [ PubMed ]
16) Colgan TJ, Woodhouse SL, Styer PE, Kennedy M, Davey
DD: Reparative changes and the false-positive/false-negative
Papanicolaou test: a study from the College of American
Pathologists Interlaboratory Comparison Program in
Cervicovaginal Cytology. Arch Pathol Lab Med 2001, 125:
134-140 [ PubMed ]
17) Özkara SK, Yıldız K: Servikovaginal smear tarama programımızın
Bethesda-2001 ışığında beş yıllık retrospektif değerlendirmesi.
(10 598 olguda, 110 sito-histopatolojik korelasyon). Patoloji Bült
18) Mete O, Yavuz E, Tuzlalı S, İlhan R, Özlük Y, Topuz S, İyibozkurt
C, İplikçi A: Retrospective study of 112 patients who had
colposcopy-guided biopsy: Comparison of the cytology results
with histology. Turk Patoloji Derg 2007, 23:33-37