Anatomic Pathology / UNNECESSARY TREATMENTS IN CERVICAL SCREENING

The Risk of False-Positive Histology According to the

Reason for Colposcopy Referral in Cervical Cancer
Screening
A Blind Revision of All Histologic Lesions Found in the NTCC Trial
Paolo Dalla Palma, MD,1 Paolo Giorgi Rossi, PhD,2 Guido Collina, MD,3 Anna Maria Buccoliero, MD,4
Bruno Ghiringhello, MD,5 Maurizio Lestani, MD,6 Gianlibero Onnis, MD,7 Daniela Aldovini, MD,1
Giuseppe Galanti, MD,8 GianPiero Casadei, MD,9 Mirella Aldi, MD,10 Vincenzo Gomes, MD,11
Pamela Giubilato, MSc,12 Guglielmo Ronco, MD,12 and the NTCC Pathology Group*

Key Words: Cervical neoplasia; Histology; Colposcopy biopsy; Sensitivity; Specificity; Positive predictive value

DOI: 10.1309/EWYGWFRRM8798U5P

Abstract When deciding which test to use for screening, specificity

All cervical intraepithelial neoplasia (CIN)
diagnoses identified during the New Technologies for
Cervical Cancer trial (ISRCTN81678807) were blindly
reviewed by 2 pathologists. Original diagnoses based
on colposcopy-guided biopsies were compared with
those made by the reviewers who had access to all
clinical histologic samples (including postsurgical).
Cases downgraded from CIN 2+ by the reviewers were
considered indicative of unnecessary treatments. The
analyses are presented according to the molecular
(high-risk human papillomavirus [HPV]) and/or
cytologic diagnosis used to refer the women for
colposcopy.
We reviewed 812 CIN 1 and 364 CIN 2+ diagnoses.
The specificity of colposcopy-guided biopsy was 98%
and the sensitivity, 84%. The probability of unnecessary
treatment was 27% for women with atypical squamous
cells of undetermined significance cytologic findings
and 8% for women with low-grade squamous
intraepithelial lesion or worse, 10% for HPV+ and
positive cytologic findings, and 16% for HPV+ alone.
The positive predictive value of the first-level screening
test was inversely associated with probability of a
histologic false-positive result (P = .015).
In screening, a low positive predictive value of the
colposcopy-referring test may result in unnecessary
treatments.
must be taken into account because tests with low specificity
applied to a healthy population with a very low prevalence of
disease will result in a high proportion of false-positive test
results (low positive predictive value [PPV]). Women with pos-
itive test results in cervical cancer screening are usually
referred for colposcopy, and treatment is based on the biopsy
results. Women with cervical intraepithelial neoplasia (CIN)
grade 2 (CIN 2) or higher usually are treated. A false-positive
histologic diagnosis very likely leads to unnecessary treatment.
Errors in cervical histologic findings have been documented,1,2
and CIN diagnoses are not entirely reproducible.3-11
A multicenter, randomized, controlled trial began in
March 2002 to evaluate the effectiveness of new technologies
(Hybrid Capture test [Digene, Gaithersburg, MD] for high-
risk human papillomavirus [HPV] alone and with liquid-based
cytology vs conventional Papanicolaou [Pap] smear) in a pop-
ulation-based cervical cancer screening program (New
Technologies for Cervical Cancer screening [NTCC]).12,13
The study involved 9 organized screening programs in 6
regions of Italy, and about 95,000 women were enrolled. A
histopathologic diagnosis of CIN 2 or higher was considered
as the study end point. To increase the validity of trial results
and avoid ascertainment bias (the study was not masked), we
blindly reviewed all histologic diagnoses of CIN 1, 2, and 3.
The unusual situation of having all histologic results
obtained during the diagnostic process (not blinded to the
cytologic and HPV results) and the blinded revision of all CIN
1, CIN 2, and higher gave us the opportunity to estimate the
probability of histologic false-positive results and, therefore,
of unnecessary future treatments, given the cytologic and
HPV results that led to colposcopy.

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75 DOI: 10.1309/EWYGWFRRM8798U5P 75
Dalla Palma et al / UNNECESSARY TREATMENTS IN CERVICAL SCREENING
Materials and Methods
The NTCC study enrolled about 95,000 women who
were screened according to various schedules. Protocols have
been detailed elsewhere.12,13 Briefly, in the first phase (about
45,000 women), women in the control arm had a convention-
al Pap smear, and women in the experimental arm had a liq-
uid-based sample taken and tested for cytologic features and
HPV. Women older than 35 years with atypical squamous
cells of undetermined significance (ASCUS)+ or HPV+
results were directly referred for colposcopy, whereas women
younger than 35 years with ASCUS+ results were directly
referred for colposcopy independent of the HPV result and
recalled after 1 year for cytologic examination and/or HPV
control if the HPV result was positive and the cytologic find-
ings negative. These latter results are not included in the pres-
ent analysis. In the second phase (50,000 women), women in
the control arm were still tested with conventional cytologic
examination, whereas women in the experimental arm
received only the HPV test and positive results were referred
directly for colposcopy, independent of age.
Colposcopic and histologic diagnoses were made without
masking cytologic and/or HPV results. Histologic diagnoses
were given by 10 pathology services.
The histologic samples diagnosed as CIN 2 or 3 or CIN 1
were blindly reviewed. We retrieved all available histologic
samples taken within 1 year from referral for colposcopy:
punch biopsies, in some cases from more than 1 colposcopy,
and the surgical specimens when an ablative treatment was
performed. Each case was randomly assigned to 1 or 2 pathol-
ogists for review. Only H&E-stained slides were used. The
only data available to reviewers were patient age and date the
sample was obtained. Each reviewer was asked to formulate a
single diagnosis for each patient, corresponding to the worst
pathologic finding among all the patients tests, according to
the following 5 categories: (1) negative or inflammation, (2)
CIN 1 encompassing HPV condyloma, (3) CIN 2, (4) CIN 3,
or (5) carcinoma (encompassing squamous carcinoma and
adenocarcinoma).
In the second phase, 2 independent pathologists random-
ly selected from a pool of 9 (1 per center, excluding the cen-
ter that made the first diagnosis) reviewed all cases. In phase
1, all diagnoses of CIN 2 or 3 and 42% of CIN 1 diagnoses
were reviewed. During phase 1 the remaining CIN 1 cases
were reviewed by only 1 pathologist who was randomly
selected from the 3 most expert. This was done to reduce the
workload and seems not to have influenced the results. Indeed,
the proportion of CIN 1 upgraded to CIN 2 or worse did not
differ by method (P = .98).
The diagnoses provided by the reviewers were compared
with the diagnoses originally given by the screening center.
The following concordance-categories were defined: (1) All
76 Am J Clin Pathol 2008;129:75-80
76 DOI: 10.1309/EWYGWFRRM8798U5P
diagnoses were identical (perfect agreement). (2) The diag-
noses differed, but all were CIN 1 or less severe. (3) The diag-
noses differed, and all were CIN 2 or more severe. (4) One
diagnosis was CIN 2 or worse, whereas the others were CIN 1
or better, or vice versa (major disagreement, to review further).
(5) At least one diagnosis was carcinoma (to review further).
Categories 4 and 5 were reviewed and discussed by all
pathologists involved, using a multiheaded microscope.
Again, all available material was examined, and only 1 diag-
nosis per woman, corresponding to the worst pathologic find-
ing, was formulated. When possible, the diagnosis was agreed
on by consensus. Otherwise the majority diagnosis was cho-
sen.
Statistical Analysis
We considered original diagnoses of CIN 2 or worse
given by the pathology clinic after colposcopy-guided histol-
ogy but before treatment. We computed the proportion that
were not confirmed by the reviewers diagnosis as an estimate
of the probability of unneeded treatment. Indeed, the decision
to refer for treatment is based on colposcopy-guided histolog-
ic findings. We used as the gold standard the reviewers final
diagnosis, based on all available material as described earlier,
because we considered it to represent the best available assess-
ment of whether a CIN 2 or worse lesion was present. The
estimated proportion corresponds to 1 (the PPV of the pre-
treatment histologic diagnosis).
We also computed the sensitivity and specificity of the
original pretreatment diagnosis vs the gold standard. In that
analysis, biopsy specimens showing no CIN, which were not
reviewed, were considered true-negatives. We calculated 95%
confidence intervals (CIs) for all proportions assuming a bino-
mial distribution.
All of these parameters were estimated separately accord-
ing to the cytologic and HPV results that preceded colposcopy
to evaluate the association between the PPV of the diagnostic
category and the probability of a false-positive histologic
result.
Results
There were 52 CIN cases unavailable for review, and
1,128 cases were reviewed: 747 had an initial diagnosis of
CIN 1, 349 were CIN 2 or worse, and 20 were CIN not other-
wise specified colposcopy-guided biopsy diagnoses. The lat-
ter 20 were considered CIN 1 or better in the analysis. We
excluded 12 cases from this analysis because the colposcopy-
guided biopsy diagnosis was unclear or not available.
Table 1 shows the distribution of the colposcopy-guid-
ed biopsy histologic diagnoses according to the final diagno-
sis after revision. The sensitivity of the pretreatment original
American Society for Clinical Pathology
 Anatomic Pathology / ORIGINAL ARTICLE

Table 1
Original Pretreatment Histologic Diagnosis by Reviewed Diagnosis Based on Pretreatment and Posttreatment Specimens

Reviewed Histologic Diagnosis

Original Pretreatment Squamous

Histologic Diagnosis Inadequate Normal CIN 1 CIN 2 CIN 3 Carcinoma Total

Unavailable 0 1 5 3 3 0 12
CIN NOS 1 7 7 5 0 0 20
CIN 1 0 44 651 48 4 0 747
CIN 2 0 6 42 107 44 1 200
CIN 3 0 0 4 32 112 1 149
Total 1 58 709 195 163 2 1,128

CIN, cervical intraepithelial neoplasia; NOS, not otherwise specified.

histologic diagnoses for CIN 2 or worse was 82.5%, and Table 2

specificity was 97.9% (2,383/2,435). The percentage of CIN 1 Dichotomized Diagnosis, Positive Predictive Value, and
Sensitivity*
cases upgraded to CIN 2 or worse after review was 8.1% (ie,
the negative predictive value for CIN 2 or worse was about Reviewed Histologic Diagnosis
92%), whereas the percentage of CIN 2 or worse downgraded Original Pretreatment CIN 1 CIN 2
(the probability of a false-positive diagnosis of CIN 2 or Histologic Diagnosis or Better or Worse Total
worse) was 14.9% (ie, the PPV was about 85%) Table 2. CIN 1 or better 710 57 767
We observed similar rates of specificity of colposcopy- CIN 2 or worse 52 297 349
guided biopsy, ranging from 97% to 99%, independent of the Total 762 354 1,116

reason for the colposcopy referral, ie, ASCUS, low-grade
squamous intraepithelial lesion (LSIL)+, HPV+ and negative
cytologic results or HPV+ and positive cytologic results
Table 3 and Figure 1. Sensitivity ranged between 75% and
approximately 90% (except for the HPV group that included
only 3 cases that were CIN 2 or worse), and there was no evi-
dence of significant variation between groups.
On the other hand, the proportion of false-positive diag-
noses of CIN 2 or worse varied according to cytologic and
HPV test results (Table 3 and Figure 1). It was higher in the
CIN, cervical intraepithelial neoplasia.
* Positive predictive value, 85.1%; sensitivity, 83.9%.
conventional arm (P = .02) for women with ASCUS cytolog-
ic findings (26.7%; 95% CI, 12%-46%) than for women who
had LSIL or more severe cytologic results (8.6%; 95% CI,
4%-16%). In the experimental arm, it was higher (P = .003)
for HPV but cytologically abnormal (ASCUS+) cases
(66.7%; 95% CI, 22%-96%) than for HPV+ cases (10.6%;

Table 3
Number of Biopsies and CIN 2 or Worse Diagnoses After Revision, Sensitivity, Specificity, and Probability of Unnecessary
Treatment According to the HPV and Cytologic Results Used to Refer Women for Colposcopy

No. of No. of Cases No. of CIN 2 or Sensitivity, % Specificity, % Probability of False CIN 2 or
HPV/Cytologic Results Cases Reviewed Worse After Review (95% CI) (95% CI) Worse Diagnosis, % (95% CI)

No HPV test
Overall 694 335 122 87.7 (74-88) 97.1 (95-98) 15.0 (8-20)
ASCUS 302 133 29 75.9 (56-90) 97.0 (94-99) 26.7 (12-45)
LSIL+ 392 202 93 91.4 (84-97) 97.2 (95-99) 8.6 (4-16)
HPV+
No test 787 371 122 87.7 (80-93) 96.9 (95-98) 15.7 (10-23)
Overall HPV and cytology 635 331 112 82.3 (74-89) 97.9 (96-99) 10.6 (5-18)
Normal cytology 255 93 20 75.0 (51-91) 99.0 (97-100) 11.8 (1-36)
ASCUS 123 60 23 87.0 (66-97) 99.0 (94-100) 4.8 (0-24)
LSIL+ 257 178 69 85.3 (74-93) 95.7 (92-98) 12.1 (5-22)
HPV
Overall 319 81 3 66.7 () 98.7 (98-100) 66.7 (22-96)
ASCUS 182 43 1 100.0 () 99.4 (97-100) 50.0 ()
LSIL+ 137 38 2 50.0 () 97.8 (94-100) 80.0 ()

ASCUS, atypical squamous cells of undetermined significance; CI, confidence interval; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LSIL, low-grade
squamous intraepithelial lesion.

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77 DOI: 10.1309/EWYGWFRRM8798U5P 77
Dalla Palma et al / UNNECESSARY TREATMENTS IN CERVICAL SCREENING

Cytology

Normal ASCUS LSIL+ None

Biopsy Biopsy
302 392
No review Reviewed No review Reviewed
169 (2 CIN 2) 133 188 (14 CIN 2) 204
None

Colposcopic Biopsy Colposcopic Biopsy

After Review

After Review
CIN 1 CIN 2+ Total CIN 1 CIN 2+ Total
CIN 1 96 8 104 CIN 1 101 8 109
CIN 2+ 7 22 29 CIN 2+ 8 85 93
Total 103 30 133 Total 109 93 202

Biopsy Biopsy Biopsy Biopsy

255 123 257 787
No review Reviewed No review Reviewed No review Reviewed No review Reviewed
HPV

Positive

163 (1 CIN 2) 92 63 (2 CIN 2) 60 80 (3 CIN 2) 177 416 (15 CIN 2) 371

Colposcopic Biopsy Colposcopic Biopsy Colposcopic Biopsy Colposcopic Biopsy
After Review

After Review

After Review

After Review
CIN 1 CIN 2+ Total CIN 1 CIN 2+ Total CIN 1 CIN 2+ Total CIN 1 CIN 2+ Total
CIN 1 70 2 72 CIN 1 36 1 37 CIN 1 101 8 109 CIN 1 229 20 249
CIN 2+ 5 15 20 CIN 2+ 3 20 23 CIN 2+ 10 58 68 CIN 2+ 15 107 122
Total 75 17 92 Total 39 21 80 Total 111 66 177 Total 244 127 371

Biopsy Biopsy
182 137
No review Reviewed No review Reviewed
Negative

139 (0 CIN 2) 43 99 (0 CIN 2) 38

Colposcopic Biopsy Colposcopic Biopsy
After Review

After Review

CIN 1 CIN 2+ Total CIN 1 CIN 2+ Total

CIN 1 41 1 42 CIN 1 33 3 36
CIN 2+ 0 1 1 CIN 2+ 1 1 2
Total 41 2 43 Total 34 4 38

Figure 1 Flow chart of the women enrolled in the trial according to the results of the first-level screening test (cytology in
columns and human papillomavirus [HPV] in rows) and results of histologic review. For the original diagnosis, we considered only
the colposcopy-guided biopsy specimen, whereas the review also included the postsurgical histologic findings, when present.
ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; CIN 1, CIN or better; CIN
2+, CIN 2 or worse; LSIL, low-grade squamous intraepithelial lesion.

95% CI, 5%-18%), without significant variation or trend
according to the severity of cytologic findings. Finally, the
lesions found in HPV+ women without a Pap test, examined
during the second phase of the trial, had a probability of being
falsely classified as CIN 2 or worse of 15.7% (95% CI, 10%-
23%). This proportion was not statistically different from that
observed overall among women with conventional cytologic
diagnoses (P = .4) or among HPV+ women recruited during
phase 1 who had simultaneous cytologic examination and
HPV testing (P = .2).
The highest probability of a false-positive histologic diag-
nosis of CIN 2 or worse (66.7%) was observed in the group
with abnormal cytologic findings (ASCUS or worse) but neg-
ative HPV results that also had the lowest PPV among all
screening test combinations (0.4%). There was a statistically
significant (P = .015) inverse correlation between the PPV of
the screening test combination that led to referral and the
probability that a histologic diagnosis of CIN 2 or worse from
a colposcopy-guided biopsy specimen was false: the r2 for lin-
ear correlation between log(PPV) and log(proportion false-
positive histologic diagnoses) was 0.66.
Discussion
The main goal of cervical screening is to identify women
with high-grade intraepithelial lesions (CIN 2 or more
severe). These women require treatment, whereas women
with low-grade lesions (CIN 1 or less severe), which are fre-
quently regressive, should be referred for cytologic or colpo-
scopic control.14
In our study, 7.4% of women with CIN 1 or less severe pre-
treatment histologic findings were judged to have CIN 2 or
worse. The clinical consequences of this upgrade were minimal

78 Am J Clin Pathol 2008;129:75-80 American Society for Clinical Pathology

78 DOI: 10.1309/EWYGWFRRM8798U5P

because every woman with a lesion was monitored and the
lesion controlled with strict follow-up.
On the other hand, about 15% of cases diagnosed as CIN
2 or worse before treatment were downgraded to CIN 1 or
less. This proportion changed according to the combination of
screening test results that preceded the colposcopy. This phe-
nomenon is the consequence of the fact that sensitivity and
specificity were constant in these groups, whereas the preva-
lence of CIN 2 or worse among women who had a biopsy var-
ied. Because the prevalence of CIN 2 or worse among women
with a biopsy is correlated to the prevalence in the entire
group, the PPV of histologic diagnoses was correlated with
the PPV of the initial screening test combination.
This observation has important clinical implications.
Histologic diagnoses determine the decision to treat.
Therefore, the proportion of cases of CIN 2 or worse down-
graded after review can be assumed to represent the probabil-
ity of a treatment for CIN 2 or worse to be unnecessary. Our
data show that this probability can be relevant in some groups
of women if they are directly referred for colposcopy, such as
women with negative HPV results but abnormal cytologic
results, especially ASCUS, which supports the use of HPV for
cytologic triage. In general, our results stress the need for ini-
tial tests with a high PPV. In screening, a low PPV of the diag-
nostic tests that directly refer to colposcopy results not only in
increased workload and costs for colposcopy units, but also
unnecessary treatments.
In the study by Hopman and colleagues,15 20% of low-
grade lesions were upgraded and 26% of high-grade lesions
were downgraded after review. In the analysis by Stoler et al,5
reviewers reclassified 27% of CIN 1 cases to CIN 2 or worse
and 24% of CIN 2 or worse cases to CIN 1.
Our high negative predictive value is the result of a low
prevalence of true CIN 2 or worse in our series. This also led
to a relatively low PPV despite high specificity, 98% overall.
It must be kept in mind that this last figure estimates the speci-
ficity of pretreatment biopsy and, therefore, represents only
women who actually had a biopsy. The specificity of the entire
second level diagnostic phase, including colposcopy and
biopsy, is probably even higher because many women did not
have a biopsy and most of them plausibly represent true-neg-
ative results for CIN 2 or worse.
Because we compared pretreatment diagnosis with
reviewed posttreatment diagnoses, false-negatives were
indicative not only of errors of local pathologists in interpret-
ing histologic features but also of the different specimens
available before and after treatment. The true sensitivity of the
whole diagnostic process of colposcopy plus biopsy is even
lower because biopsies were not done for all women, and
some of the biopsy specimens may not have been taken from
the most severe lesion.16 This results in an overestimate of
sensitivity. It has been shown that the portion of CIN 2 or
American Society for Clinical Pathology
Anatomic Pathology / ORIGINAL ARTICLE
worse missed by colposcopy is not negligible.5,17 Because
biopsy specimens from women with negative diagnoses were
not reviewed, we assumed they were all negative for CIN 2 or
worse. It is possible that a small number of true cases of CIN
2 or worse are present in this group. This would result in a
slight overestimate of sensitivity and a negligible overestimate
of specificity.16
Remarkably, sensitivity and specificity were stable over
the different groups, which suggests that knowing why the
women were referred for colposcopy had little influence on
the interpretation of histologic findings. The similar values of
specificity and sensitivity among groups with such a different
prevalence of lesions give consistency to our results.
Our results also stress the need for quality assurance in
cervical histologic diagnosis. Indeed, even if the diagnosis of
CIN is believed to be simple and reproducible by most pathol-
ogists, in the historic study by Siegler,18 10 of 20 cases of car-
cinoma in situ (actually CIN 3 or high-grade SIL [HSIL])
were missed by a group of 25 pathologists. More recent work
found higher agreement: Robertson and collaborators10 found
a Cohen (the statistic that measures agreement not due to
chance19) of 0.46 for HSIL vs less severe than HSIL; Stoler et
al5 found a of 0.69; and Park et al7 and Parker et al4 found a
of about 0.8. Indeed biopsy diagnoses are always considered
the gold standard in any study of diagnostic accuracy, but the
subjective interpretation of histologic classification is a big
obstacle in many interinstitutional studies.5
In screening, a low PPV of the diagnostic test that direct-
ly precedes colposcopy not only has consequences on the col-
poscopy workload and costs but also leads to unnecessary
treatment. This consideration is true independent of the type
of first-level test, cytologic examination or HPV testing.
From the 1Pathology Unit, S. Chiara Hospital of Trento, Trento,
Italy; 2Agency for Public Health, Lazio Region, Rome; 3Pathology
Section, University of Bologna, Bologna; 4Department of Human
Pathology and Oncology, University of Firenze, Firenze;
5Pathology Unit, S. Anna Hospital of Torino, Torino; 6Department
of Pathology, University of Verona, Verona; 7Section of
Cytopathology, Hospital of Padova, Padova; 8Pathology Unit,
Hospital of Imola, Bologna; 9Pathology Unit, Maggiore Hospital
of Bologna, Bologna; 10Pathology Unit, Hospital of Faenza,
Ravenna; 11Pathology Unit, Belcolle Hospital of Viterbo,
Viterbo; and 12Centro per la Prevenzione Oncologica, Torino.
The NTCC trial was financially supported by the European
Union (Europe against Cancer contracts SI.2.327046 and
SPC.2002475), by the Italian Ministry of Health (Progetto
Speciale Valutazione di nuove tecnologie per lo screening del
cervicocarcinoma and project ex L 138/2004), Regione Piemonte,
Torino, Regione Toscana, Firenze, Regione Veneto, Venezia,
Regione Emilia-Romagna, Bologna, Provincia Autonoma di
Trento, Agenzia di Sanit Pubblica, Regione Lazio, by the Special
Project Oncology, Compagnia di S. Paolo FIRMS, Torino.
Address reprint requests to Dr Giorgi Rossi: Agency for Public
Health, Lazio Region, via di S. Costanza 53, 00198 Rome, Italy.
Am J Clin Pathol 2008;129:75-80 79
79 DOI: 10.1309/EWYGWFRRM8798U5P 79
Dalla Palma et al / UNNECESSARY TREATMENTS IN CERVICAL SCREENING
* The following are contributing members of the NTCC
Pathology Group: G.L. Taddei, F. Castiglione, and A.M.
Buccolero, Unit of Pathology, University, Florence; P. Dalla
Palma and D. Aldovini, Unit of Pathology, Ospedale di Trento; B.
Ghiringhello and S. Privitera, Unit of Pathology, OIRM, S. Anna,
Turin; G. Collina, Unit Section of Anatomic Pathology M.
Malpighi, Bellaria Hospital, Bologna University, Bologna; G.P.
Casadei and P. Pierotti, Unit of Pathology, Ospedale Maggiore di
Bologna, Bologna; M. Aldi and C. Sintoni, Unit of Pathology,
Presidio Ospedaliero di Ravenna, Ravenna; G. Galanti, Unit of
Pathology, Presidio Ospedaliero di Imola, Bologna; V. Gomes and
G. Verrico, U.O.C. di Anatomia e Istologia Patologica, Ospedale
Belcolle, Viterbo; M. Lestani, Unit of Pathology, University of
Verona; E. Bragantini, Unit of Pathology, Ospedale Borgo Trento,
Verona; and G.L. Onnis and D. Minucci, Unit of Pathology,
University of Padova.
The following are contributors to the article: P. Dalla Palma
was the coordinator of the NTCC Pathologist Working Group and
designed and conducted the review; P. Dalla Palma, G. Collina,
A.M. Buccoliero, B. Ghiringhello, M. Lestani, G. Onnis, D.
Aldovini, G. Galanti, G. Casadei, M. Aldi, and V. Gomes reviewed
the histologic specimens; G. Ronco was the NTCC project leader
and designed the study. P. Giorgi Rossi with P. Dalla Palma and G.
Ronco drafted the manuscript. P. Giorgi Rossi, G. Ronco, and P.
Giubilato were responsible for data analysis. All authors critically
revised the manuscript. All members of the NTCC Pathologist
Working Group reviewed the histologic specimens.
Acknowledgments: We thank all staff who assisted in running
the study, Margaret Becker for editing the text, and the thousands
of women who participated in the study.
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