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

© American Society for Clinical Pathology Am J Clin Pathol 2008;129:75-80 75
75 DOI: 10.1309/EWYGWFRRM8798U5P 75

We calculated 95% only data available to reviewers were patient age and date the confidence intervals (CIs) for all proportions assuming a bino- sample was obtained.1309/EWYGWFRRM8798U5P . During phase 1 the remaining CIN 1 cases 1.000 women). In the second phase. We computed the proportion that examination. and only 1 diag- cells of undetermined significance (ASCUS)+ or HPV+ nosis per woman. 349 were CIN 2 or worse. The were blindly reviewed. to review further). The reviewed. was formulated. were considered true-negatives. adenocarcinoma). and women in the experimental arm had a liq. The lat- workload and seems not to have influenced the results. guided biopsy diagnosis was unclear or not available. (4) One were screened according to various schedules. but all were CIN 1 or less severe. excluding the cen- Results ter that made the first diagnosis) reviewed all cases.000 women who noses differed. to refer for treatment is based on colposcopy-guided histolog- Colposcopic and histologic diagnoses were made without ic findings.98). (4) CIN 3. using a multiheaded microscope. in the first phase (about or better. the decision directly for colposcopy. Statistical Analysis ings negative. Indeed. The diagnoses provided by the reviewers were compared ❚Table 1❚ shows the distribution of the colposcopy-guid- with the diagnoses originally given by the screening center. ed biopsy histologic diagnoses according to the final diagno- The following concordance-categories were defined: (1) All sis after revision. ter 20 were considered CIN 1 or better in the analysis. were given by 10 pathology services. (2) to evaluate the association between the PPV of the diagnostic CIN 1 encompassing HPV condyloma. 2 independent pathologists random- ly selected from a pool of 9 (1 per center. and all were CIN 2 or more severe. which were not ogists for review. and 20 were CIN not other- selected from the 3 most expert. whereas women ing. the diagnosis was agreed younger than 35 years with ASCUS+ results were directly on by consensus. and were reviewed. The sensitivity of the pretreatment original 76 Am J Clin Pathol 2008. This was done to reduce the wise specified colposcopy-guided biopsy diagnoses. women in given by the pathology clinic after colposcopy-guided histol- the control arm were still tested with conventional cytologic ogy but before treatment.128 cases were reviewed: 747 had an initial diagnosis of were reviewed by only 1 pathologist who was randomly CIN 1. because we considered it to represent the best available assess- The histologic samples diagnosed as CIN 2 or 3 or CIN 1 ment of whether a CIN 2 or worse lesion was present. We retrieved all available histologic estimated proportion corresponds to 1 – (the PPV of the pre- samples taken within 1 year from referral for colposcopy: treatment histologic diagnosis). biopsy specimens showing no CIN. Indeed. We used as the “gold standard” the reviewers’ final masking cytologic and/or HPV results. We also computed the sensitivity and specificity of the and the surgical specimens when an ablative treatment was original pretreatment diagnosis vs the gold standard. punch biopsies. 45. single diagnosis for each patient. Otherwise the majority diagnosis was cho- referred for colposcopy independent of the HPV result and sen. In phase 1. according to ing to the cytologic and HPV results that preceded colposcopy the following 5 categories: (1) negative or inflammation. HPV. Women older than 35 years with atypical squamous Again. Histologic diagnoses diagnosis.Dalla Palma et al / UNNECESSARY TREATMENTS IN CERVICAL SCREENING Materials and Methods diagnoses were identical (perfect agreement).12. (3) The diag- The NTCC study enrolled about 95. whereas women in the experimental arm were not confirmed by the reviewers’ diagnosis as an estimate received only the HPV test and positive results were referred of the probability of unneeded treatment. When possible. Only H&E-stained slides were used. (3) CIN 2. We considered original diagnoses of CIN 2 or worse ent analysis. These latter results are not included in the pres. Protocols have diagnosis was CIN 2 or worse. Categories 4 and 5 were reviewed and discussed by all uid-based sample taken and tested for cytologic features and pathologists involved. category and the probability of a false-positive histologic or (5) carcinoma (encompassing squamous carcinoma and result. corresponding to the worst pathologic find- results were directly referred for colposcopy. women in the control arm had a convention. independent of age. all diagnoses of CIN 2 or 3 and 42% of CIN 1 diagnoses There were 52 CIN cases unavailable for review. whereas the others were CIN 1 been detailed elsewhere. recalled after 1 year for cytologic examination and/or HPV control if the HPV result was positive and the cytologic find. analysis. al Pap smear. all available material was examined. based on all available material as described earlier.13 Briefly. corresponding to the worst All of these parameters were estimated separately accord- pathologic finding among all the patient’s tests. or vice versa (major disagreement.000 women).129:75-80 © American Society for Clinical Pathology 76 DOI: 10. in some cases from more than 1 colposcopy. Each reviewer was asked to formulate a mial distribution. In the second phase (50. In that performed. (2) The diag- noses differed. (5) At least one diagnosis was carcinoma (to review further). Each case was randomly assigned to 1 or 2 pathol. We the proportion of CIN 1 upgraded to CIN 2 or worse did not excluded 12 cases from this analysis because the colposcopy- differ by method (P = .

* Positive predictive value.0 (—) 99. the PPV was about 85%) ❚Table 2❚.8 (1-36) ASCUS 123 60 23 87. On the other hand. confidence interval.9% (ie. LSIL.7 (22-96) ASCUS 182 43 1 100.7 (80-93) 96. CI.128 CIN. 4%-16%).7 (92-98) 12. sensitivity.0 (51-91) 99.1309/EWYGWFRRM8798U5P 77 . % Probability of False CIN 2 or HPV/Cytologic Results Cases Reviewed Worse After Review (95% CI) (95% CI) Worse Diagnosis. and there was no evi.3 (74-89) 97. % (95% CI) No HPV test Overall 694 335 122 87.1%. HPV+ and negative cytologic results or HPV+ and positive cytologic results ❚Table 3❚ and ❚Figure 1❚. 95% CI. ❚Table 3❚❚ Number of Biopsies and CIN 2 or Worse Diagnoses After Revision. ic findings (26. not otherwise specified.2 (95-99) 8.0 (94-99) 26. It was higher in the (66. low-grade CIN. ranging from 97% to 99%. HPV.9 (56-90) 97. Sensitivity ranged between 75% and approximately 90% (except for the HPV– group that included conventional arm (P = . and Probability of Unnecessary Treatment According to the HPV and Cytologic Results Used to Refer Women for Colposcopy No. of No.5%.6 (5-18) Normal cytology 255 93 20 75.4 (84-97) 97.6 (4-16) HPV+ No test 787 371 122 87.9% (2.7 (98-100) 66. 95% CI.8 (0-24) LSIL+ 257 178 69 85. the proportion of false-positive diag. Positive Predictive Value. cervical intraepithelial neoplasia. CIN 2 or worse 52 297 349 guided biopsy. 83.116 reason for the colposcopy referral.1 (95-98) 15.1% (ie.9 (96-99) 10. 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 1.0 (97-100) 11.0 (—) ASCUS. In the experimental arm. 12%-46%) than for women who dence of significant variation between groups.9 (95-98) 15.435). it was higher (P = . Sensitivity.0 (94-100) 4. had LSIL or more severe cytologic results (8.0 (8-20) ASCUS 302 133 29 75.7%. CIN 1 or better 710 57 767 We observed similar rates of specificity of colposcopy.0 (—) 97.6%.0 (66-97) 99. The percentage of CIN 1 Dichotomized Diagnosis. human papillomavirus.8 (94-100) 80. cervical intraepithelial neoplasia.1 (5-22) HPV– Overall 319 81 3 66. NOS.7 (12-45) LSIL+ 392 202 93 91. % Specificity.7%.3 (74-93) 95.383/2.7 (74-88) 97. ie. atypical squamous cells of undetermined significance. © American Society for Clinical Pathology Am J Clin Pathol 2008. independent of the Total 762 354 1. squamous intraepithelial lesion (LSIL)+. ASCUS. CIN.0 (—) LSIL+ 137 38 2 50.7 (10-23) Overall HPV and cytology 635 331 112 82. and Sensitivity* cases upgraded to CIN 2 or worse after review was 8. 95% CI. 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. 22%-96%) than for HPV+ cases (10. histologic diagnoses for CIN 2 or worse was 82. low-grade squamous intraepithelial lesion. Specificity. of Cases No.9%.7 (—) 98. 85.02) for women with ASCUS cytolog- only 3 cases that were CIN 2 or worse).003) noses of CIN 2 or worse varied according to cytologic and for HPV– but cytologically abnormal (ASCUS+) cases HPV test results (Table 3 and Figure 1). of CIN 2 or Sensitivity.129:75-80 77 77 DOI: 10. and ❚Table 2❚❚ specificity was 97.6%. cervical intraepithelial neoplasia.4 (97-100) 50. the negative predictive value for CIN 2 or worse was about Reviewed Histologic Diagnosis 92%).

1309/EWYGWFRRM8798U5P . 5%-18%).4% of women with CIN 1 or less severe pre- significant (P = . quently regressive. which are fre- with abnormal cytologic findings (ASCUS or worse) but neg. 95% CI.7% (95% CI. These women require treatment. CIN 1–. Finally. with high-grade intraepithelial lesions (CIN 2 or more The highest probability of a false-positive histologic diag. The clinical consequences of this upgrade were minimal 78 Am J Clin Pathol 2008. This proportion was not statistically different from that observed overall among women with conventional cytologic Discussion diagnoses (P = .66. the a colposcopy-guided biopsy specimen was false: the r2 for lin- lesions found in HPV+ women without a Pap test.4%). atypical squamous cells of undetermined significance. without significant variation or trend probability that a histologic diagnosis of CIN 2 or worse from according to the severity of cytologic findings. CIN. 10%- 23%). CIN 2+. whereas the review also included the postsurgical histologic findings.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. falsely classified as CIN 2 or worse of 15. low-grade squamous intraepithelial lesion. severe). had a probability of being positive histologic diagnoses) was 0. For the original diagnosis. cervical intraepithelial neoplasia. ASCUS. examined ear correlation between log(PPV) and log(proportion false- during the second phase of the trial.2). CIN or better. we considered only the colposcopy-guided biopsy specimen. There was a statistically In our study. CIN 2 or worse.129:75-80 © American Society for Clinical Pathology 78 DOI: 10.7%) was observed in the group with low-grade lesions (CIN 1 or less severe). LSIL. 7.015) inverse correlation between the PPV of treatment histologic findings were judged to have CIN 2 or the screening test combination that led to referral and the worse. when present.4) or among HPV+ women recruited during phase 1 who had simultaneous cytologic examination and The main goal of cervical screening is to identify women HPV testing (P = . should be referred for cytologic or colpo- ative HPV results that also had the lowest PPV among all scopic control. whereas women nosis of CIN 2 or worse (66.14 screening test combinations (0.

S. lower because biopsies were not done for all women. biopsy specimens from women with negative diagnoses were On the other hand. ogists.2. More recent work of women if they are directly referred for colposcopy. cytologic examination or HPV testing. 00198 Rome. represents only 5Pathology Unit. This phe. such as found higher agreement: Robertson and collaborators10 found women with negative HPV results but abnormal cytologic a Cohen κ (the statistic that measures agreement not due to results. by the Special some of the biopsy specimens may not have been taken from Project “Oncology. Torino. ficity of pretreatment biopsy and. Maggiore Hospital of Bologna. 2Agency for Public Health. whereas the preva. Lazio Region. 10Pathology Unit. 6Department women who actually had a biopsy. cervical histologic diagnosis. Provincia Autonoma di Trento. we assumed they were all negative for CIN 2 or 2 or worse before treatment were downgraded to CIN 1 or worse. © American Society for Clinical Pathology Am J Clin Pathol 2008. about 15% of cases diagnosed as CIN not reviewed. Indeed. in the historic study by Siegler. 3Pathology Section. a low PPV of the diagnostic test that direct- grade lesions were upgraded and 26% of high-grade lesions ly precedes colposcopy not only has consequences on the col- were downgraded after review. Hospital of Padova. 9Pathology Unit. κ of about 0. Torino.5 In the study by Hopman and colleagues. This would result in a screening test results that preceded the colposcopy. therefore. Our results also stress the need for quality assurance in Histologic diagnoses determine the decision to treat. Firenze. which suggests that knowing why the ied. and Park et al7 and Parker et al4 found a tial tests with a high PPV. Torino. “Belcolle” Hospital of Viterbo. Stoler et cytologic triage. Pathology and Oncology. to a relatively low PPV despite high specificity. slight overestimate of sensitivity and a negligible overestimate nomenon is the consequence of the fact that sensitivity and of specificity. Trento. but the increased workload and costs for colposcopy units. In screening.17 Because lesion controlled with strict follow-up. sensitivity and specificity were stable over lence of CIN 2 or worse among women who had a biopsy var. Remarkably. It is possible that a small number of true cases of CIN less. This observation has important clinical implications. Anatomic Pathology / ORIGINAL ARTICLE because every woman with a lesion was monitored and the worse missed by colposcopy is not negligible. ative results for CIN 2 or worse.16 specificity were constant in these groups.5 poscopy workload and costs but also leads to unnecessary reviewers reclassified 27% of CIN 1 cases to CIN 2 or worse treatment. Agenzia di Sanità Pubblica. In the analysis by Stoler et al. 7Section of “second level” diagnostic phase. Our high negative predictive value is the result of a low prevalence of true CIN 2 or worse in our series. Italy. and Regione Emilia-Romagna. the most severe lesion. Firenze. In screening. CIN is believed to be simple and reproducible by most pathol- graded after review can be assumed to represent the probabil. Regione Piemonte. The similar values of group. Costanza 53. our results stress the need for ini. This proportion changed according to the combination of 2 or worse are present in this group. University of Bologna. including colposcopy and Cytopathology. Lazio Region. This also led From the 1Pathology Unit. have a biopsy and most of them plausibly represent true-neg- Ravenna. Regione Veneto. Anna Hospital of Torino. false-negatives were Union (Europe against Cancer contracts SI. of first-level test. Bologna.1309/EWYGWFRRM8798U5P 79 . 4Department of Human It must be kept in mind that this last figure estimates the speci. SPC.5. Rome. Indeed biopsy diagnoses are always considered nostic tests that directly refer to colposcopy results not only in the gold standard in any study of diagnostic accuracy. S. by the Italian Ministry of Health (Progetto ing histologic features but also of the different specimens Speciale “Valutazione di nuove tecnologie per lo screening del available before and after treatment. University of Firenze. Venezia. prevalence of lesions give consistency to our results. Padova. Bologna.327046 and indicative not only of errors of local pathologists in interpret.” Compagnia di S. This consideration is true independent of the type and 24% of CIN 2 or worse cases to CIN 1. Bologna.16 This results in an overestimate of Address reprint requests to Dr Giorgi Rossi: Agency for Public sensitivity.69. Chiara Hospital of Trento.129:75-80 79 79 DOI: 10. Italy.15 20% of low. Our cinoma in situ (actually CIN 3 or high-grade SIL [HSIL]) data show that this probability can be relevant in some groups were missed by a group of 25 pathologists. even if the diagnosis of Therefore.18 10 of 20 cases of car- ity of a treatment for CIN 2 or worse to be unnecessary. Because the prevalence of CIN 2 or worse among women women were referred for colposcopy had little influence on with a biopsy is correlated to the prevalence in the entire the interpretation of histologic findings.46 for HSIL vs less severe than HSIL. Verona. In general. Regione Lazio. and 12Centro per la Prevenzione Oncologica. the PPV of histologic diagnoses was correlated with specificity and sensitivity among groups with such a different the PPV of the initial screening test combination. 8Pathology Unit. but also subjective interpretation of histologic classification is a big unnecessary treatments. biopsy. Viterbo. the different groups. 98% overall. Because we compared pretreatment diagnosis with The NTCC trial was financially supported by the European reviewed posttreatment diagnoses. the proportion of cases of CIN 2 or worse down. obstacle in many interinstitutional studies. via di S. It has been shown that the portion of CIN 2 or Health. especially ASCUS. which supports the use of HPV for chance19) of 0. Bologna. Paolo FIRMS. Regione Toscana.2002475). whole diagnostic process of colposcopy plus biopsy is even Torino. al5 found a κ of 0. 11Pathology Unit. is probably even higher because many women did not Hospital of Imola. Hospital of Faenza. The specificity of the entire of Pathology. a low PPV of the diag.8. University of Verona. The true sensitivity of the cervicocarcinoma” and project ex L 138/2004).

Obstet Gynecol.C.129:75-80 © American Society for Clinical Pathology 80 DOI: 10.42:231-238. Van Niekirk D. University. Margaret Becker for editing the text. Matisic JP. 2006. Anna. J Clin Pathol. and the Atypical Squamous Cells 19. Taddei. P. Gynecol cancer after a colposcopic diagnosis of CIN 1 or less. a comparative study of pathologists’ diagnoses. Florence. Ronco G. 1960. measure interrater and intrarater agreement for 1790 cervical 17. Cancer. Bologna. Unit of Pathology. Spires SE. Genest DR. Kenemans P.O. J Natl Cancer Inst. 1995. M. Peterson P. E. Unit Section of Anatomic Pathology “M. biopsy after positive human papillomavirus (HPV) DNA 1995. Subsequent risk and biopsy specimens among twelve pathologists: qualitative presentation of cervical intraepithelial neoplasia (CIN) 3 or histopathologic analysis and methodology issues. Crum CP. Aldi and C. Eltoum I. Minucci. Robertson AJ. Carozzi F. Ravenna. 2001. Lancet Oncol. et al. Collina. and P. specimens. 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