Cytology and Human Papillomavirus Screening Test Results Associated With 2827 Histopathologic Diagnoses of Cervical Intraepithelial Neoplasia 2/3

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1 Cytology nd Humn Ppillomvirus Screening Test Results Associted With 2827 Histopthologic Dignoses of Cervicl Intrepithelil Neoplsi 2/3 Chengqun Zho, MD; Milon Amin, MD; Boying Weng, MD, PhD; Xingbi Chen, MD, PhD; Aml Knbour-Shkir, MD, PhD; R. Mrshll Austin, MD, PhD Context. Cervicl screening in the United Sttes incresingly involves newer US Food nd Drug Administrtion pproved cytologic methods nd djunctive highrisk humn ppillomvirus (hrhpv) DNA testing. Objective. To document cervicl screening test performnce preceding histopthologic cervicl intrepithelil neoplsi (CIN) 2/3 dignoses. Design. Preceding screening test results with computer-imged, liquid-bsed cytology (LBC) nd hrhpv results were nlyzed for 2827 ptients with histopthologic CIN 2/3 dignoses. Results. Of 2827 ptients with CIN 2/3 dignoses, 2074 (73.4%) hd system LBC findings within 4 months of CIN 2/3 dignoses: high-grde squmous intrepithelil lesion (n ¼ 862; 41.6%), low-grde squmous intrepithelil lesion (n ¼ 464; 22.4%), typicl squmous cells of undetermined significnce (n ¼ 445; 21.5%), typicl squmous cells, cnnot exclude high-grde squmous intrepithelil lesion (n ¼ 288; 13.9%), nd typicl glndulr cells/denocrcinom in situ (n ¼ 15; 0.7%). Of the 2827 ptients, 1488 (52.6%) lso hd erlier system LBC results t more thn 4 months to 3 yers before CIN 2/3 dignoses: one or more bnorml LBC results (n ¼ 978; 65.7%), one or more negtive LBC results (n ¼ 911; 61.2%), both bnorml nd negtive LBC (n ¼ 401; 26.9%). Of 807 ptients with hrhpv cotest results within 4 months of CIN 2/3 dignoses, 786 (97.4%) hd hrhpv þ results. Of 454 ptients who lso hd erlier hrhpv results t more thn 4 months to 3 yers before CIN 2/3 dignoses: 377 (83.0%) hd one or more hrhpv þ result, 110 (24.2%) hd one or more hrhpv result, nd 33 (7.3%) hd both positive nd negtive HPV results. Conclusion. Ptients with histopthologic CIN 2/3 hd recent bnorml LBC results, most often, high-grde squmous intrepithelil lesions. Among cotested ptients, 97.4% (786 of 807) tested hrhpv þ. However, significnt number of ptients tested during n extended period of severl yers hd erlier negtive Ppnicolou or negtive HPV test results, suggesting the recent development of some CIN 2/3 lesions nd supporting the vlue of cotesting for enhnced detection of other developing, smll, inccessible, or nondignostic precursor lesions. (Arch Pthol Lb Med. 2013;137: ; doi: / rp oa) The primry gol of cervicl screening is the identifiction nd removl of intrepithelil precncerous lesions, which, if left untreted, would, t some future time, become invsive cervicl cncer. 1 The desired result is decrese in the incidence of invsive cervicl cncer in the screened popultion. 2 Histopthologic results remin key foundtion of cervicl screening efforts in the United Sttes, nd Accepted for publiction August 7, Published s n Erly Online Relese October 10, From the Deprtment of Pthology, Mgee-Womens Hospitl of University of Pittsburgh Medicl Center, Pittsburgh, Pennsylvni (Drs Zho, Amin, Knbour-Shkir, nd Austin; nd the Deprtment of Pthology, Conemugh Helth System, Johnstown, Pennsylvni (Drs Weng nd Chen). The uthors hve no relevnt finncil interest in the products or compnies described in this rticle. Presented in prt t the nnul meeting of the United Sttes nd Cndin Acdemy of Pthology; Februry 26 Mrch 4, 2011; Sn Antonio, Texs. Reprints: Chengqun Zho, MD, Deprtment of Pthology, Mgee-Womens Hospitl of University of Pittsburgh Medicl Center, 300 Hlket St, Pittsburgh, PA (e-mil: zhoc@upmc.edu). biopsy dignoses of cervicl intrepithelil neoplsi (CIN) 2 or worse represent the clinicl threshold leding to bltive or excisionl therpy. 3 Despite evidence tht intrepithelil lesions clssified s CIN 3 re more likely to progress to invsive cncer nd less likely to regress thn intrepithelil lesions clssified s CIN 2, 4 CIN 2/3 threshold for excision is still generlly retined becuse the distinction between CIN 2 nd CIN 3 is not lwys cler. 5 Furthermore, colposcopic evlution nd biopsy of ptients with bnorml cytologic screening test results tht re less severe thn high-grde squmous intrepithelil lesion (HSIL) hve been recommended to mximize histopthologic identifiction of CIN 2/3 lesions commonly ssocited with cytologic bnormlities less severe thn HSIL. 6 In fct, the lrgest vilble US studies reflecting the use of the conventionl Ppnicolou (Pp) test hve repetedly shown tht more histopthologic CIN 2/3 lesions re identified in ptients with preceding bnorml Pp test interprettion of typicl squmous cells of undetermined significnce (ASC-US) thn re identified in ptients with preceding bnorml Pp test interprettion of HSIL or ny other specific bnorml cytologic result. 7,8 In contrst, lrge US 942 Arch Pthol Lb Med Vol 137, July 2013 Ppnicolou nd HPV Tests for Women With CIN 2/3 Zho et l

2 Tble 1. Abnorml Ppnicolou Test Results Triggering Dignostic Procedures in 2074 Ptients Abnorml Ppnicolou Test Ptients, No. (%) HSIL 862 (41.6) LSIL 464 (22.4) ASC-US 445 (21.5) ASC-H 288 (13.9) AGC/AIS 15 (0.7) Totl 2074 (100%) Abbrevitions: AGC, typicl glndulr cells; AIS, denocrcinom in situ; ASC-H, typicl squmous cells, cnnot exclude HSIL; ASC-US, typicl squmous cells of undetermined significnce; CIN 2/3, cervicl intrepithelil neoplsi 2 or 3; HSIL, high-grde squmous intrepithelil lesion; LSIL, low-grde squmous intrepithelil lesion. Test results were from 4 mo before CIN 2/3 dignoses. series documenting prior cytologic screening test results in ptients with histopthologic CIN 2/3 lesions dignosed fter screening with newer prevlent methods of liquidbsed cytology (LBC), computer-ssisted screening, nd djunctive high-risk humn ppillomvirus (hrhpv) testing remin surprisingly limited. Accordingly, we conducted retrospective study nd evluted screening test histories of women with CIN 2/3 dignoses in lrge, integrted helth system using new technology methods of cervicl screening. MATERIALS AND METHODS Ptient Accrul After obtining institutionl review bord pprovl t the University of Pittsburgh Medicl Center (UPMC), retrospective study ws initited. A computer-bsed serch of the CoPth (Cerner Corportion, Knss City, Missouri) lbortory informtion system dtbse t Mgee-Womens Hospitl (MWH) of the UPMC ws crried out to retrieve cses with histopthologic dignoses of CIN 2 or CIN 3 (CIN 2/3) dignosed during 65-month period between July 2005 nd November The results of surgicl pthology reports, preceding Pp tests, nd preceding hrhpv DNA tests were collected from the lbortory informtion system. The UPMC is lrge, integrted privte helth system in which Pp tests re collected by highly diverse group of clinicl providers tht includes gynecologists, fmily physicins, internists, nurse prctitioners, physicin ssistnts, nd house-stff trinees. Cytologic Methods Cytologic testing used ThinPrep Pp tests 9 prepred ccording to mnufcturer s specifictions from PreservCyt smples using n utomted processor (ThinPrep 3000, Hologic Inc., Mrlborough, Msschusetts). Stining of slides ws performed on Skur Tissue-Tek Automted Slide Stiner (Skur Finteck USA Inc, Torrnce, Cliforni). Beginning in December 2004, loctionguided, computer-ssisted screening of ThinPrep Pp tests slides ws used, employing the ThinPrep Imging System 10 (Hologic Inc, Mrlborough, Msschusetts). The ThinPrep Imging System performed nlyses on btches of up to 250 ThinPrep Pp tests slides with specilized imging softwre. All specimens were processed nd evluted in the pthology lbortory t MWH nd reported using current Bethesd System 2001 terminology. 11 In this report, ll low-grde squmous intrepithelil lesion (LSIL) nd HSIL results nd other current Bethesd System result terminology refer to cytologic interprettions. The MWH cytopthology lbortory is lrge, subspecilized cdemic hospitl lbortory tht usully reports more thn Pp tests per yer from lrge, integrted hospitl helth system tht serves metropolitn re with significntly older-ge popultion profile thn tht of the ntionl verge. 12 The reporting profile of the lbortory is documented in numerous recent publictions hrhpv DNA Screening Testing The hrhpv DNA testing ws ordered by UPMC system clinicl providers ccording to severl ordering options s follows: reflex HPV testing following typicl squmous cell (ASC) Pp test interprettions, routine HPV cotesting with Pp tests from women 30 yers nd older, nd HPV cotesting regrdless of either ge or Pp test results. The hrhpv DNA detection in ThinPrep Pp test PreservCyt vil fluid ws performed using the US Food nd Drug Administrtion (FDA) pproved Hybrid Cpture 2 (HC2) ssy method (Qigen Corp, Minden, Germny) 29 tht tests for hrhpv nd intermedite-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, nd 68. The results of hrhpv DNA testing were either positive or negtive, bsed on threshold of 1 pg/ml HPV DNA. Histopthologic Dignosis All dignoses of CIN 2/3 in this study refer to histopthologic interprettions of surgicl pthology specimens, including cervicl biopsies, endocervicl curettge specimens, nd/or dignostic, excisionl procedures using loop electrosurgicl excision procedures or cold knife cervicl coniztion. Histopthologic dignoses were rendered by subspecilized stff pthologists t MWH whose prctices re lrgely limited to exmintion of gynecologic nd brest pthology specimens. Cses initilly dignosed s CIN 2/3 re required to be confirmed by second reviewing pthologist. 30 Immunohistochemicl stining with P16 nd Ki-67 is lso liberlly used by stff pthologists to increse the relibility of CIN 2/3 dignoses. 31 Cytology results reported before initil histopthologic dignoses of CIN 2/3 re usully recorded in the surgicl pthology report. Prior negtive Pp tests re rescreened nd evluted s prt of deprtmentl qulity improvement procedures. Prior bnorml Pp tests re lso routinely reviewed nd correlted with follow-up histopthology. For this study, if n bnorml cytology result occurred within 4 months before the surgicl procedure estblishing the initil histopthologic dignosis of CIN 2/3, the immeditely preceding bnorml Pp test result ws regrded s the trigger for the surgicl procedure nd histopthologic dignosis of CIN 2/3. RESULTS A totl of 2827 ptients with histopthologic CIN 2/3 dignoses were identified during the study period. Dignostic excisionl procedures were documented in 1638 ptients (57.9%), nd 118 ptients (4.2%) hd subsequent hysterectomies. The verge ptient ge ws 30.7 yers, with rnge from 16 to 91 yers. Triggers of Dignostic Surgicl Procedures Ppnicolou test findings within 4 months of CIN 2/3 dignoses preceded dignostic surgicl procedures in 2074 of 2827 ptients (73.4%) identified in our dtbse. Ppnicolou test findings leding to dignostic procedures nd CIN 2/3 dignoses included wide spectrum of bnorml Pp test findings (Tble 1). High-grde squmous intrepithelil lesion ws the most common bnorml cytologic result (41.6%; 862 of 2074), wheres LSIL nd ASC-US results preceded 22.4% (464 of 2074) nd 21.5% (445 of 2074) of CIN 2/3 dignoses, respectively. Atypicl squmous cells, cnnot exclude HSIL (ASC-H) results preceded 13.9% (288 of 2074) of CIN 2/3 dignoses, nd typicl glndulr cells/denocrcinom in situ preceded less thn 1% (15 of 2074). Other Cytology Results Of the 2827 ptients with CIN 2/3 dignoses, 1488 (52.6%) were found to hve other, erlier, UPMC system cytology results t more thn 4 months to 3 yers before histopthologic CIN 2/3 dignoses (Tble 2). These less- Arch Pthol Lb Med Vol 137, July 2013 Ppnicolou nd HPV Tests for Women With CIN 2/3 Zho et l 943

3 Tble 2. Erlier Ppnicolou Test Results in 1488 Ptients Ppnicolou Test Results Ptients, No. (%) At lest one bnorml test result 978 (65.7) At lest one norml test result 911 (61.2) Both norml nd bnorml test results 401 (26.9) Totl 1488 (100) Ptients with erlier cytology results do not include those whose bnorml Ppnicolou tests were performed 4 mo before histopthologic cervicl intrepithelil neoplsi 2 or 3 dignoses. Erlier tests were performed more thn 4 mo up to 3 y before cervicl intrepithelil neoplsi 2 or 3 dignoses. proximte Pp test results were in ddition to the bnorml Pp tests obtined during the 4 months immeditely preceding CIN 2/3 dignoses. Of those 1488 ptients with CIN 2/3 dignoses, 978 (65.7%) hd t lest one erlier, bnorml cytology result, wheres 911 of 1488 (61.2%) hd t lest one erlier, negtive cytology result during the more-extended, preceding period; 401 of 1488 (26.9%) hd both bnorml nd norml Pp test results, nd 510 of 1488 (34.3%) hd n erlier, negtive Pp test result only. The rnge of cytologic bnormlities mong 978 ptients with erlier, bnorml cytology results re shown in Tble 3. For ptients with multiple erlier, bnorml Pp test results involving squmous cells, the most-bnorml result ws recorded using the following hierrchicl order: HSIL. ASC-H. LSIL. ASC-US. Ptients with either prior typicl glndulr cells results or both LSIL nd ASC-H results were listed seprtely. Low-grde squmous intrepithelil lesion nd ASC-US were the most-common erlier, bnorml Pp test results: 166 of 978 ptients (17.0%) with erlier bnorml cytology findings hd prior HSIL results. HPV Test Results Of 2827 ptients with CIN 2/3 dignoses, 807 (28.6%) hd HC2 hrhpv test results within 4 months of initil dignostic biopsies; 786 of 807 (97.4%) hd HPV þ results. Ppnicolou nd ccompnying HPV test results preceding the 807 follow-up CIN 2/3 dignoses re shown in Tble 4. Atypicl squmous cells of undetermined significnce in the Pp test results were the most-common bnorml cytology result with djunctive HPV testing, ccounting for roughly hlf of Tble 3. Abnorml Ppnicolou (Pp) Test Results From Ptients With Erlier Abnorml Pp Results Abnorml Pp Ptients, No. (%) HSIL 166 (17.0) LSIL 363 (37.1) ASC-H 108 (11.0) ASC-US 310 (31.7) LSIL/ASC-H b 26 (2.7) AGC 5 (0.5) Totl 978 (100.0) Abbrevitions: AGC, typicl glndulr cells; ASC-H, typicl squmous cells, cnnot exclude HSIL; ASC-US, typicl squmous cells of undetermined significnce; HSIL, high-grde squmous intrepithelil lesion; LSIL, low-grde squmous intrepithelil lesion. Ptients erlier tests were performed more thn 4 mo up to 3 y before cervicl intrepithelil neoplsi 2 or 3 dignoses. The bnorml Pp tests tht triggered the surgicl procedures re not included. b LSIL/ASC-H refers to LSIL nd ASC-H in different Pp tests or in the sme Pp test. Tble 4. Liquid-Bsed Cytology Results in 807 Ptients With Adjunctive High-Risk Humn Ppillomvirus (hrhpv) Test Results Accompnying Abnorml Ppnicolou Cses With hrhpv Test Results, No. (%) Cses With Positive hrhpv Test Results, No. (%) ASC-US 410 (50.8) 404 (98.5) ASC-H 180 (22.3) 172 (95.6) LSIL 51 (6.3) 50 (98.0) HSIL 137 (17.0) 136 (99.3) AGC 4 (0.5) 4 (100) Ppnicolou N/A 25 (3.1) 20 (80.0) Totl 807 (100) 786 (97.4) Abbrevitions: AGC, typicl glndulr cells; ASC-H, typicl squmous cells, cnnot exclude HSIL; ASC-US, typicl squmous cells of undetermined significnce; hrhpv, high-risk humn ppillomvirus; HSIL, high-grde squmous intrepithelil lesion; LSIL, low-grde squmous intrepithelil lesion; N/A, not vilble. Both Ppnicolou tests nd HPV testing were performed 4 months before cervicl intrepithelil neoplsi 2 or 3 dignosis. the cses. High-grde squmous intrepithelil lesion ws the third most-common Pp test result, following ASC-US nd ASC-H. The HPV þ rtes ssocited with CIN 2/3 dignoses were similr in the vrious bnorml Pp test ctegories. In ddition to HPV results from tests within 4 months before the CIN 2/3 dignoses, 454 of 807 ptients (56.3%) hd erlier UPMC system HPV results more thn 4 months nd up to 3 yers before the CIN 2/3 dignoses (Tble 5). Of the 454 ptients, 377 (83.0%) hd t lest one HPV þ result during the more-extended preceding period. COMMENT Among 2074 ptients with CIN 2/3 dignoses nd bnorml UPMC system, computer-imged, LBC Pp test results within the previous 4 months, HSIL ws the most common bnorml cytology result, documented in 862 ptients (41.6%). Low-grde squmous intrepithelil lesion ws the next most-common bnorml, prior Pp test result in 22.4% (464 of 2074), followed by ASC-US in 21.5% (445 of 2074), ASC-H in 13.9% (288 of 2074), nd typicl glndulr cells/denocrcinom in situ in less thn 1% (15 of 2074) (Tble 1). The lrgest comprble reported US dt set is from Kiser Permnente in Northern Cliforni, which reported screening-test dt ssocited with 3649 histopthologic CIN 2/3 dignoses rendered between Jnury 1, 2003, nd June 30, 2009, on ptients 30 yers nd older screened with conventionl Pp smers nd HC2 hrhpv cotesting. 8 Among the 3649 ptients with CIN 2/3 dignoses nd preceding, bnorml, Kiser conventionl Pp test results, ASC-US ws the most common bnorml cytology Tble 5. High-Risk Humn Ppillomvirus (hrhpv) Test Results in 454 Ptients With Erlier Test Results Erlier hrhpv Test Results Cses, No. (%) At lest one negtive test result 110 (24.2) At lest one positive test result 377 (83.0) Both positive nd negtive test results 33 (7.3) Totl 454 (100) Ptients erlier tests were performed more thn 4 mo up to 3 y before cervicl intrepithelil neoplsi 2 or 3 dignoses. The bnorml Ppnicolou tests tht triggered the surgicl procedures re not included. 944 Arch Pthol Lb Med Vol 137, July 2013 Ppnicolou nd HPV Tests for Women With CIN 2/3 Zho et l

4 result, documented in 1323 ptients (36.3%). High-grde squmous intrepithelil lesion ws the second mostcommon, bnorml Pp test result in 917 of 3649 ptients (25.1%), followed by LSIL in 751 of 3649 ptients (20.6%), ASC-H in 481 of 3649 ptients (13.2%), nd typicl glndulr cells in 177 of 3649 ptients (4.9%). Similr results were reported erlier from the sme Kiser Permnente fcility in 1998 report, which documented ASCUS s the leding bnorml, conventionl Pp test result, preceding high-grde cervicl neoplsi in 38.8% ( of ) of cses. 7 Preservtion of cytologic nucler detil with immedite wet fixtion in the LBC vil, hrvesting in the LBC vil of most collected cells otherwise routinely discrded on conventionl test collection devices, 32 computer-ssisted screening, 10 nd conservtive MWH cytotechnologist worklod policies, 17 re ll likely contributing fctors for the incresed likelihood of n HSIL result preceding histopthologic CIN 2/3 dignosis in our report. Although the dvntges of LBC hve been questioned in Itlin nd Dutch clinicl trils 33,34 using lbortories reltively inexperienced with the LBC method nd lcking clerly documented LBC proficiency, clinicl trils in the more tightly qulity-ssured UK Ntionl Helth System hve documented significntly enhnced performnce with LBC compred with conventionl cytology. 35 Most (65.7%; 978 of 1488) ptients with CIN 2/3 dignoses nd dditionl erlier UPMC system Pp test results t 4 months to 3 yers before the CIN 2/3 dignoses hd t lest one bnorml Pp test result. Tht finding reflects observtions tht CIN 2/3 lesions often develop nd enlrge slowly during period of yers in mnner llowing detection during routine periodic screening, even when reltively insensitive screening method is employed. 14 Indeed, studies djusted for verifiction bis hve estimted the verge sensitivity of the conventionl Pp test t bout 50%, 36 but modeling still estimtes tht periodic screening every 3 yers with the conventionl Pp test cn prevent bout 85% of ll (mostly slow-growing) cervicl cncers. 37 On the other hnd, 61.2% of the sme 1488 ptients (n ¼ 911) hd t lest one erlier negtive Pp test result during period of severl yers. During the study period between July 2002 nd November 2010, less thn 1.5% of ll cervicl cytology smples were conventionl Pp tests. Prior negtive Pp results likely reflect both some newly developing incident CIN 2/3 lesions s well s other CIN 2/3 lesions, which were either initilly too smll to be relibly smpled or were locted in more difficult-to-smple loctions in the cervix. 14 Internl qulity ssurnce reviews t MWH generlly confirm negtive findings in negtive Pp test results obtined within 5 yers of CIN 2/3 dignoses; qulity ssurnce reviews less-commonly document questionble cellulr chnges identifible t lest prtilly becuse of hindsight or outcome bis. Avilble dt now indicte tht the intervl between incident HPV 16 or HPV 18 infection nd biopsy-confirmed CIN 2/3 cn be s short s few months. 38 Only 17% (166 of 978) of erlier, vilble, bnorml Pp tests were interpreted s HSIL, documenting predominnce of less-proximte, low-grde or indeterminte, bnorml Pp test findings. The rnge of erlier Pp bnormlities likely reflect both the effects of multiple HPV infections unrelted to lter dignosed CIN 2/ 3 lesions s well s progression of some less-dvnced lesions to CIN 2/3. 39 Along these lines, intrepithelil lesions ssocited with HPV 18 induced cervicl neoplsis re more likely to be ssocited with nondignostic or indeterminte intrepithelil chnges thn they re with intrepithelil lesions ssocited with HPV 16 induced cervicl neoplsis. 40 Positive HPV test results were reported within 4 months of histopthologic CIN 2/3 dignoses in 786 of 807 ptients (97.4%), findings similr to the observtion tht crcinogenic HPV genotypes were detectible in 95.4% (580 of 608) of women with confirmed CIN 3 in the Atypicl Squmous Cells of Undetermined Significnce nd Low Grde Squmous Intrepithelil Lesion Trige Study (ALTS). 41 Avilble HPV test results in our study were ordered most often s reflex HPV tests fter ASC Pp test results nd less commonly s routine cotests. Reflex HPV testing hs been common t MWH for mny yers, reflecting our center s prticiption s 1 of 4 clinicl tril sites in ALTS, which helped estblish reflex HPV testing of ASC-US Pp tests s stndrd US prctice. 42 In recent yers, the percentge of MWH clinicins ordering routine HPV cotesting in women 30 yers nd older hs been incresing. Routine cotesting hs been formlly dvocted by 2 of the uthors s n pproch judged most likely to minimize flse-negtive screening test results nd cervicl cncer dignoses in screened women. 43 Erlier dditionl HPV test results t more thn 4 months to 3 yers before the CIN 2/3 dignoses were lso vilble in 454 ptients; 83% (n ¼ 377) hd t lest one prior positive result, likely reflecting the current consensus tht persistent hrhpv infection is prerequisite for development of CIN 2/ On the other hnd, 24.2% (110 of 454) of ptients with erlier HPV test results hd t lest one negtive result. Some of these erlier negtive HPV results could reflect subsequent HPV infections cusing CIN 2/3 fter erlier negtive HPV results. In other ptients, however, fluctuting positive nd negtive HPV test results my reflect number of fctors: multiple HPV infections with clernce of erlier infections, filure to smple lesionl cells, unrecognized technicl testing problems, vrible host immunologic responses, nd chnges over time in the virl lod of developing cervicl neoplsis Ntionwide monitoring dt from Austrli reports fewer negtive HPV results (11%) concurrent with high-grde cervicl histology dignoses nd much more-frequent negtive HPV results (29%) when HPV tests precede high-grde histology findings by 24 to 30 months. 51 Kiser Permnente hs documented tht, in the setting of routine conventionl Pp test nd FDApproved HC2 HPV cotesting, 27 of 87 ptients (31%) who develop invsive cervicl cncers hd negtive bseline HPV test results within 5 yers of cncer dignoses. 52 In the UK, in the ARTISTIC tril, 3 of 12 women (25%) dignosed with invsive cervicl crcinom in the first round of screening during severl yers hd bseline, negtive HC2 hrhpv test results. 35 At MWH, negtive HC2 HPV test results were documented in 3 of 31 cervicl squmous cell crcinoms (9.7%) where HC2 hrhpv testing occurred in the previous 12 months; crcinogenic HPV DNA ws detected by polymerse chin rection in squmous cell crcinom tumor tissues of ll 3 ptients with erlier, negtive hrhc2 results. 53 Additionl studies re needed to better understnd fctors ssocited with negtive hrhpv DNA test results in women developing both histopthologic CIN 2/3 lesions nd invsive cervicl crcinoms. This study documents tht ptients with histopthologic CIN 2/3 dignoses hd recent, bnorml Pp results, with HSIL the most-common, recent, bnorml cytology result in 41.6% (862 of 2074) of ptients. This finding differs from Arch Pthol Lb Med Vol 137, July 2013 Ppnicolou nd HPV Tests for Women With CIN 2/3 Zho et l 945

5 lrge, conventionl test series in which ASC-US test results hve been the most-common, bnorml Pp result (36% 39%) preceding CIN 2/3 dignoses. 7,8 Among ptients cotested for hrhpv within 4 months of CIN 2/3 dignoses, 97% lso tested hrhpv þ. However, significntly few ptients with CIN 2/3 hd negtive Pp or negtive HPV test results over more-extended period of severl yers, consistent with recent onset of some CIN 2/3 lesions, s well s reflecting the chllenges inherent in detecting other developing, smll, inccessible, or nondignostic intrepithelil CIN 2/3 precursor lesions. 14 Becuse this ws retrospective rther thn prospective study, ptients my hve hd dditionl tests or procedures not reflected in the lbortory informtion system records or provided clinicl histories. References 1. Sigurdsson K, Hrfnkelsson J, Geirsson G, Gudmundsson J, Slvrsdóttir A. Screening s prognostic fctor in cervicl cncer: nlysis of survivl nd prognostic fctors bsed on Icelndic popultion dt, Gynecol Oncol. 1991;43(1): Gustfsson L, Pontén J, Zck M, Admi HO. Interntionl incidence rtes of invsive cervicl cncer fter introduction of cytologicl screening. Cncer Cuses Control. 1997;8(5): Wright T, Mssd S, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D consensus guidelines for the mngement of women with cervicl intrepithelil neoplsi or denocrcinom in situ. Am J Obstet Gynecol. 2007;197(4): Solomon D, Cstle PE. Findings from ALTS: impct on cytology screening, trige, nd ptient mngement. Pthol Cse Rev. 2005;10(3): Cstle PE, Stoler MH, Solomon D, Schiffmn M. The reltionship of community-dignosed cervicl intrepithelil neoplsi grde 2 to the qulity control pthology-reviewed dignoses. Am J Clin Pthol. 2007;127(5): Wright TC Jr, Mssd LS, Dunton CJ, et l consensus guidelines for the mngement of women with bnorml cervicl cncer screening tests. 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Americn Community Survey (ACS) Web site. Accessed Jnury 16, Austin RM, Onisko A, Druzdel M. The Pittsburgh cervicl cncer screening model: risk ssessment tool. Arch Pthol Lb Med. 2010;134(5): Austin RM, Zho C. Type 1 nd type 2 cervicl crcinoms: some cervicl crcinoms re more difficult to prevent with screening. Cytopthology 2012; 23(1):6 12. doi: /j x. 15. Zho C, Austin RM. Humn ppillomvirus DNA detection in ThinPrep Pp test vils is independent of cytologic smpling of the trnsformtion zone. Gynecol Oncol. 2007;107(2): Zho C, Austin RM. Adjunctive high-risk humn ppillomvirus DNA testing is useful option for disese risk ssessment in ptients with negtive Ppnicolou tests without n endocervicl/trnsformtion zone smple. Cncer. 2008;114(4): Zho C, Flore A, Onisko A, Austin RM. Histologic follow-up results in 662 ptients with Pp test findings of typicl glndulr cells: results from lrge cdemic womens hospitl lbortory employing sensitive screening methods. 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