Anal Cancer Incidence in the United States, : Distinct Patterns by Histology and Behavior

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1 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Rsarch Articl Anal Cancr Incidnc in th Unitd Stats, : Distinct Pattrns by Histology and Bhavior Mrdith S. Shils, Aim R. Krimr, Anna E. Coghill, Trsa M. Darragh 2, and Susan S. Dvsa Cancr Epidmiology, Biomarkrs & Prvntion Abstract Background: Although anal squamous cll carcinoma (SCC) and adnocarcinoma (ADC) ar gnrally combind in cancr survillanc, thir tiologis likly diffr. Hr, w dscrib dmographic charactristics and trnds in incidnc rats (IR) of anal cancr by histology (SCC, ADC) and bhavior (invasiv, in situ) in th Unitd Stats. Mthods: With data from th Survillanc, Epidmiology, and End Rsults (SEER) Program, w stimatd ag-adjustd anal cancr IRs across bhavior/histology by dmographic and tumor charactristics for Trnds in IRs and annual prcnt changs during wr also stimatd and compard with rctal cancr. Rsults: Womn had highr rats of SCC [rat ratio (RR),.45; 95% confidnc intrval (CI),.40.50] and lowr rats of ADC (RR, 0.68; 95% CI, ) and squamous carcinoma in situ (CIS; RR, 0.36; 95% CI, ) than mn. Blacks had lowr rats of SCC (RR, 0.82; 95% CI, ) and CIS (RR, 0.90; 95% CI, ) than non-hispanic whits, but highr rats of ADC (RR,.48; 95% CI,.29.70). Anal cancr IRs wr highr in mn and blacks agd <40 yars. During , SCC IRs incrasd 2.9%/yar, ADC IRs dclind nonsignificantly, and CIS IRs incrasd 4.2%/yar.SCCandADCIRpattrnsandtrndswrsimilar across anal and rctal cancrs. Conclusions: Rats of anal SCC and CIS hav incrasd strongly ovr tim, in contrast to rats of anal ADC, similar to trnds obsrvd for rctal SCC and ADC. Impact: Anal SCC and ADC likly hav diffrnt tiologis, but may hav similar tiologis to rctal SCC and ADC, rspctivly. Strong incrass in CIS IRs ovr tim may rflct anal cancr scrning pattrns. Cancr Epidmiol Biomarkrs Prv; 24(); Ó205 AACR. Introduction With only 7,270 cass stimatd to occur in th Unitd Stats during 205, anal cancr is a rlativly rar malignancy (). Howvr, anal cancr rats hav incrasd stadily for dcads in th Unitd Stats and intrnationally (2 5). Although th caus of ths rising rats is unclar, it has bn hypothsizd that changing sxual practics, lading to incrasd prvalnc of anal infction with carcinognic human papillomavirus (HPV), and an incrasing numbr of individuals living with HIV, a group known to hav lvatd anal cancr risk, hav contributdtothisincras(6). Th majority of anal cancrs ar squamous cll carcinomas (SCC), but adnocarcinomas (ADC) mak up 9% to 4% of diagnosd cass in th Unitd Stats, although ths proportions Division of Cancr Epidmiology and Gntics, National Cancr Institut, Rockvill, Maryland. 2 Dpartmnt of Pathology, Univrsity of California San Francisco, San Francisco, California. Not: Supplmntary data for this articl ar availabl at Cancr Epidmiology, Biomarkrs & Prvntion Onlin ( Corrsponding Author: Mrdith S. Shils, Division of Cancr Epidmiology and Gntics, National Cancr Institut, 9609 Mdical Cntr Driv, Room 6E-28 MSC 9767, Bthsda, MD Phon: ; Fax: ; shilsms@mail.nih.gov doi:.58/ epi Ó205 Amrican Association for Cancr Rsarch. may vary considrably intrnationally (6 9). Although SCC and ADC ar usually combind in cancr survillanc, thir tiologis may diffr. Ninty prcnt of anal SCCs ar causd by infction with oncognic typs of HPV, primarily HPV-6, whras HPV has bn dtctd in a smallr fraction of ADCs (8,, ). Bcaus of th rarity of anal ADC, littl is known about its tiology. Furthrmor, it may b difficult to dtrmin whthr th primary sit of som tumors is th lowr rctum or anus; SCCs and ADCs arising across ths two sits may hav shard tiologis and b pron to misclassification of thir primary location. In th currnt analysis, w usd data from th National Cancr Institut's (NCI) Survillanc, Epidmiology and End Rsults (SEER) Program to provid a dtaild dscription of th dmographic charactristics and tmporal trnds in incidnc rats (IR) of anal cancr by histology (i.., SCC and ADC) and bhavior (i.., invasiv vs. in situ) in th Unitd Stats. W also compar pattrns to rctal cancr to assss similaritis across ths two sits according to histology. Matrials and Mthods W usd data from SEER to assss rcnt IRs in th 8 rgistris with data for cass diagnosd during (i.., SEER 8, including approximatly 28% of th U.S. population; rf. 2), and to assss tmporal trnds in th rgistris that participatd in SEER 9 (977 20) and SEER 3 (992 20; rfs. 3, 4). 548 Cancr Epidmiol Biomarkrs Prv; 24() Octobr 205 Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

2 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Anal Cancr Incidnc in th Unitd Stats by Histology and Bhavior Microscopically confirmd anal cancrs wr ascrtaind using SEER sit rcod, basd on th Intrnational Classification of Disass for Oncology, 3rddn.(ICD-O-3;sitcod:C2.0 C2.2, C2.8, xcluding histology cods , 940, ; rf. 5). Anal cancrs wr classifid by sit (anal, not othrwis spcifid [NOS; C2.0]; anal canal [C2.], cloacognic zon [C2.2], and ovrlapping lsion of rctum, anus, and anal canal [C2.8]). Invasiv cass (i.., bhavior ¼ 3) wr furthr classifid by histology (SCC: , , ; ADC: , , , 83, 840, , ; mlanoma: , , ; and othr typs; basd on a modifid vrsion of rf. 6). In situ cass (i.., bhavior ¼ 2) wr rstrictd to SCCs ( , 808, , ) or carcinoma in situ (CIS), NOS (80), as ths wr likly SCCs. For comparison, rats for invasiv SCC and ADCs of th rctum (sit cod: C20.9) wr also calculatd to assss similaritis across sits. Statistical analysis Using data from SEER 8, w stimatd anal cancr IRs pr,000,000 prson-yars, ag-adjustd to th 2000 U.S. population across bhavior/histology by ag group (<30, 30 49, 50 59, 60 69, 70þ yars), rac/thnicity (non-hispanic whit, black, Hispanic whit, Asian/Pacific Islandr, Amrican Indian/Alaskan Nativ, and othr/unknown), cancr rgistry, and anatomic subsit. IRs for Amrican Indian/Alaskan Nativs wr rstrictd to Contract Halth Srvic Dlivry Aras (CHSDA). Rat ratios (RR) and 95% confidnc intrvals (CI) wr stimatd by sx (womn vs. mn) and rac/thnicity (blacks and Hispanic whits vs. non- Hispanic whits). Data from SEER 8 wr also usd to assss pattrns across ag groups by sx, rac/thnicity, and histology/ bhavior. Information on Hispanic thnicity is not availabl in SEER <992. Thrfor, trnds in ag-standardizd IRs of anal cancr ovr calndar tim (prsntd in 5-yar calndar priods) wr stimatd using SEER 9 for whits and blacks (977 99) and SEER 3 for non-hispanic whits, blacks, and Hispanic whits (992 20), stratifid by sx, rac/thnicity, and histology/ bhavior. Trnds for Asian/Pacific Islandrs and Amrican Indians/Alaska Nativs wr not shown du to scarcity of th data. For comparison, calndar trnds (977 20) wr also assssd for rctal cancrs, rstrictd to whits/non-hispanic whits, as th data in othr racial/thnic groups wr too spars for analysis. Annual prcnt changs (APC) in IRs during wr assssd with last squars rgrssion of th natural logarithm of th rat (7). IRs wr supprssd if basd on <6 cass. All analyss wr carrid out with SEER Stat 8..5 (8). Rsults During in th 8 SEER rgistris, a total of 6,4 cass of invasiv anal cancr wr diagnosd during 993,234,972 prson-yars of follow-up (IR ¼ 6.3/,000,000; Tabl ). Cass wr primarily SCC (n ¼ 3,274, 82.2%), followd by ADC (n ¼,992; 2.3%), and mlanoma (n ¼ 254;.6%). Thr wr 62 invasiv anal cancrs with othr/poorly spcifid histologis (3.8%). An additional 6,686 cass of anal squamous CIS wr diagnosd during th sam tim priod. W xcludd from analysis th 3 invasiv anal cancrs that wr not microscopically confirmd and th 3 anal CIS with non-scc or CIS, NOS histologis. Tabl prsnts IRs by bhavior/histology across catgoris of ag, sx, rac/thnicity, rgistry, and anal sit. IRs incrasd across ag groups for all invasiv cancrs. For squamous CIS, th highst IR occurrd among 40 to 49 yar-olds. Th IR for anal SCC was gratr among womn than among mn. In contrast, rats of both anal ADC and squamous CIS wr gratr in mn than in womn. Th SCC IR was highst among non-hispanic whits, whil th ADC IR was highst among blacks. Th IRs varid notably across rgistris. Th total invasiv anal cancr rat was highst among Alaska Nativs, but th small numbr of cass prcludd stimation of th typ-spcific rats. Th SCC IRs xcdd 5/million in Atlanta, San Francisco-Oakland, Kntucky, and Sattl and wr </million in Utah and Hawaii. Rats of anal CIS wr dramatically highr in San Francisco-Oakland (35.2/million), about thr tims th nxt highst rat of.9 in Sattl. Eighty-thr prcnt of SCC dvlopd in th anal canal or anus, NOS. In contrast, narly half of th ADCs had th primary sit dsignatd as ovrlapping lsion of th rctum, anus, and anal canal. Th diffrnt ag-spcific incidnc pattrns for SCC, ADC, and anal CIS ar shown in Fig.. Across rac/thnicitis, SCC IRs gnrally incrasd stply until ags 50 or 60 yars, and thn incrasd mor gradually at oldr ags, xcpt among black mals. Among non-hispanic whits and blacks, anal ADC IRs incrasd stadily with advancing ag, whil rats among Hispanic whits wr too spars to valuat. In contrast, squamous CIS IRs wr highst among 40- to 49-yar-old mn and 50- to 59-yar-old womn who wr non-hispanic whit or black. Among Hispanic whits, CIS rats dcrasd with ag among mn and incrasd among womn. Th IR for invasiv anal cancr was highr among womn compard with mn (ovrall RR,.29; 95% CI,.25.33) with th xcss particularly notabl among thos of ags 50 yars (RR,.32.53) and among cass arising in th cloacognic zon (RR, 2.29; 95% CI, ; Tabl 2). Thr wr a fw notabl xcptions, howvr, whr anal cancr IRs wr highr among mn; including <40 yar-olds (RR, 0.4 and 0.62) and blacks (RR, 0.84; 95% CI, ). Consistnt with data prsntd in Tabl, IRs of ADC (RR, 0.68; 95% CI, ) and squamous CIS (RR, 0.36; 95% CI, ) wr also highr in mn. Compard with non-hispanic whits, Hispanic whits (ovrall RR, 0.64; 95% CI, ) and Asian/Pacific Islandrs (ovrall RR, 0.27; 95% CI, ) had lowr rats of invasiv anal cancr across sxs, ag groups, primary sits, and histology, with th xcption of mlanoma (Tabl 3). Compard with non- Hispanic whits, blacks also had somwhat lowr rats of invasiv anal cancr ovrall (RR, 0.9; 95% CI, ), and lowr rats among womn (RR, 0.72; 95% CI, ) and 60þ yar-olds (RR, 0.72 and 0.80). Rats of anal cancr occurring in th anal canal (RR, 0.8; 95% CI, ) or cloacognic zon (RR, 0.62; 95% CI, ), and SCC (RR, 0.82; 95% CI, ) wr also lowr among blacks. In contrast, consistnt with Tabl 2, invasiv anal cancr rats wr highr among black mn ovrall (RR,.9; 95% CI,..28), and particularly among mn of ags <40 (RR, 4.56 and.73), and for ADCs (RR,.48; 95% CI,.29.70). During in th 3 SEER rgistris, invasiv anal cancr IRs incrasd 2.2%/yar ovrall (95% CI,.8 2.6) and among mn (95% CI,.6 2.8), and 2.3%/yar (95% CI,.9 2.8) among womn (Supplmntary Tabl S and Fig. 2). Th incrass wr limitd to SCC (ovrall APC, 2.9%; 95% CI, Cancr Epidmiol Biomarkrs Prv; 24() Octobr Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

3 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Shils t al. Tabl. Anal cancr IRs pr,000,000 by tumor and cas charactristics, SEER 8, a Invasiv anal cancrs All SCC ADC Mlanoma Othr b In situ N IR N IR N IR N IR N IR N IR Total 6, , , , Ag, y < , , , , , , , , , þ 4, , , Sx Fmal 9, , , Mal 6,4 4. 4,969.7, , Rac/thnicity c Non-Hispanic whit 2, , , , Black, , Hispanic whit,255.8, Asian/Pacific Islandr Amrican Indian/Alaskan nativ d Rgistry Alaska Nativs Atlanta San Francisco-Oakland, , Kntucky, Sattl (Pugt Sound), California xcluding SF/SJM/LA 3, , , Los Angls, , , Louisiana Gratr Gorgia, Dtroit (Mtropolitan) Nw Jrsy,7 5., Iowa Rural Gorgia Conncticut San Jos-Montry Nw Mxico Utah Hawaii Anal sit C2.0-Anus, NOS 6, , , C2.-Anal canal 6, , , C2.2-Cloacognic zon C2.8-Ovrlapping lsion of rctum, anus, and anal canal 2,83 2.9, a IR pr,000,000, ag-adjustd to th 2000 U.S. population standard, rstrictd to microscopically confirmd cass. b 333 of othr invasiv anal cancrs had othr spcifid histologic typs and 288 of othr invasiv anal cancrs had poorly/unspcifid histologic typs. c Excluds 35 cass with othr or unknown rac. d Rstrictd to CHSDA. IRs supprssd bcaus of cas counts <6, cas counts supprssd whn ), with significant incrass among non-hispanic whit and black mn and womn, and nonsignificant incrass among Hispanic whits. Among non-hispanic whits, APCs for SCC incrasd for both mn and womn across ag groups with th xcption of 0 to 39 yar-olds (Supplmntary Fig. S). Of not, SCC IRs hav bn consistntly highr among womn compard with mn ovr tim among non-hispanic and Hispanic whits; howvr, rats hav bn highr among black mn compard with black womn sinc Sinc 992, ADC IRs hav bn stabl among mn (APC, 0.6; 95% CI,.9 0.8) and dclind among womn (APC,.8; 95% CI, ). Squamous CIS IRs incrasd 4.2%/yar ovrall (95% CI, ), with mor rapid incrass among mn (APC, 5.5%; 95% CI, ) than womn (APC,.%; 95% CI, 8.7.6); ths pattrns ar apparnt in ach racial/thnic group. Whn th San Francisco- Oakland rgistry was xcludd (i.., th rgistry with th highst rats of squamous CIS), a stp inclin in rats rmaind (APCs: ovrall, 3.4%; 95% CI, %; mn: 5.2%, 95% CI, %; womn: 9.3%, 95% CI, 7.7.0%). Bcaus of th juxtaposition of th anus and rctum and th potntial for misclassification of sit of origin, w additionally xamind trnds in rctal cancr IRs by histology among whits/ non-hispanic whits during (Fig. 3). Th trnds ovr tim wr quit similar for rctal and anal SCCs and, to a lssr xtnt, for rctal and anal ADCs. Lik anal cancr, rctal SCC IRs hav bn consistntly highr among womn, and rctal ADC IRs hav bn consistntly highr among mn. During , similar to th anal cancr APCs, among womn, rctal SCC IRs incrasd 3.9%/yar (95% CI, ) and ADC IRs dclind.3%/yar (95% CI,.8, 0.9). In contrast to th significant incras in anal SCC IRs and stabl anal ADC IRs among mn, rctal SCC IRs hav bn rlativly stabl sinc 992 (APC, 0.3; 550 Cancr Epidmiol Biomarkrs Prv; 24() Octobr 205 Cancr Epidmiology, Biomarkrs & Prvntion Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

4 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Anal Cancr Incidnc in th Unitd Stats by Histology and Bhavior All invasiv Squamous cll carcinoma Adnocarcinoma In situ Non-Hispanic whits Incidnc rats pr,000, Figur. Anal cancr IRs across ag groups by sx, rac, histology, and bhavior using data from SEER 8, All rats wr ag-standardizd within ag groups to th 2000 U.S. population and rstrictd to microscopically confirmd cass. Solid triangls indicat rats among womn and opn triangls indicat rats among mn. All points with <6 cass ar xcludd. Blacks Incidnc rats pr,000, Hispanic whits Incidnc rats pr,000,000 Ag groups, yars Ag groups, yars Ag groups, yars Ag groups, yars Fmals Mals 95% CI,.7 2.4), and ADC IRs significantly dclind (APC,.4; 95% CI,.9 to 0.8). Whn rctal and anal cancrs wr combind, during , ADC rats wr 98.3/,000,000 among mn and 56.7/,000,000 among womn, whil SCC rats wr 3.6/,000,000 among mn and 2.3/,000,000 among womn. Discussion Using population-basd data from th SEER program, w hav shown that th dmographic charactristics and tmporal trnds in anal cancr IRs diffr dramatically by histologic typ. SCCs ar mor common among womn and occur at youngr ags than ADCs. Cancr Epidmiol Biomarkrs Prv; 24() Octobr Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

5 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Shils t al. Tabl 2. RRs for anal cancr, comparing fmals with mals, SEER Fmal Mal N IR N IR RR (95% CI) All invasiv 9, , (.25.33) Ag, y <30 5 a ( ) ( ) 40 49, , (0.97.2) , , (.44.62) , , (.32.52) 70þ 3, (.25.4) Rac/thnicity Non-Hispanic whit 7, , (.34.44) Black ( ) Hispanic whit (.22.57) Asian/Pacific Islandr ( ) Amrican Indian/Alaskan Nativ ( ) Anal sit C2.0-Anus, NOS 3, , (.09.2) C2.-Anal canal 4, , (.3.45) C2.2-Cloacognic zon ( ) C2.8-Ovrlapping lsion of rctum, anus, and anal canal, , (.4.33) Histology SCC 8, , (.40.50) ADC 927.7, ( ) Mlanoma ( ) Othr (0.85.7) All in situ, , ( ) NOTE: IR pr,000,000, ag-adjustd to th 2000 U.S. population standard. Statistically significant associations ar prsntd in bold. RRs compar fmal with mal rats. Rstrictd to microscopically confirmd cass. a IRs supprssd bcaus of cas counts <6. Furthrmor, during , anal SCC IRs incrasd significantly, whras ADC IRs dclind, at last among womn. In addition, anal squamous CIS IRs incrasd stply ovr tim, with rats highst among mn and in th San Francisco-Oakland rgistry. Eighty-two prcnt of all anal cancrs in th Unitd Stats ar SCCs, though ADCs may compris a largr fraction of cass in som countris (9). Anal SCCs ar largly causd by infction with oncognic HPV, primarily HPV-6 (,, 9). In Tabl 3. RRs for anal cancr by rac/thnicity, compard with non-hispanic whits, SEER NHW Black Hispanic whit Asian/Pacific Islandr N IR N IR RR (95%CI) N IR RR (95%CI) N IR RR (95%CI) All invasiv 2, , ( ), ( ) ( ) Sx Fmal 7, ( ) ( ) ( ) Mal 4, (..28) ( ) ( ) Ag, y < ( ) 7 a a a a a (.4 2.) ( ) 9 a a , (0.93.5) ( ) (3 0.22) , ( ) ( ) (9 0.28) , ( ) ( ) ( ) 70þ 4, ( ) ( ) ( ) Anal sit C2.0-Anus, NOS 4, (0.9.07) ( ) (5 0.23) C2.-Anal canal 5, ( ) ( ) ( ) C2.2-Cloacognic zon ( ) (0.63.) (4 0.42) C2.8-Ovrlapping lsion 2, (0.92.8) ( ) ( ) of rctum, anus, and anal canal Histology SCC, , ( ), ( ) (6 0.20) ADC, (.29.70) ( ) ( ) Mlanoma a a (.6 2.5) ( ) Othr (0.97.6) ( ) ( ) All in situ 4, ( ) ( ) (8 0.25) NOTE: IR pr,000,000, ag-adjustd to th 2000 US population standard; RR compard with NHW; statistically significant associations ar prsntd in bold. Abbrviation: NHW, non-hispanic whits. a IRs and RRs supprssd bcaus of cas counts <6, cas counts supprssd whn 5. Rstrictd to microscopically confirmd cass. 552 Cancr Epidmiol Biomarkrs Prv; 24() Octobr 205 Cancr Epidmiology, Biomarkrs & Prvntion Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

6 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Anal Cancr Incidnc in th Unitd Stats by Histology and Bhavior All invasiv Squamous cll carcinoma Adnocarcinoma In situ Whits/non-Hispanic whits Incidnc rats pr,000, Figur 2. Ag-adjustd anal cancr IRs across calndar yars by sx, rac, histology, and bhavior using data from SEER 3, and SEER 9, All rats wr ag-standardizd to th 2000 U.S. population and rstrictd to microscopically confirmd cass. Rats for whits and blacks ar prsntd using data from SEER 9 during , and rats for non-hispanic whits, blacks, and Hispanic whits ar prsntd using data from SEER 3, Solid triangls indicat rats among womn and opn triangls indicat rats among mn. Rats basd on <6 cass ar xcludd. Blacks Incidnc rats pr,000, Hispanic whits Incidnc rats pr,000,000 *Data for Hispanics wr too spars to prsnt trnds Yar of diagnosis Yar of diagnosis Yar of diagnosis Yar of diagnosis Fmals Mals contrast, thr ar vry limitd data on th caus of anal ADC. In a mta-analysis, basd on only svn anal ADCs, thr wr positiv for HPV infction (). Many of th risk factors that hav bn dscribd for anal cancr rflct infction with or prsistnc of anal HPV infction, including liftim numbr of sxual partnrs, rcptiv anal intrcours, and HIV infction (8,20).GivnthprdominancofSCCsamonganalcancrs, ths risk factors likly rflct th causal association btwn HPV infction and anal SCC. In contrast to SCC, littl is known about risk factors for anal ADC. Dscriptivly, anal ADC diffrs from SCC in cas dmographics and tmporal trnds, with highr rats among mals, stp incrass in rats with ag and stabl or dclining rats ovr tim, providing vidnc that ADC is tiologically distinct from SCC. Cancr Epidmiol Biomarkrs Prv; 24() Octobr Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

7 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Shils t al. A Whits/non-Hispanic whits Incidnc rats pr,000,000 Squamous cll carcinoma, Yar of diagnosis Fmal Mal Anal Anal SCC IRs ar highr among womn than mn, and consistntly lowr among Hispanic whits and Asian/Pacific Islandrs than among non-hispanic whits. Ths diffrncs ar likly drivn by a highr prvalnc of anal infction with carcinognic HPV among womn and non-hispanic whits. Compard with mn, womn ar mor likly to ngag in anal rcptiv intrcours, which is known to b associatd with anal HPV infction (2). In addition, transmission of crvical HPV infction to th anus may occur indpndnt of anal intrcours, as thos with crvical HPV infction hav thr tims th risk of anal HPV infction (22). Although not stablishd in th litratur, it is possibl that Hispanics and Asian/ Pacific Islandrs may also hav a lowr rat of anal HPV infction than non-hispanic whits. In th Hawaii Multithnic Cohort Study, anal and crvical HPV infctions (ithr dtctd singularly or with infction at both anatomic sits) tndd to b mor common among Caucasian womn compard with womn who wr Japans, Hawaiian, or Filipino (22). Incrasing rats ovr tim across sxs and rac/thnicitis ar likly drivn by changs in sxual bhavior and ar consistnt with th ris of othr HPV-associatd cancrs (23). B,000 0 Adnocarcinoma 77 8 Yar of diagnosis Rctal Figur 3. Ag-adjustd invasiv IRs among whits/non-hispanic whits by sx for anal and rctal SCC (A) and anal and rctal ADC (B). Primary sits wr dfind by Intrnational Classification of Disass for Oncology, 3rd dn. (ICD-O-3; anal cancr: C2.0 C2.2, C2.8 and rctal cancr: C20.9). All rats wr ag-standardizd to th 2000 U.S. population and rstrictd to microscopically confirmd cass. Rats ar prsntd using data for whits from SEER 9 during and for non-hispanic whits from SEER 3 during Triangls (solid for womn, opn for mn) indicat rats of anal cancr and circls (solid for womn, opn for mn) indicat rats of rctal cancr. 07 Unlik non-hispanic whits, anal SCC IRs hav bn highr in black mn than black womn in rcnt yars. In addition, among thos <40 yars old, IRs ar highr in mn than womn, particularly among young, black mn. Ths pattrns ar consistnt with th impact of HIV on anal cancr rats. HIV-infctd individuals hav a 30-fold incrasd risk of anal cancr compard with th gnral population, du to an lvatd prvalnc of anal intrcours among mn who hav sx with mn and othr sxual bhaviors lading to incrasd HPV acquisition and a rol of immunosupprssion (24, 25). Approximatly 28% of mal and % of fmal anal cancrs in th Unitd Stats occur among popl with HIV (6). Th HIV prvalnc is particularly high (84%) among anal cancr cass occurring in young, black mn (6). In addition, HIV-infctd anal cancr cass hav contributd strongly to th rising anal cancr rats in mn but not womn (6). Th HIV status of anal cancr cass is not collctd by SEER; thus, w could not addrss HIV dirctly in th currnt analysis. Although anal SCC and ADC diffr from ach othr, thy rsmbl rctal SCC and ADC, rspctivly, particularly among womn. For xampl, both rctal and anal SCCs ar mor common among womn, and th rats among womn hav incrasd for both sits ovr tim. Similarly, both rctal and anal ADCs ar mor common in mn, and rats for both malignancis hav dclind significantly ovr tim among womn. Ths similaritis within histologic typs could hav multipl xplanations, including distinct malignancis arising in th anus and th rctum with similar tiologis and difficultis dtrmining th primary sit. Although rar, rctal SCC and anal ADC may b distinct cancrs that shar tiologic risk factors with anal SCC and rctal ADC, rspctivly. Thr hav bn cas rports of HPV dtctd in rctal SCC tumors (26, 27), and on small study found 77% of rctal SCCs to b HPV positiv (8). Anothr study showd an incrasd risk of rctal SCC in HIV-infctd individuals, similar to what is obsrvd for anal SCC (28), implicating a potntial rol of HPV in th dvlopmnt of rctal SCC. In addition, thr is limitd vidnc that Crohn's disas and chronic inflammation may b associatd with anal ADC risk, similar to colorctal cancr (29). Givn th juxtapostion of th anus and th rctum, it is also likly that som tumors arising in th anus or th lowr part of th rctum would ovrlap ths two anatomic sits. Thrfor, anal SCCs may b misclassifid as rctal SCCs and th rarr primary anal ADCs may b misclassifid rctal ADCs. For xampl, as narly half of th ADCs had th primary sit dsignatd as ovrlapping lsion of th rctum, anus, and anal canal, it is possibl that many anal ADCs actually aros in th rctum. Th anal canal is slightly shortr in womn than mn, prhaps lading to a gratr dgr of misclassification consistnt with th data in this study (30). Th anal squamous CIS IRs incrasd dramatically during across sxs and racial groups and wr highst in middl ag, likly rflcting th uptak of anal cancr scrning in crtain gographic aras. Th consistncy across racial/thnic groups suggsts a lack of racial/thnic disparitis in anal cancr scrning, and th highr rats among mn than womn likly rflct incrasd anal cancr scrning, particularly among mn who hav sx with mn. Svral organizations now rcommnd anal cancr scrning for HIV-infctd individuals (3). Notably, th anal squamous CIS IR in San Francisco is thr to 7 tims highr than othr rgistry aras, likly du to th stablishmnt of 554 Cancr Epidmiol Biomarkrs Prv; 24() Octobr 205 Cancr Epidmiology, Biomarkrs & Prvntion Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

8 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Anal Cancr Incidnc in th Unitd Stats by Histology and Bhavior an anal noplasia clinic at th Univrsity of California San Francisco in 990 (32). It is unclar whthr anal cancr scrning and subsqunt tratmnt prvnts th dvlopmnt of anal cancr; howvr, th Anal Cancr/HSIL Outcoms Rsarch (ANCHOR) Study (NIH clinical trials idntification numbr: NCT023549), has bn undrtakn to dirctly assss th bnfits of trating prcancrous anal lsions. Givn th rapid incras in anal SCC rats ovr tim, thr is an urgnt nd for prvntion and arly dtction stratgis, particularly in high-risk populations. Although HPV vaccination has bn shown to protct against anal HPV infction (33, 34), uptak rmains suboptimal among adolscnts, with only 57% of fmals and 35% of mals rciving at last on dos in 203 (35). Furthrmor, th rduction of anal cancr du to vaccination will not b sn for dcads. Th us of high-quality, population-basd SEER cancr rgistry data is th main strngth of this analysis. W provid a dtaild analysis of rats and trnds by primary sit, histology and bhavior, and, for th first tim, provid comparisons btwn anal and rctal cancr rats by histology. W sparat Hispanic whits from non-hispanic whits during , which is important as th fraction of whits who wr of Hispanic thnicity in SEER 3 incrasd from 2% in to 28% in In addition, du to th xpansion of th SEER Program ovr tim, w usd data from both SEER 9 and 3 to assss tmporal trnds. Although rats wr similar in SEER 9 and 3 (Supplmntary Fig. S2), changs in IRs btwn and rflct small changs attributabl to th inclusions of additional rgistris with somwhat diffrnt population compositions, in addition to changs du to th sparation of Hispanic whits and non-hispanic whits. During , total invasiv anal cancr rats among whits wr.8/million in SEER 9 and 2.3/million in SEER 3, whr rats wr highr among non-hispanic whits (2.7/million) compard with Hispanic whits (9.4/million). Rats among blacks wr also similar in SEER 9 (4.2/million) and SEER 3 (4.5/million). Th main limitation of this analysis is th lack of dirct information on HPV or HIV infction and anal cancr scrning, important factors that hav likly influncd tmporal trnds. Furthrmor, although anal squamous CIS is rportabl to SEER rgistris, bcaus it is primarily dtctd via scrning, it is possibl that it is not compltly ascrtaind. Thus, rats of CIS may b undrstimatd and should b intrprtd with caution. Only in San Francisco was th CIS rat highr than th invasiv SCC rat, rflcting activ scrning programs in San Francisco, which ar not as prominnt in othr rgistry aras. In an analysis of svral dcads of U.S. data on anal cancr, w hav shown that anal SCC rats hav incrasd rapidly ovr tim. Importantly, w hav highlightd th diffrncs in anal SCC and ADC, which likly hav diffrnt tiologis, and rval th importanc of analyzing ths histologic typs sparatly. Furthrmor, w hav shown th similarity of rctal SCC to anal SCC, which may call for th rclassification of anal and rctal cancr tumors basd on thir histologis. Finally, w hav shown dramatic incrass in th dtction of anal squamous CIS, prsumably rflcting anal cancr scrning in crtain gographic locations in th Unitd Stats. Disclosur of Potntial Conflicts of Intrst T.M. Darragh has rcivd spakrs burau honoraria from Roch and Vntana Roch, is a consultant/advisory board mmbr for ThVax, and has providd xprt tstimony for Hologic. No potntial conflicts of intrst wr disclosd by th othr authors. Authors' Contributions Concption and dsign: M.S. Shils, A.R. Krimr, S.S. Dvsa Dvlopmnt of mthodology: M.S. Shils, T.M. Darragh, S.S. Dvsa Analysis and intrprtation of data (.g., statistical analysis, biostatistics, computational analysis): M.S. Shils, A.R. Krimr, A.E. Coghill, T.M. Darragh, S.S. Dvsa Writing, rviw, and/or rvision of th manuscript: M.S. Shils, A.R. Krimr, A.E. Coghill, T.M. Darragh, S.S. Dvsa Study suprvision: S.S. Dvsa Grant Support This study was supportd by th Intramural Rsarch Program of th National Cancr Institut (to M.S. Shils, A.R. Krimr, A.E. Coghill, and S.S. Dvsa). Th costs of publication of this articl wr dfrayd in part by th paymnt of pag chargs. This articl must thrfor b hrby markd advrtismnt in accordanc with 8 U.S.C. Sction 734 solly to indicat this fact. Rcivd January 6, 205; rvisd Jun 23, 205; accptd July 2, 205; publishd OnlinFirst July 29, 205. Rfrncs. Amrican Cancr Socity. Cancr facts and figurs, 205. Atlanta, GA: Amrican Cancr Socity; Frisch M, Mlby M, Mollr H. Trnds in incidnc of anal cancr in Dnmark. BMJ (Clinical rsarch d) 993;306: Johnson LG, Madlin MM, Nwcomr LM, Schwartz SM, Daling JR. Anal cancr incidnc and survival: th survillanc, pidmiology, and nd rsults xprinc, Cancr 2004; : Nilsn A, Munk C, Kjar SK. Trnds in incidnc of anal cancr and highgrad anal intrapithlial noplasia in Dnmark, Int J Cancr 202;30: Nlson RA, Lvin AM, Brnstin L, Smith DD, Lai LL. Changing pattrns of anal canal carcinoma in th Unitd Stats. J Clin Oncol 203;3: Shils MS, Pfiffr RM, Chaturvdi AK, Krimr AR, Engls EA. Impact of th HIV pidmic on th incidnc rats of anal cancr in th Unitd Stats. J Natl Cancr Inst 202;4: Josph DA, Millr JW, Wu X, Chn VW, Morris CR, Goodman MT, t al. Undrstanding th burdn of human papillomavirus-associatd anal cancrs in th US. Cancr 2008;3: Daling JR, Madlin MM, Johnson LG, Schwartz SM, Shra KA, Wurschr MA, t al. Human papillomavirus, smoking, and sxual practics in th tiology of anal cancr. Cancr 2004;: Frisch M, Mlby M. Anal Cancr. In:Schottnfld D, Fraumni JF Jr, ditors. Cancr pidmiology and prvntion. 3rd d. Nw York, NY: Oxford Univrsity Prss; p Hoots BE, Palfsky JM, Pimnta JM, Smith JS. Human papillomavirus typ distribution in anal cancr and anal intrapithlial lsions. Int J Cancr 2009;24: Almany L, Saunir M, Alvarado-Cabrro I, Quiros B, Salmron J, Shin HR, t al. Human papillomavirus DNA prvalnc and typ distribution in anal carcinomas worldwid. Int J Cancr 205;36: Survillanc, Epidmiology, and End Rsults (SEER) Program ( cancr.gov): SEER Stat Databas: Incidnc SEER 8 Rgs Rsarch Data þ Hurrican Katrina Impactd Louisiana Cass, Nov 203 Sub ( ) <Katrina/Rita Population Adjustmnt> Linkd To County Attributs Total U.S., Countis. National Cancr Institut, DCCPS, Survillanc Rsarch Program, Survillanc Systms Branch; Cancr Epidmiol Biomarkrs Prv; 24() Octobr Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

9 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Shils t al. 3. Survillanc, Epidmiology, and End Rsults (SEER) Program ( cancr.gov): SEER Stat Databas: Incidnc SEER 3 Rgs Rsarch Data, Nov 203 Sub (992-20) <Katrina/Rita Population Adjustmnt> Linkd To County Attributs Total U.S., Countis. National Cancr Institut, DCCPS, Survillanc Rsarch Program, Survillanc Systms Branch; Survillanc, Epidmiology, and End Rsults (SEER) Program ( cancr.gov): SEER Stat Databas: Incidnc SEER 9 Rgs Rsarch Data, Nov 203 Sub (973-20) <Katrina/Rita Population Adjustmnt> Linkd To County Attributs Total U.S., Countis. National Cancr Institut, DCCPS, Survillanc Rsarch Program, Survillanc Systms Branch; World Halth Organization. Intrnational classification of disass for oncology. 3rd d. Gnva: World Halth Organization; Egvad L, Hanu M, Brny D, Flming K, Frlay J. Chaptr 4: Histological groups. In:Curado MP, Edwards B, Shin HR, t al. ditors. Cancr incidnc in fiv continnts, Vol. IX. IX d. Lyon, Franc: IARC Scintific Publications; 204. p Kim HJ, Fay MP, Fur EJ, Midthun DN. Prmutation tst for joinpoint rgrssion with applications to cancr rats. Stat Md 2000;9: Survillanc Rsarch Program, National Cancr Institut SEER Stat softwar (sr.cancr.gov/srstat) vrsion DVuyst H, Clifford GM, Nascimnto MC, Madlin MM, Francschi S. Prvalnc and typ distribution of human papillomavirus in carcinoma and intrapithlial noplasia of th vulva, vagina and anus: a mtaanalysis. Int J Cancr 2009;24: Chaturvdi AK, Madlin MM, Biggar RJ, Engls EA. Risk of human papillomavirus-associatd cancrs among prsons with AIDS. J Natl Cancr Inst 2009;: Hrbnick D, RcM, Schick V, Sandrs SA, Dodg B, Fortnbrry JD. Sxual bhavior in th Unitd Stats: rsults from a national probability sampl of mn and womn ags J Sx Md 20;7(Suppl 5): Hrnandz BY, McDuffi K, Zhu X, Wilkns LR, Killn J, Kssl B, t al. Anal human papillomavirus infction in womn and its rlationship with crvical infction. Cancr Epidmiol Biomarkrs Prv 2005;4: Kurdglashvili G, Dors GM, Srour SA, Chaturvdi AK, Huyck MM, Dvsa SS. Incidnc of potntially human papillomavirus rlatd noplasms in th Unitd Stats, 978 to Cancr 203;9: Robbins HA, Shils MS, Pfiffr RM, Engls EA. Epidmiologic contributions to rcnt cancr trnds among HIV-infctd popl in th Unitd Stats. AIDS 204;28: Silvrbrg MJ, Lau B, Justic AC, Engls E, Gill MJ, Godrt JJ, t al. Risk of anal cancr in HIV-infctd and HIV-uninfctd individuals in North Amrica. Clin Infct Dis 202;54: Matsuda A, Takahashi K, Yamaguchi T, Matsumoto H, Miyamoto H, Kawakami M, t al. HPV infction in an HIV-positiv patint with primary squamous cll carcinoma of rctum. Int J Clin Oncol 2009;4: Dzltovic I, Pasha S, Lighton JA. Human papillomavirus-rlatd rctal squamous cll carcinoma in a patint with ulcrativ colitis diagnosd on narrow-band imaging. Clin Gastrontrol Hpatol 20;8: Coghill AE, Shils MS, Rycroft R, Engls EA. Excss risk of rctal squamous cll carcinoma in HIV-infctd prsons. AIDS 205. In prss. 29. Anwar S, Wlbourn H, Hill J, Sbag-MontfiorD. Adnocarcinomaofth anal canal a systmatic rviw. Colorctal Dis 203;5: Nivatvongs S, Strn HS, Fryd DS. Th lngth of th anal canal. Dis Colon Rctum 98;24: Wlls JS, Holstad MM, Thomas T, Brunr DW. An intgrativ rviw of guidlins for anal cancr scrning in HIV-infctd prsons. AIDS Patint Car STDS 204;28: Simard EP, Watson M, Saraiya M, Clark CA, Palfsky JM, Jmal A. Trnds in th occurrnc of high-grad anal intrapithlial noplasia in San Francisco: Cancr 203;9: Krimr AR, Gonzalz P, Katki HA, Porras C, Schiffman M, Rodriguz AC, t al. Efficacy of a bivalnt HPV 6/8 vaccin against anal HPV 6/8 infction among young womn: a nstd analysis within th Costa Rica Vaccin Trial. Lanct Oncol 20;2: Palfsky JM, Giuliano AR, Goldston S, Morira ED Jr, Aranda C, Jssn H, t al. HPV vaccin against anal HPV infction and anal intrapithlial noplasia. N Engl J Md 20;365: Elam-Evans LD, Yanky D, Jyarajah J, Singlton JA, Curtis RC, MacNil J, t al. National, rgional, stat, and slctd local ara vaccination covrag among adolscnts agd 3-7 yars Unitd Stats, 203. MMWR Morb Mortal Wkly Rp 204;63: Cancr Epidmiol Biomarkrs Prv; 24() Octobr 205 Cancr Epidmiology, Biomarkrs & Prvntion Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.

10 Publishd OnlinFirst July 29, 205; DOI:.58/ EPI Anal Cancr Incidnc in th Unitd Stats, : Distinct Pattrns by Histology and Bhavior Mrdith S. Shils, Aimé R. Krimr, Anna E. Coghill, t al. Cancr Epidmiol Biomarkrs Prv 205;24: Publishd OnlinFirst July 29, 205. Updatd vrsion Supplmntary Matrial Accss th most rcnt vrsion of this articl at: doi:.58/ epi Accss th most rcnt supplmntal matrial at: Citd articls Citing articls This articl cits 26 articls, 3 of which you can accss for fr at: This articl has bn citd by HighWir-hostd articls. Accss th articls at: alrts Sign up to rciv fr mail-alrts rlatd to this articl or journal. Rprints and Subscriptions Prmissions To ordr rprints of this articl or to subscrib to th journal, contact th AACR Publications Dpartmnt at pubs@aacr.org. To rqust prmission to r-us all or part of this articl, us this link Click on "Rqust Prmissions" which will tak you to th Copyright Claranc Cntr's (CCC) Rightslink sit. Downloadd from cbp.aacrjournals.org on April 27, Amrican Association for Cancr Rsarch.