Pregnancy related cancer in Apulia. A population based linkage study.

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Pregnancy

cancer

in

Apulia.

A

population

based

linkage

study

Ferdinando

Murgia

*

,

Marco

Marinaccio,

Gennaro

Cormio,

Vera

Loizzi,

Rossana

Cicinelli,

Stefano

Bettocchi,

Ettore

Cicinelli

2ndUnitofObstetricsandGynecology,DepartmentofBiomedicalandHumanOncologicalScience(DIMO),UniversityofBari,70124,Bari,Italy

ARTICLE INFO Articlehistory:

Received14December2018

Receivedinrevisedform25March2019 Accepted16April2019

Availableonline12May2019 Keywords:

Pregnancyassociatedcancer Gynecologiconcology Obstetrics

Rarediseases Epidemiology

ABSTRACT

Objective:Despiteaquite largenumberofpapersinliterature,thecurrentincidence ofpregnancy

associated cancer still remainsuncertain. Moreover, differentinclusion criteria and timeintervals

consideredafterdeliverymakethesedatapoorlycomparable.Theaimofthisstudywastoinvestigatethe

incidence ofPACsinApulia,anItalianregion,whilestressingdifferencesorsimilaritieswithother

populations.

Studydesign:Wecollected682,173pregnanciesfromnationaldischargeforms,regardinghospitalsin

ApuliafromJanuary2003toDecember2015.OuraimwasnotonlytoobtaintherawincidenceofPACs

butalsotoestimatetheoddsratio(OR)forsomepotentialriskpredictorssuchascalendaryear,age,

nationalityandpregnancyoutcomeusingalogisticmodel.Womenweresortedintodifferentgroupsby

age(<30,30–34,35–39,>=40)andbynationality(Italianorforeignnationals).Eachpregnancyhadtwo

possibleoutcomes:deliveryorabortion.

Results:We achievedaﬁnalcohortof867PACs:therefore,therawincidenceis 127.1per100,000

pregnancies.Breastcancerwasthemostcommoncancer(37.7casesper100,000pregnancies)andasa

typicalfeatureinourpopulationthyroidcancersfolloweditbyincidence(22.3per100,000pregnancies).

Cervicalcanceris,asexpected,theﬁrstgynaecologicalcancerbyincidence(3.8per100,000).Younger

womenhavethelowestriskforPACs(64.5per100,000,OR=1)whilethehighestriskforPACswasfor

womenaged>=40years(OR=4.29,p<0.05).Consideringcalendaryears,weobservedanincreasedOR

from2006to2009(OR=1.39andOR=1.41respectively)withoutspottingatrendthroughoutthewhole

decade.

Conclusions: The ranking of each tumour by incidence more or less reﬂects its demographics in

reproductiveagefemalesinwesterncountriesandtheincidenceforanycancerisexpectedtogrowasthe

rateofﬁrstdeliveriesinolderwomencontinuestorise.Wereportednoticeabledifferencesregardingthe

incidenceofsomecancers(suchasthyroidcancer)withpreviousliterature,reﬂectinganepidemiologic

featureofourcohort.Womenolderthan40yearshaveamorethanfourfoldriskforoncologicdiagnosis

duringpregnancy,andthisﬁndingisofpivotalclinicalandsocialimportancebecauseofthetendencyof

womenlivingindevelopedcountriestopostponechildbearing.

license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Pregnancyassociatedcancer(PAC),althoughfairlyuncommon, raisespuzzlingethical, social, familialand religiousissues. This situationalso affects patients' physicaland psychosocial health whilethreateningfoetalintegrity[1].

Theincidenceofcancerduringorimmediatelyafterpregnancy hasgenerallybeenreportedtorangebetween0.09and0.14%[2–8]. However,despiteaquitelargenumberofpapersinliterature,the currentincidenceofPACsstillremainsuncertain.Indeed,available

data are poorly comparable due to different inclusion criteria (invasiveandnoninvasivedisease),incoherenttimeintervals(12 or 18 months) after delivery and ﬁnally dissimilar population references.Moreover,theincidenceofdifferenttypesofcancerin womenshowsawidevariationworldwidewithmanygeneticand epigenetic inﬂuences. This implies that data from a certain geographicalareacannotbegeneralizedand asamatteroffact arenearlyuselessforpublichealthpurposesincancerscreening policies.

In 2017,Parazzini etal.reportedtheincidenceof pregnancy associatedcancers(PACs)inLombardy(aregioninnorthernItaly), basedondatafromregionalhospitaldischargeformsfrom2001to 2012. Their studyshowed that the risk of PACs was 122.9 per 100,000pregnancieswiththemostcommoncancersbeingbreast, * Correspondingauthor.

E-mailaddress:ferdinandomurgia89@gmail.com(F.Murgia).

http://dx.doi.org/10.1016/j.eurox.2019.100025

EuropeanJournalofObstetrics&GynecologyandReproductiveBiology:X3(2019)100025

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology:

X

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thyroidandbloodcancers.Furthermore,theincidenceincreased signiﬁcantlywithagebutitdidnotshowanyincreaseovertimein theconsidereddecade[3].

Theaimofthepresentstudywastoinvestigatetheincidenceof pregnancy related cancers in Apulia, a region with 4 million inhabitantsinthesouthernItalianpeninsulafrom2003to2015, andtocomparetheApuliandatawiththosereportedfromother geographicalareas.

Materialsandmethods

We evaluated data from the National electronic database containingallthehospitaldischargeforms,inItalian“Schedadi DimissioneOspedaliera(SDO)”regardinghospitalsinApuliafrom January 2003 to December 2015. In each SDO the patient is identifiedbyanationwideuniquereferenceanonymouscodeand aseriesofclinicalinformationisreported.Moreprecisely,each SDOcontainspersonalanddemographicdata(e.g.dateofbirth, nationality, qualification, job), patients’ main complaint, a comprehensiveprovisionofmedicalservicesduring hospitaliza-tion,historyofthepresentillness,remotepathological anamne-sis,reviewofsystemswithprincipalvitalparameters,regularand acutemedications,allergies,dischargedates.Themaindiagnosis and5secondarydiagnosesare codedaccording tothe Interna-tionalClassificationofDisease,NinthRevision(ICD-9)whileupto 5 interventionsand hospitalization- relatedcosts are encoded accordingtothenationaldiagnosis-relatedgroup(DRG)system. ThefirststepwastoselectallthoseSDOsreportingDRGcodes 370-375 and 380-381 (regarding deliveries and abortions respectively),andtocheckforanypossiblelapseincludingonly the SDOs reporting diagnoses or delivery/abortion-related interventions.

InthisreportweconsiderPACasthediagnosisofmalignancy occurring9or3monthsbeforedeliveryorabortionrespectively,or within12monthsafterthedateofpregnancyoutcomeconsidered asthedischargedate.Amongthosepatients,weselectedallSDOs reporting ICD codes 140.-208., which mean a diagnosis of malignantcanceramong the mainor secondary diagnoses. We excluded SDOs in which cancer was recorded as secondary diagnosis or if a previous SDO reported cancer as the main diagnosisbecauseouraimwastoobtainonlyincidentneoplasms. The date of admission was tabbed as the date of cancer diagnosis and for each woman we collected only the ﬁrst discharge form reporting an oncologic diagnosis. We divided tumoursby principalanatomicsites using theaforementioned ICD-9codes:breast(174.),thyroid(193.),skinexceptmelanoma (173.), lymphoma (200.-202.), melanoma (172.), cervix (180.), nervous system (191.-192.), leukaemia (204.-208.), colorectum (153.-154.),ovary(183.),headandneck(140.-149.,160.),skeletal orconnectivetissue(170.-171.),kidney(189.),urinarytract(188., 189.1-189.4,189.8-189.9),lung(162.),othergastrointestinal(150., 152.,156.,158.-159.),stomach(151.),pancreas(157.), endometri-um (182.), placenta (181.), other gynaecologic tract (184.), multiple myeloma(203.),other (164.,190.,194.-199.). The risk ofPACis theratiobetween thewholenumberofPACs andall pregnanciesoccurringduringtheintervalbetweenJanuary1st, 2003andDecember31st,2015.

As secondary endpoints we also expressed the odds ratio (OR)forsome potential riskpredictors usinga logisticmodel andso we stratiﬁed the incidence rate of PACs by year, age, nationality,pregnancy outcome.Women were divided byage into 4 groups (<30, 30–34, 35–39, >=40) and by nationality between Italianwomen or foreign nationals. Eachpregnancy hadtwopossibleoutcomes:deliveryorabortion.Theeffectof theaboveitemsas potential riskpredictors wasestimatedas weretheoddsratio(OR).

Results

From January 2003 to December 2015 we recorded a total numberof682,173pregnanciesinwomenresidinginApulia;as rawdata,we obtained1008women withpregnancyassociated cancerwithin9 or 3 monthsbeforethedate ofthe pregnancy outcome(deliveryorabortionrespectively)andwithin12months afterthesameoutcome,butwemustexcludeseveralcasesfrom theSDOdatabasetoachieveouraim.

Weidentified876womenwithcancerasmaindiagnosisand 132withcancerassecondarydiagnosisaccordingtoICD-9codes. Amongthelatter,werejected81patientswhohadanon-cancer primarydiagnosisandother15caseswithcancerdiagnosisbefore pregnancy,withatotalofonly36womenwithincidentcancerasa secondaryitemintheSDOform.Thusthenumberofpregnancy associatedcancerswas912cases;afurther50caseswereexcluded becauseofunclearcancersiteormetastasisofunspecifiedorigin. Overallweachievedafinalcohortof867womenwithincident cancerinpregnancy:thus,theriskforaPACinourpopulationwas calculatedas127.1per100,000pregnancies.Table1showsthe incidenceofcancerbyanatomicalregion.Breastcancerwasthe mostcommonpregnancyassociatedcancer(257cases)withan incidenceof37.7cancersper100,000pregnancies:229women werediagnosed inpost-pregnancy while28duringpregnancy. Thyroidcancersfollowedbreastbyincidence(22.3per100,000 pregnancies)with133malignanciesinpost-pregnancy(19.5per 100,000)and19cancerinpregnancy(2.8per100,000cases).The rankinggoesasfollows:skinexceptmelanoma(89cancersand 13.0per100,000pregnancies),lymphoma(77casesand11.3per 100,000 pregnancies), melanoma (6.2 per 100,000), cervical cancerandcentralnervoussystem(3.8per100,000),leukaemia (3.7per100,000).

Accordingtothedata19.2and107.9per100,000pregnancies were diagnosed with cancer during pregnancy and in post-pregnancyrespectively.Table2showsdistributionofpregnancies stratiﬁed by four items or potential risk predictors. Women youngerthan30yearswereabout1/5(20.07%)ofourcohortwith thelowestriskforPACs(64.5per100,000,OR=1)whileonethird Table1

Classiﬁcationofpregnancy-associatedcancerbysite.

Pregnancy Post-pregnancy All

Cancersite No Risk No Risk No Risk

Breast 28 4,1 229 33,6 257 37,7

Thyroid 19 2,8 133 19,5 152 22,3

Skinexcludingmelanoma 15 2,2 74 10,8 89 13,0

Lymphoma 19 2,8 58 8,5 77 11,3 Melanoma 6 0.9 36 5,3 42 6,2 Cervix 3 0.4 23 3,4 26 3,8 Nervoussystem 2 0.3 24 3,5 26 3,8 Leukemia 6 0.9 19 2,8 25 3,7 Colorectum 4 0,6 20 2,9 24 3,5 Ovary 4 0.6 18 2,6 22 3,2

Headandneck 6 0.9 15 2,2 21 3,1

Otherorilldeﬁned 2 0,3 19 2,8 21 3,1

Connectivetissue 6 0,9 11 1,6 17 2,5

Kidney 5 0.7 9 1,3 14 2,1

Urinarytract 3 0.4 8 1,2 11 1,6

Lung 1 0,1 7 1,0 8 1,2

Othergastrointestinaltract 0 0,0 8 1,2 8 1,2

Stomach 0 0,0 7 1,0 7 1,0 Pancreas 0 0.0 6 0,9 6 0,9 Endometrium 0 0.0 4 0,6 4 0,6 Uterus 0 0.0 3 0,4 3 0,4 Placenta 0 0.0 3 0,4 3 0,4 Other Gynecological 1 0.1 1 0,1 2 0,3 Multiplemyeloma 1 0,1 1 0,1 2 0,3 Allcancers 131 19,2 736 107,9 867 127,1

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(33.10%)ofourcohortwasmadeupofwomenrangingfrom35to 39yearsandthehighestriskforPACswasforwomenaged_>/=40 years(296.3cancersper100,000pregnancies,OR=4.29,p<0.05). Eighty-sevenpercentofwomenwereItalianwith759cancers versus108cancers(12.46%)inforeignpregnantwomen:beinga foreignerdidnotincreasetheriskforPACswhilebeingItalianor born in Italy meant higher association with cancer during pregnancy. More than 500 pregnancies out of 867 ended with abortionsowecanconcludethattheincidencerateofdevelopinga pregnancy-associatedcancerwashigherforpregnanciesresulting in miscarriage. Considering calendar years, we observed an increased OR from 2006 to 2009 (OR=1,39 and OR=1,41 respectively).

Comments

Benignneoplasms, suchasleiomyomas oradnexal cystsare commonly found in pregnant women while data regarding malignancies are scarce [1,9,10]. Knowing the exact incidence anddistributionofcancerinpregnancyineachgeographicalarea representsakeypointintheﬁeldofobstetricsandgynaecology. In2016,Parazzinietal. reportedtheincidenceofpregnancy associatedcancerinLombardy(aregioninnorthernItaly),based ondatafromregionalhospitaldischargeformsandwedecidedto usethesamesystemtocollectdata[3].Inthecurrentstudyaraw incidenceof127.1cancersper100,000pregnancieswassimilarto thatreportedinLombardy(122.9per100,000maternities),andin other geographical areas such as Australia (137 per 100,000 pregnancies),California(94per100,000livebirths),Washington DC,Germanyandothersinglecentreandmulticentricexperiences fromnearbyorfarawayCountries[2_–8].Sowecanassumethat thereisnocriticalgeographicaldifference.

However,therearenoticeabledifferencesregardingeachcancer indifferentregions:melanomaisthemostcommoninAustralia (45.7per100,000maternities)[11]whileitistheﬁfthcancerby frequencyinourexperience(6.2per100,000maternities).Inour studytherankingofeachtumourduringpregnancyreﬂectsmoreor

lessitsdemographicsinreproductiveagefemalesintheso-called high-resourcecountries[15]:breastcanceristhemostfrequentPAC [12–14]andasforanyothercancer,itisexpectedtobecomemore frequentsinceﬁrstbirthsinolderwomencontinuetorise[16].The secondmostfrequentcancerinourseriesisthyroidcancer:this resultisspeciﬁcforItalianpopulationwhichshowsanimportant increaseinincidenceforthisneoplasminbothsexescomparedto other countries worldwide [17]: it is the second neoplasm by incidenceinwomenyoungerthan49yearsoldwhileitisthe18thby number of deathsfromcancer in women.That means thatthe increasingincidencejustrelatestothemilderhistotypesandthis goesalongwiththeimproving5yearsoverallsurvivalrate(2005– 2009,95%;1990–1994,86%)[18].

Notably,theincidenceofpregnancy-associatedthyroidcancer inourstudywashigherthanthatrecordedinLombardy.Infact thereisastatisticallysigniﬁcantdiscrepancybetweenitsincidence innorthernandsouthernItaly:contrarytoalmostallcancers,the incidence of thyroid cancer is higher in southern Italy (27.5100,000 inhabitants vs 23.5 in northern Italy) with a greater(+17%;100,000inhabitants)incidenceratestandardized forgeographicalareaandsex[18].

Wealsodetected77casesper100,000womenoflymphoma, which represents the most common haematological malignant disorderinpregnancy,followedbyacuteleukaemia. Approximate-ly3every100women[19]withHL(Hodgkinlymphoma)receive thediagnosisduringpregnancy,usuallyatthesamestageasin non-pregnantcounterparts.Melanomaistheﬁfthmostfrequent cancer in our series with special concerns about this PAC in literature:oneofthefeaturesofmelanomaistheriskfor trans-placentalmetastases,withnewbornsdevelopingclinicalevidence ofmetastaseshavingapoorprognosis[20].Cervicalcanceristhe mostfrequentgynaecologiccancerinbothourandotherseries.As previouslymentioned,itisreasonabletoexpectarisingincidence ofPACsbut,surprisingly,thetrendinourseriesdivergesfromthis expected corollary with a peak in 2009 and unexplained statisticallynoticeablespikesin2006and2011and2012without increase.

Table2

Distribution,risksandORforpregnancy-associatedcancerandtheirrelativep-value. Pregnancies Pregnancy-associatedcancer Frequency

(n.)

Frequency(n.) % Risk OR p-value

Age <30 269820 174 20,07 64,5 1 30-34 215169 259 29,87 120,4 1,88 <0,05 35-39 147567 287 33,10 194,5 2,96 <0,05 >=40 49617 147 16,96 296,3 4,29 <0,05 Nationality Foreign 111507 108 12,46 96,9 1 Italian 570666 759 87,54 133,0 1,33 <0,05 Outcome Delivery 212924 334 38,52 156,9 1 Abortion 469249 533 61,48 113,6 1,26 <0,05 Yearofpregnancy 2003 58901 60 6,92 101,9 1 2004 59877 70 8,07 116,9 1,12 0,51 2005 56959 56 6,46 98,3 1,22 0,387 2006 56545 84 9,69 148,6 1,39 0,05 2007 55518 52 6,00 93,7 0,87 0,46 2008 54254 77 8,88 141,9 1,31 0,12 2009 54213 84 9,69 154,9 1,41 <0,05 2010 54100 57 6,57 105,4 0,95 0,78 2011 52180 78 9,00 149,5 1,34 0,09 2012 49546 76 8,77 153,4 1,32 0,11 2013 46790 71 8,19 151,7 1,33 0,1 2014 44510 58 6,69 130,3 1,13 0,49 2015 38780 44 5,07 113,5 0,99 0,97

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Italian women seem to have an increased risk for PACs (OR=1,29)comparedtoothercountriesandinApuliaweﬁnda greaterproportionformiscarriage/abortion(200.4every100,000 pregnancies in our report) compared to our counterpart in Lombardy (116 per 100,000 pregnancies). Probably the main weaknessesofourstudyisinherenttothespeciﬁcnatureofour databasewhichpreventsusfromobtaininganymoredatathan thoseconsidered,thuswehadnoinformationonthegestational ageatbirthoronneonataloutcomes.

Finally,asexpected,theincidenceoftumoursbyageshowedan increasingtrend inolderwomencompared toyoungerones.In fact,inagreementwithdatafromeitherfar-awaycountrieslike Australiaor nearbyregions (e.g.Lombardy), ageseemstobe a majorfactorintheincidenceofPACs:infactbeingolderthan40 yearsduringchildbearingincreasestheriskforoncologicdiagnosis morethan four-fold. Thisﬁnding is of great clinical and social importanceasindevelopedcountrieswomentendtopostpone childbearingbecauseofsocio-economicreasons.Thisstudydoes notprovideanyinformationonclinicalmanagementandfollowup ofcancerduringpregnancy.However,webelievethatimproved knowledgeoftheexactincidenceofthisrareconditionmightmake asigniﬁcantcontributionforabettermanagementandtreatment. References

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