Ascites in Ovarian Carcinoma - Reliability and Limitations of Cytological Analysis.
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This retrospective study of 170 patients found that peritoneal cytology for ovarian carcinoma is highly specific but has low sensitivity, particularly for endometrioid tumors, necessitating combined use with other markers.
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This retrospective study evaluated the validity of peritoneal cytology in detecting malignant cells within ascitic fluid from 76 patients with ovarian carcinoma and a control group of 94 patients with benign tumors or liver cirrhosis. The results indicated that while peritoneal cytology is highly specific at 93.61%, its sensitivity is relatively low at 68.92%, with false negative rates varying significantly by histological type, reaching 77% for endometrioid carcinomas. The authors note that reactive mesothelial cells and endometriosis itself pose challenges for differential diagnosis, potentially leading to misinterpretation of samples. Relevance to endometriosis: endometriosis is mentioned as a confounding factor in differential diagnosis that can cause false positive cytological results, but the paper is not centrally about endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
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Abstract
ObjectiveThe objective of this study was to examine the validity of ascitic fluid cytology in the detection of pathological findings, to examine the percentage of false positive and false negative results in the cytology of ascitic fluid and to determine the validity of peritoneal cytology in relation to the histopathological type of the ovarian tumour.MethodsThis retrospective study included 170 peritoneal cytology findings. The study was conducted from January 2010 to December 2012. The experimental group included 76 cytology findings obtained from patients diagnosed with ovarian carcinoma, whereas the control group was composed of 94 cytology findings of benign ovarian tumours and liver cirrhosis ascites. The patients with ovarian carcinoma had grades III, as well as grades I and IIc but only in cases where operative and pathological finding indicated a ruptured or perforated tumour capsule.ResultsThe sensitivity of peritoneal cytology is 68.92%, specificity is 93.61%, positive predictive value is 89.65% and negative predictive value is 78.57%. In 30.02% of patients, the peritoneal cytology showed false negative results, while in 6.38%, the results were false positive. The highest percentage of false negative findings was 77%, found in endometrioid carcinoma.ConclusionPeritoneal cytology of ascitic fluid is highly specific but has relatively low sensitivity, particularly in the case of endometrioid ovarian carcinoma. In order to increase sensitivity, peritoneal cytology should be combined with monoclonal antibodies and other biochemical and immunohistochemical markers.
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Abstract
Objective :Theobjectivesofthisstudyweretoexaminethevalidityofasciticfluidcytologyinthedetec -
tionofpathologicalfindings,toexaminethepercentageoffalsepositiveandfalsenegativeresultsinthe
cytologyofasciticfluidandtodeterminethevalidityofperitonealcytologyinrelationtothehistopatho -
logicaltypeoftheovariantumour.
Methods
:Thisretrospectivestudyincluded 170peritonealcytologyfindings.Thestudywasconducted
fromJanuary2010toD ecember2012.Theexperimentalgroupincluded76 cytologyfindingsobtained
frompatientsdiagnosedwithovariancarcinoma,whereasthecontrolgroupwascomposedof94cytol-
ogyfindingsofbenignovariantumoursandlivercirrhosisascites.Thepatientswithovariancarcinoma
had gradesIIIaswellasgradesIandIIcbutonlyincaseswhereoperativeandpathologicalfindingin -
dicatedarupturedorperforated tumourcapsule.
Results
Thesensitivityofperitonealcytologyis68.92%,specificityis 93.61%,positivepredictivevalue
is89.65%,andnegativepredictivevalueis78.57%. In30.02% of patients,theperitonealcytology
showedfalsenegativeresults,whilein6.38% ,theresultswerefalsepositive.Thehighestpercentageof
falsenegativefindingswas77%, foundinendometrioidcarcinoma.
Conclusion
Peritonealcytologyofasciticfluidishighlyspecificbuthasrelativelylowsensitivity,par -
ticularlyinthecaseofendometrioidovariancarcinoma.Inordertoincreasesensitivity,peritonealcy -
tologyshouldbecombinedwithmonoclonalantibodiesandotherbiochemicalandimmunohistochemical
markers.
Keywords
Ascites,asciticfluidcytology,ovariancarcinoma
AscitisenelCarcinomaOvárico–ConfiabilidadyLimitacionesdelAnálisis
Citológico
RŽivadinović 1,2 ,A Petrić 1,2 ,D Krtinić 1,JStevanovićMilosević 1,2 ,SPop TrajkovićDinić 1
RESUMEN
Objetivo: Losobjetivosdeesteestudiofueronexaminarlavalidezdelacitologíadellíquidoascíticoen
ladeteccióndehallazgospatológicos,examinarelporcentajederesultadospositivosfalsosynegativos
falsosenlacitologíadellíquidoascítico ,ydeterminarlavalidezdelacitologíaperitonealenrelación
coneltipohistopatológicodeltumorovárico.
Métodos: Esteestudioretrospectivoincluyó170hallazgosdecitologíaperitoneal.Elestudiosellevóa
cabodesdeenerode2010hastadiciembrede2012.Elgrupoexperimentalincluyó76 resultadosdeci-
tologíaobtenidosdepacientesdiagnosticadosconcarcinomaovárico,mientrasqueelgrupodecontrol
estuvointegradopor94hallazgosdecitologíadetumoresováricosbenignosyascitisdelacirrosishe -
pática.LospacientesconcarcinomaováricoteníangradosIII,asícomogradosIyIIc ,perosóloenlos
casosenlosqueelhallazgooperativoypatológicoindicabaunacápsuladetumorrotaoperforada .
Resultados: La sensibilidaddelacitologíaperitoneales68.92%,laespecificidad93.61% ,elvalorpre -
dictivopositivo89.65%,yelvalorpredictivonegativo78.57%. En30.02%delospacientes,lacitolo -
gíaperitonealmostróhallazgosnegativosfalsos,mientrasqueenel6.38%,los hallazgosfueronpositivos
falsos.Elmayorporcentajedeloshallazgosnegativosfalsosfue77%, encontradosenelcarcinomaen -
dometrioide .
From:1ClinicforGynecology and Obstetrics,ClinicalCenterNišand
2FacultyofMedicine,UniversityofNiš,Niš,Serbia.
DOI: 10.7727/wimj.2014.230
Correspondence:DrD Krtinić,ClinicofGynecologyandObstetrics,Clinical
CenterNiš,18000Niš,Serbia.E-mail:[email protected]
237
Introduction
Ascitesisalargeamountoffluidaccumulatedintheabdomen.
Undernormalconditions,severallitresofperitonealfluidare
produceddailyand itisnotaccumulated buteffectivelyab -
sorbed.
Ascitesofmalignantaetiologyappearinonly10% ofall
ascitescases(1).Non-malignantaetiologyascitesaremost
commonlycausedbyliverandheartdiseases . Malignant
ascitesmostfrequentlypresentingynaecological,gastroin -
testinalandbreastcarcinomas .A combinationofmalignant
ascitesandcarcinomatosisoftheperitoneumispresentin15–
30%ofcases(2).
Ascitescanbeexudativeandtransudative.Transudates
makeup90% ofasciticfluidsandtheyarecausedbycondi-
tionsofnon-malignantaetiology.Thisfluidisclear,witha
smallnumberofcellsandlowlevelofalbumin.Anexudateis
usuallymalignant,cloudy ,withagreaternumberofcellsand
ahigherlevelofproteinsthantransudate(3).
Thisdifferentiationisenhanced bytheserum-ascites-
albumingradient(SAAG). IfSAAG is> 1.1,thevaluespoint
toatransudatecausedbyportalhypertension,cirrhosis,he -
paticcongestion,portalveinthrombosisetc. IfSAAG is< 1.1,
theexudateismostlikelyofmalignantaetiologyorbyanin -
fectiousprocessintheperitoneum,nephroticsyndromeand
hypoalbuminaemia frommalnourishment(4).
Itisbelievedthatthepathogenesisofmalignantascites
ismultifactorialandthatthemostimportantpathogenetic
mechanismsinclude increased vascularpermeability,lym -
phaticdrainageobstruction,increaseddifferenceinhydraulic
pressureandreduceddifferenceinoncoticpressure(5).
A two-waypermeabilityofbloodvesselsisnecessary
fornormalsupplyofnutrientsandgasesandwasteremoval.
Thepermeabilitycanbebasal,acutevascular(aconsequence
ofshortexposuretovascularendothelialgrowthfactor–
VEGF) andchronic,whichisacharacteristicofpathological
angiogenesis .
Vascularendothelialgrowthfactorcausestheprocessof
neovascularizationandangiogenesisandtheresultishyper -
permeabilityandincreasedporosityoftheendothelialmem -
brane ,whichisfollowedbymigrationandproliferationof
endothelialcellsandcreationofnewcapillaries.Besides
VEGF ,neovascularizationisalsoinfluencedbyfibroblast
growthfactor(bFGF),angiogenin,transforminggrowthfac -
tor(TGFαandβ)andinterleukin8 .
Ascitesisthemostcommoncomplaintofpatientswith
ovariancarcinoma.In54% ofpatientswithperitonealcarci-
nomatosis,asciteswasthefirstdetectablesignofmalignancy
(6).
M orethantwo-thirdsofpatientsthatreporttothedoctor
havegradesIII andIV ofthedisease . Survivalrateinad -
vancedstages(IIIandIV)is5– 20%(7).
Thepresenceofmalignantascitesinmalignanciesofthe
secondarylocalizationisaworseprognosticmarkercompared
toovariancarcinoma,andthesurvivalperiodfromthemoment
ofdetectionis7–13weeks(8).
Thepurposeofthisstudywastotestthevalidityofas -
citicfluidcytologyinthedetectionofpathologicalcytology
results,totestthepercentageoffalsepositiveandfalse
negativeresultsofasciticfluidcytologyandtodeterminethe
validityofperitonealcytologyinrelationtothehistopatho -
logicaltypeofovariantumour.
SUBJECTS AND METHODS
A retrospectiveanalysiswasusedfortheresearchwhichin -
cluded170peritonealcytologyresultsduringtheperiodfrom
January2010toDecember2012.Theexperimentalgroupwas
composedof76 cytologicalfindingsobtainedfrompatients
diagnosedwithovariancarcinoma,whilethecontrolgroupin -
cluded94cytologicalfindingsofbenignovariantumours(fi-
broma,dermoid cysts,endometrioses,serousandmucinous
cysts)andascitesinlivercirrhosis.Thepatientswithovarian
carcinomawereinstagesIIIaswellasinstagesIandIIcbut
onlyincaseswhereoperativeandpathologicalfindingsindi-
catedarupturedorperforatedtumourcapsule.C ytological
findingsofasciticfluidand peritonealcavityeffusionwere
sampledattheGynecologyandObstetricsClinicinNišand
scannedattheInstituteofPathologyattheC linicalCenterNiš .
Allresultswerestatisticallyprocessedbyaformulaformeas -
uringvalidity,χ2testandpresentedintablesandgraphs .
Results
Thehistopathologicaldistributionoffindingsfromtheexperi-
mentalgroupispresentedinFig.1.Thehighestpercentageof
patientshadseroustypeofcarcinoma(71%),whichisdes-
cribedasthehistopathologicallymostfrequenttypeofovarian
carcinomaintheliterature.
C ytologicalfindingsofasciticfluid obtainedfromthe
mentioned76 patientswithovariancarcinomawhowereclas -
sifiedintotheexperimentalgroup(stageIIIandstageIandIIc
withperforatedcapsule)wasnegative-falsenegativein23
(30.2%)patients(Table1).
Conclusión: La citología peritoneal del líquido ascítico es altamente específica , pero su sensibilidad es
relativamente baja, particularmente en el caso del carcinoma ovárico endometrioide. Con el fin de au -
mentar la sensibilidad, la citología peritoneal debe combinarse con anticuerpos monoclonales y otros
marcadores bioquímicos e immunohistoquímicos.
Palabras claves :Ascitis,citologíadellíquidoascítico,carcinomaovárico
West Indian Med J 2015; 64 (3): 237
Živadinović etal
238 A scitesinO varianCarcinoma
Table1: Distributionoffalsenegativecytologicalfindingsofasciticfluidwithrespecttothe
histologicaltypeoftumour
Histologicaltype Totalnumberof Numberofnegative Percentageoffalse
histologicaltype cytologicalfindings negativefindings
Serous 54 15 27.77%
Mucinous 62 33.33%
Endometrioid 43 77%
Clearcell 62 33.33%
Anaplastic 41 25%
Granulo-cellular 20 0%
Total 76 23 30.2%
Table2 : Distributionoffalsepositiveperitonealcytologyfindingswithrespecttothecause and
histologicaltypeoftumour
Histologicaltype Totalnumberof Numberofpositive Percentageoffalse
histologicaltype cytologicalfindingspositivefindings
Fibroma 90 0%
Dermoid 11 0 0%
Endometrioma 13 2 15.38%
Serous 39 2 5.12%
Mucinous 20 2 10%
Livercirrhosis 20 0%
Total 94 6 6.38%
Fig .1: Distributionof histopathologicalfindingsfromtheexperimental
group.
Fig .2: Distributionofhistopathologicalfindingsfromthecontrolgroup.
Histopathologicaldistributionoffindingsfrom thecon -
trolgroupisshow ninFig.2anditalsoshows thehighestfre -
quencyofbenigntumourstobeoftheseroustype(41.98%).
The findingsofperitonealcytologyobtainedfrom thecontrol
group (94patients)withbenignhistopathologicalovariantu -
mourorascitescaused bylivercirrhosiswas positive-false
positiveinsix(6.38%)patients(Table2).
Figure3shows thatthepercentageoffalsenegativere -
sultsinpatientswithovariancarcinomaintheexperimental
group wa s30.2%,whereasthepercentageoffalsepositivere -
sultsinpatientswithbenigntumourwa s6.38%.
Usingtheformula formeasuringsensitivityand speci-
ficity ,thedata forperitonealcytologyvaliditywereobtained.
The measuredsensitivityofperitonealcytologywas 68.92%,
specificitywas 93.61%,positivepredictivevalue(PPV)was
89.65%,negativepredictivevalue (NPV) was 78.57%and
overallvaliditywas 82.35%(Fig.4)
Table1shows thenumberoffalsenegativeresultswith
respecttohistologicaltypeofmalignanttumo ur.Itcanbeseen
that,withrespecttothehistologicaltype,thehighestpercent-
age (77%)offalsenegativeresultswas inendometrioidovar -
iancarcinoma (out of fourendometrioidcarcinoma s,three
239
werefalsenegative results),whilethe lowest percentagewas
withthegranulo-cellulartype.Althou gh thepercentagesshow
thatserous carcinomawas themost frequent(71%ofallfind -
ings),27.77%werefalsenegative.The differenceinfrequency
offalsenegativecytologicalfindingswithrespecttothehis -
tologicaltypeisstatisticallysignificantbecause χ2e=34.75 >
χ20.01 =9.21.
Table2shows the numberoffalsepositiveresultswith
respectto thehistologicaltypeof tumour.The highestper -
centageoffalsepositiveresultsinthe controlgroup wa swith
endometrioidova riancysts–15.38%(out of 13endometri-
omas,two werefalsepositive).The differencewas notstatis -
ticallysignificantbecause χ2e=5.34< χ20.05 =5.99.
DISCUS SION
The maincharacteristicsof malignantascitesareincreased
concentrationofascticfluidproteins,increasedlactatedehy -
drogenase,a largenumberofleukocytesandpositivecytology
forthepresenceofmalignantcells.
A positivecytologicalfindingisimportantinsubclassi-
ficationof stagesIand IIof thediseaseand itrepresentsan
importantpredictivefactorinprognosisandrecurrence.How -
ever,anincreasingnumberofstudiesshows thatmorphologi-
calexaminationofcytologicalsamplesisnota highlysensitive
diagnostictool.
Thereasonforfalsepositivecytologicalresultsisinade-
quate interpretationof reactivelyalteredmesothelialcells.
Thesecellsareenlarged and theyhave a densecytoplasm,a
bignucleuswitha nucleolus and may containvacuoles. En -
dosalpigniosiscanalsopresenta problemindifferentialdiag -
nosis and itshould be carefullydetermined that itis a
well-organizedgroupofuniformcellswithscarcebasophilcy -
toplasm and a nucleuswitha well-definedmembrane,fine
chromatinand a smallnucleolus.
Endometriosisrepresenteda big problemindifferential
diagnosis.Inendometriosis,thereareroundcellsorganized
intothree-dimensionalgroupsandlayers,withroundandbean-
shaped nucleuswhichhasfinechroma tinand scarcevacu o -
latedcytoplasm.The most sensitivefindingsforendometriosis
aremacrophages with haemos iderin.
Thesearethereasonswhy literaturedata statethatperi-
tonealcytology canbefalsepositivein4.5%ofcases(inour
researchitwas 6.38%).Some recentstudiesalso describea
relativelyhighpercentageoffalsenegativefindingswhichex -
ceeds20%(inourresearch itwas 30.2%).Thereasonsfor
such a highpercentageoffalsenegativecytologicalresultsof
asciticfluidmay beinthebad distributionofcellsinthesam -
pledasciticfluid,badpreparation ,orinsufficientcellexfolia -
tion ,andsincecytologyisa subjectivemethod,errorsmay be
due toinadequateinterpretationoffindings(9).
The highestpercentageof falsenegativeresultsinour
researchwas inthegroupofpatientswithendometrialcarci-
noma. Inaddition to thestatedparameterswhichpointtothe
benignnatureofendometrioidcarcinoma,cytologicalelements
whichpointtotheendometrioidcarcinoma should alsobecon -
sidered:theappearanceof three-dimensionalgroupsof cells
withlargepleomorphiceccentricnucleiwithrou gh chromatin,
emphasizednucleolusand abundant cytoplasm. Cytological
findingwhichpointsto serous carcinoma shows cellswhich
areseparateorinirregularincohesivegroups,withlargepleo -
morphicnucleusand emphasizednucleolus.
The sensitivityof peritonealcytologystatedinother
studiesrangesfromonly50to 60%(inourresearch itwas
68.92%),up to 97%dependingon thestudy,diseasestageand
peritonealinclusion(10).
InpatientswithstageIc,cytologywas positivein75%
andwhentheperitoneum was included ,itwas 94%(11).The
sensitivityofcytologywhen peritoneum was included was
82.9%and specificitywas 98.1%[inourresearch itwas
93.61% ](12).The examinationoftotalvalidityofcytologyin
some publications showed somewhat lowersensitivitywhich
was 60%and highspecificityofalmost 100%(13).
The resultofprimarycytologyofasciticfluidisan im -
portantparameterinthe diagnosis,therapeuticapproachand
diseaseprognosis.The resultofsecondarycytologyafterthe
treatmentisalso an importantindependentprognosticmarker
which ishighlycorrelatedwiththeoptimaleffectofsurgical
treatment,recurrenceand overallsurvivalrate.Inpositive
Živadinović etal
Fig .3: Combinedrepresentationofthedistributionofperitonealcytology
findingsfromexperimental(pathologicalfindings –stagesI,IIand
III)and control(benignfindings)groups .
Fig4: Graphicrepresentationofvalidityparametersofperitonealcytology .
PPV: positivepredictivevalue;NPV: negativepredictivevalue
240
secondarycytology,survivalis13to32months,whileinnega-
tivecytology ,itis> 48months(14).
Consideringallaspectsofvalidityofasciticfluidcytol-
ogy,particularlywithcertainhistologicaltypes(endometrioid
ovariancarcinoma),itisbelievedthat furtherresearchis
necessaryaswellastheuseofspecificadditionalimmunohis -
tochemicalmarkersinordertoreduceas much aspossiblethe
percentageofcytologicalerrorswh ich causewronggrading
andinappropriatetreatment.
Inadditionto measuringtheconcentration of alkaline
phosphatase,lactatedehydrogenase,fibronectin,aswellastu -
mou rmarkersCA-125,CEA ,p53,βHCG,thereisalsoa spe -
cific group of panel antibodies,primarilyMOC -31and
Ber-EP4.Theseantibodiesareimportantfordifferentiationof
mesothelialandcancerouscellsand itmay alsocontributeto
thedifferentiationof antibodiesintoadherentcellsand non-
adherentcarcinogenic(15).
Fromtheremainingbiomarkers,telomerasehas lately
beenmostlytested.Telomeraseisan enzymenecessaryfor
normalreplicationof chromosome sandconstantgrowthof
cancercells.Telomeraseactivityisabsentinthemajorityof
somat iccells.On theotherhand,telomerase expressionhas
beenconfirmedinalmost100%ofovariancarcinomacases .
Contraryto24–54%ofcases ,where ,despitethefactthatresi-
dualdiseasewas diagnosed,cytologyandsecond-looksurgery
werenegative,telomerasewas almost 100%positive(16).
Inourstudy ,we concludedthatperitonealcytologyof
asciticfluidishighlyspecific(93.61%)butithas a relatively
low sensitivity(68.92%).In30.02% ,peritonealcytologyhad
falsenegativeresultsand in6.38% ,itshowe dfalsepositive
results.Such distributionof cytologicalfindingsmaycause
inadequategradingofthedisease and inadequate therapeutic
approach (notapplyingthenecessarychemotherapyorappli-
cationofunnecessarychemothe rapy).The highestpercentage
offalsenegativeresultswas withendometrioidovariancarci-
nom a (77%) ,so itisnecessarytobeverycarefulwhen cyto -
logicalscanning isusedwiththistype.Inorderto increase
sensitivity,peritonealcytologyshould becombinedwithother
availablebiochemicaland immunohistochemicalmarkers.
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