Testicular microlithiasis: Systematic review and Clinical guidelines

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LITERATURE REVIEW

Testicular microlithiasis: Systematic review and Clinical guidelines

Micro-lithiases Testiculaires: revue systématique de la littérature et arbre décisionnel

Fouad Aoun

^a^,^b^,∗

, Amine Slaoui

^a^,^c

, Elias Naoum

^b

, Touﬁc Hassan

^b

, Simone Albisinni

^d

,

Jean Michel Azzo

^e

, Anthony Kallas-Chemaly

^b

, Grégoire Assenmacher

^a

, Alexandre Peltier

^a

, Thierry Roumeguère

^d

aServiced’Urologie,InstitutJulesBordet,UniversitéLibredeBruxelles,1rueHéger-Bordet, 1000Brussels,Belgique

bServiced’Urologie,HôtelDieudeFrance,Facultédemédecine-UniversitéSaintJoseph, AlfredNaccacheboulevard,Beyrouth,Liban

cServiceUrologieBHôpitalAvicenne,UniversitéMohamedV,Maroc

dServiced’Urologie,CliniquesUniversitairesdeBruxelles,hôpitalErasme,routedeLennik 808,1070Bruxelles,UniversitéLibredeBruxelles,Belgique

eServiced’Urologie,HôpitalMontLiban,UniversitéLibano-Américaine,MickhaelGharios street,Hazmieh,Liban

Received30January2019;accepted2July2019 Availableonline2August2019

KEYWORDS Testicular microlithiasis;

Testiculartumor;

Testicularcancer;

Germcelltumor;

Infertility;

Ultrasound

Summary

Introduction.—Therearenoclearrecommendationsonhowpatientswithtesticularmicrolithi- asisshouldbefollowedup.Theaimofoursystematicreviewistogiveclinicalguidelinesbased ontheevidenceintheliterature.

Methods.—AwebsearchwasconductedduringFebruary2018basedonPubmeddata,Embase and Cochrane database.The eligibilityof articles was deﬁned using the PICOS method,in concordancewiththePRISMArecommendations.

Results.—Fiftythreearticleswereselectedforourﬁnalsynthesis.Ourreviewhighlightedan associationbetweentesticularmicrolithiasisandthealreadyknownriskfactorsoftesticular germcelltumor. The presenceoftesticular microlithiasisinpatients withsuch riskfactors

∗Correspondingauthorat:Serviced’urologie,InstitutJulesBordet,1,rueHéger-Bordet,Bruxelles,1000,Belgique.

E-mailaddress:[email protected](F.Aoun).

https://doi.org/10.1016/j.purol.2019.07.001

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increasesmoretheriskofcancer.Intheabsenceofriskfactors,therisktodeveloptesticular cancerissimilartotheriskingeneralpopulation.

Conclusion.—In patients at risk to develop testicular cancer, observation versus testicular biopsyisdebatable.Werecommendanindividualizedapproachbasedontheageofthepatient, thepresenceofconcurrentfeaturesoftesticulardysgenesissyndrome,thefertilityofthecou- ple,thedesireofpaternityandtheultrasoundpattern(bilateralandclusteredvs.unilateral andlimited).

MOTSCLÉS Microlithiases testiculaires; Cancertesticulaire; Tumeurgerminale; Infertilité; Échographie testiculaire

Résumé

Introduction.—Iln’yapasdanslalittératureunconsensusclairsurladémarcheàsuivreencas demicrolithiasestesticulaires.Lebutdenotrerevuesystématiquedelalittératureestd’aider lecliniciendanssaconduiteàtenir.

Méthodes.—Unerechercheaétémenée,enfévrier2018,surlesbasedesdonnéesPubmed, Embaseet Cochrane enutilisantles motscléssuivant: «testicular microcalciﬁcations» et« testicularmicrolithiases».

Résultats.—Cinquante-troisarticlesontétéretenus.Notrerevueamisenévidenceuneasso- ciationdesmicrolithiasestesticulairesaveclesfacteursderisquedecancertesticulaireetque cetteassociationaugmenteencorelerisquedecancertesticulaire.Laprésencedemicrolithi- asessansaucunfacteurderisquedecancertesticulairen’apasdesigniﬁcationclinique.

Conclusion.—Laprésencedemicrolithiasestesticulaireschezdespatientsàrisquededévelop- peruncancertesticulaire,mériteunesurveillancerapprochée.Labiopsietesticulairechezces patientspourraêtreindiquéeenfonctiondel’âgedupatient,desondésirdepaternité,dela fertilitéducouple,etdelaprésenced’unsyndromededysgénésietesticulaire.

Introduction

Testicular microlithiasis is an ultrasonographic incidental ﬁndingofmultiple,1to3mm-sized,non-shadowinghyper- echogenicfociwithintheparenchyma ofthetesticles[1].

Recently, the European Society of Urogenital Radiology proposeda classificationof testicular microlithiasisbased on their number per field of vision: limited (<5/field of view),classic(≥5/fieldof view)anddiffuse [2].Ofnote, testicular microlithiasis are commonly found bilaterally.

Histologically, they are defined as testicular microcalci- fications [3]. They consist of a core of hydroxyapatite surroundedbyconcentriclayersofcollagenfibersandglyco- gen.Thisdepositisfoundinthelumenoftheseminiferous tubules.

Testicularmicrolithiasiswerefirstidentifiedonimaging in1970whentwoAmericanresearchersdescribedthemon aradiographof thepelvisin a4-year-oldchild [4].Three yearslater,Weinbergetal.werethefirsttohistologically characterize these microlithiasis as intra-tubular deposits in a normally appearing testicular parenchyma on histol- ogy [4]. Three years later, Schantz and Milsten reported acaseofmaleinfertilityassociatedwithtesticularmicro- calcifications.Theirfirstassociationwithtesticularcancer datesbackto1982whenIkingeretal.examined92pieces

oforchiectomyusingradiographictechniques[5].Theinci- dence ofthesemicrocalcifications wassignificantlyhigher intumorspecimenscomparedtonormalpeers(74%vs.16%, P<0.05).The firstdescription oftesticularmicrocalcifica- tions onultrasoundwasinthe lateeightieswhere scrotal ultrasound-albeitofpoorqualityatthattime-wasincreas- inglyused[1].Theseintra-tubulardepositsweredescribed as‘‘snowstorm’’or‘‘starryskyappearance’’.In1988,Mar- tinetal.describedforthefirsttimeanassociationbetween testicularmicrocalcifications on ultrasoundand a testicu- lartumorinanorchiectomyspecimen[6].Fewyearslater, theincidenceoftesticularmicrocalcificationsincreasedsig- nificantly due to the improvement of the image quality of the ultrasound machines (more efficacious transducers of 12-15MHz) andthe awareness of medicalprofessionals to describeand report thesefindings. In the late90s, an increaseintheprevalenceoftesticularmicrocalcifications inthesubfertilepopulationwasalsonoted[7].Thirtyyears later,despitetechnologicalprogressandmultitudeofepi- demiological studies, their clinical significance and their associationwithtesticulargermcelltumors(TGCTs)remain controversial[8].Thepurposeofoursystematicreviewisto synthesize knowledge about testicularmicrocalcifications, tohighlighttheirclinicalsignificanceandtoproposeadeci- siontreefordailymedicalpractice.

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Material and methods Research Strategy

AwebsearchwasconductedduringFebruary2018basedon Pubmeddata,EmbaseandCochranedatabase. Theuseof ﬁltersmadeitpossibletolimitthesearchtoclinicaltrials writtenineitherEnglishorFrench.Thekeywordsused(MesH language)were: ‘‘TesticularMicrolithiasis’’ or ‘‘Testicular microcalciﬁcations’’.

Selection of articles (PICOS/PRISMA method)

The eligibility of articles was deﬁned using the PICOS method,inconcordancewiththePRISMArecommendations:

Participants (P), Interventions (I), Comparators (C), Out- comes(O)andStudyDesign(S)[9].Anarticlewasconsidered relevantforthisreviewof theliteratureifitevaluated: a malepopulationwithtesticularmicrolithiasis(P);observed witha goodfollow-up (I); compared the association with testicular cancer or infertility (C); in terms of incidence orprevalence(O).Onlyoriginalandresearcharticleshave been included in thisreview (S). Two of the authors(AS, JMA)reviewedall theabstractsandselectedtherelevant articles.Thesewerefullyreadbyathirdauthor(FA)before proceedingtoﬁnaleligibility.

Extraction of data

Dataextraction wasperformed by twoauthors(AS, JMA).

The data collected were arranged by type of study, country of origin, time interval and the date of publi- cation. The quality of studies, the number of patients, the presence of a comparison arm, the incidence or the prevalence of testicular cancer and infertility were also reported.

Evaluation of the quality of studies and level of proof

Randomized clinical trialswere evaluatedby theiradher- encetotheCONSORT2010checklist[10].Non-randomized trials(case-control studies or case series)wereevaluated usingtheNewcastle-Ottawa scale.Thisscalegivesascore withstarsaccordingtothequalityoftheselection(4stars), thecomparabilitybetweenselectedpopulationandthecon- trolgroup(2stars),andtheﬁndingofresultsinrelationto theexposure (3stars). The maximumscore being9stars, a study with a score ≥7 wasconsidered of good quality.

Thelevelofevidenceprovidedbyeachstudywasreported following the recommendations of the Oxford Center for Evidence-BasedMedicine.

Results

Threehundredthirtytwoarticleswereidentiﬁed.Ofthese, 263 wereexcluded by examining thetitleor the abstract (articles not written in French or English, case reports, reviewarticles,meta-analyses,editorial,andletterstothe editor).Nineteenarticleswerethenexcludedwhenthefull article wasread (missingdata,overlappingpopulation). A

total of 53 articles were selected for our ﬁnal synthesis (Fig.1).

Prevalence of testicular microlithiasis in asymptomatic cases (general population) vs.

symptomatic cases

Two studies were identified regarding the asymptomatic population. In the first, Peterson et al. examined ultra- sonographically 1504 healthy volunteers aged between 18 to 35 years old from the annual Army Reserve Officer Training Corps [11]. They found a 5.6% prevalence of testicular microlithiasis. At a 5 year follow-up interval, only one patient with testicular microlithiasis developed testicular tumor 64 months after the initial screening study [12]. In the second, healthy male volunteers were recruited from the training camp at Manisa, Turkey [13]. The testicular microlithiasis prevalence was 2.4%. No cases of testicular tumor were observed in the two groups after a short follow-up of 12 months.

Of note, testicular microlithiasis was deﬁned, in these two studies, as more than 5 high intensity signals on ultrasound. This deﬁnition could underestimate the true prevalenceof testicularmicrolithiasis in thegeneral population.

Fifteen studies were identiﬁed regarding symptomatic population. In symptomatic patients, the testicular microlithiasis prevalence varied between 0.6% and 18.1%

[14—28].This widerangeiscertainly relatedtotheretro- spective natureof the majority of studies, the deﬁnition of microlithiasis andthe quality of the ultrasoundprobe.

Scrotal ultrasound was performed for testicular pain, testicularedema,testicularatrophy,previous orchidopexy or increased testicular volume. In nine studies, scrotal ultrasounds were retrospectively reviewed but reasons for testicular ultrasound were not mentioned [29—33].

Otiteetal.followed-up theirpatients fora medianof 36 months and demonstrated an increased relative risk of testiculartumorsinthepresenceoftesticularmicrolithiasis (RR 13.2, 95% CI:8.3—21.5). A recent pooled analysis of all these data showed an increased prevalence of testicular tumor in symptomatic patients with testicular microlithiasis compared to symptomatic patients without testicular microlithiasis (11.2% vs. 1%, P<0.0001), respectively[34].

Prevalence of testicular microlithiasis in subfertile population

Fourteen studies reportedon testicularmicrolithiasis and subfertility[7,35—47].The testicularmicrolithiasis prevalence varied between 0.9% and 20.1%. In the study with thehighest prevalence, the authors examined the association between testicular microlithiasis on ultrasound and CIS on testicular biopsy in a group of 263 men referred for subfertility. No CIS or TGCT was identiﬁed in men withunilateraltesticularmicrolithiasis.Incontrast,20%of menwithbilateraltesticularmicrolithiasiswerediagnosed withCIS. Therefore, the authors concludedthat bilateral testicular microlithiasis is indicative for CIS in subfertile men.

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Figure1. Flowchartoftheresearchstrategyforselectionofarticleseligibleforthissystematicreview.

Prevalence of testicular microlithiasis in undescended testis

Eight studies regarding cryptorchidism and testicular microlithiasiswereincludedintheﬁnalsynthesis[48—55].In alargestudyof500patientswithundescendedtestis,Goede etal. found atesticularmicrolithiasis prevalence of 2.8%

andNicolasetal.reportedatesticularmicrolithiasispreva- lenceof 9.52% in patients operated several yearsago for cryptorchidism[49].Higher prevalencewerealsoreported byseveralresearchers[50,51].Renshawexamined alarge seriesof orchiectomy specimenand found microcalciﬁca- tionsintwooutoffourundescendedtestes[56].

Prevalence of testicular microlithiasis in patients with familial or personal history of testicular cancer

Only three studies dealing with the association between testicularmicrolithiasis andfamilialor personalhistoryof testicular cancer were included in the ﬁnal synthesis. A Danishstudy comparedclinical andhistologicaldata from the records of 79 men regarding the contralateral testi- cleinapopulationof mendiagnosedwithtesticulargerm cellcancer[57].The testicularultrasoundpatternshowed microlithiasisin14%ofcases.Thefrequencyofmicrolithiasis seenonultrasoundwassigniﬁcantlyhigheramongpatients

withCIScomparedtothosewithanormalechopattern.A slightly higherpercentagewasreportedin a similarstudy [23].Thepresenceofacontralateraltesticulartumorwas signiﬁcantly higherin patients withtesticularmicrolithia- siscompared topatients without testicularmicrolithiasis, respectively (21% vs. 2%) [23]. Korde et al. reported the ultrasoundﬁndingsinmenwithfamilialtesticulargermcell tumorsandtheirunaffectedrelatives.Testicularmicrolithi- asisweremorefrequentinthecontralateraltesticlesofmen withahistory ofTGCT(affected men)thanin unaffected men (48% vs. 24%, P=0.04) [58]. In this study, testicular microlithiasisweremoreprevalentamongfamilymembers than described previously in the general population, and were more common among familial testicular germ cell tumorscasesvs.unaffectedbloodrelatives.Similarly,higher prevalenceoftesticularmicrolithiasisweredemonstratedin patients withtesticulargerm celltumor(36.7% vs.17.8%, P<0.0001) and their relatives (34.5% vs. 17.8%, P<0.02) comparedtothegeneralpopulation[59].

Discussion

Thesuperﬁcialpositionoftesteswithinthescrotummakes them ideally suited to ultrasound evaluation, which per- mitsimagingwithhighfrequencylineararraytransducers, producing images of high resolution. Advances in ultrasound technology in recent years have further increased

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Figure2. Adiagramexplainingthelinkbetweendifferentfeatureofdysgenetictestisandtesticularcancer.

Figure3. Adecisiontreeforpatientshavingtesticularmicrolithiasis.

ultrasoundimagequalityandresultedinincreaseddetection of testicular microlithiasis. These testicularmicrolithiasis consist histologically of concretions of calciﬁcations sur- rounded by concentric layers of collagen ﬁbers found in the lumen of the seminiferous tubules. The physiopatho- logic mechanism proposed initially by Vegni-talluri in the 80s was revisited in 2002 [60,61]. It is believed to be a failure of phagocytosis by Sertoli cells of the sper- matic or epithelial cells of the seminiferoustubules. The

result is the accumulation of debris and initiation of an immune reaction. This increases the permeability of the basalmembraneandleadstotheabovementioneddeposits inthelumenandtheinterstitium.Theclinicalsigniﬁcance of these microlithiasis and their association with testicular germ cell tumorsremains to beelucidated. Testicular microlithiasismaybedetectedindifferentclinicalscenarios which mayrequire an individualized approach for follow- up.

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It is well knownthat intra-tubular germ cellneoplasia (ITGCN)istheprecursorlesionforinvasivetesticulargerm celltumorsofadolescentsandyoungadultswithevidence suggesting a70% risk todevelop an invasive tumorin the affectedtestisby7years[62].Inaddition,ITGCNiscom- monlyfound intheparenchyma adjacenttothetumor on orchiectomyspecimens(90%ofcases)[63].Twostudiescom- paredultrasonographicfindingsof testicularmicrolithiasis and pathological correlates on systematic biopsies. They demonstratedan increasedrisk of ITGCN in patients with microlithiasis[39,57].Tanetal.confirmedthesefindingsina meta-analysisperformedin2010[64].Epidemiologicalstud- ieshavedemonstratedanincreasedprevalenceoftesticular microlithiasisinpatientswithriskfactortoharbor/develop testiculartumors:cryptorchidism, testicularatrophy,subfertility, family or personal history of testicular cancer, testiculardysgenesissyndrome,CIS andsymptomatic.Tes- ticularmicrolithiasisperseisnotanindependentriskfactor fortesticularcanceraccordingtothesestudies[8,65—67].

However, the association of testicular microlithiasis with cryptorchidism, testicular atrophy, subfertility, family or personalhistory oftesticularcancer, testiculardysgenesis syndromeincreasessigniﬁcantlytherisktoharboraCISor todevelopatesticulargermcelltumor[65].Theprevalence ofCIS in anundescended testisis2 to4% [68]. The pres- enceof testicularmicrolithiasis in an undescended testis increasesthe riskto harboraCIS up to39% (7-39%)[69].

The risk toharbora CIS is signiﬁcantlyhigher inthe sub- fertilepopulationwithtesticularmicrolithiasiscomparedto theirpeerswithouttesticularmicrolithiasis(20%vs.1.1%), therisk in the general population being less than1% [8].

Similarly,thepresenceofmicrolithiasisinthecontralateral

testis in a patientwitha past medical history of testicu- larcancerincreasestheriskofharboringaCISfrom5%up to78%(22%-78%)[39].Additionally,testicularmicrolithiasis appeartoclusterincertainfamilies[58].Thesefindingssug- gestbothafamilialpredispositiontotesticularmicrolithiasis and an association between testicular microlithiasis and familialtesticulargerm celltumors.Thusthepresence of testicularmicrolithiasis ina firstdegree relativecouldbe considered asa predispositiontotesticularcancer. Symp- tomaticpatientswithtesticularmicrolithiasiscouldhavea higherrisktodeveloptesticulargermcelltumors.However, patientsincludedinthesereportshadanincreasedtesticu- larvolume,testicularedemaandpainthatmayreflectthe presenceofa germcelltumorandconsequently influence theresults.

The most plausible theory linkingall thesefeatures is summarized in Fig.2. Fetal gonadis composed of Sertoli cells,Leydigcellsandfetalgermcells.Intrauterinegrowth disorders,geneticdefectsandpolymorphismaswellaslife stylefactorsandenvironmentalexposurewilldisruptfetal gonadleadingtotesticulardysgenesis.DisturbedSertolicell functioncanleadtoimpairedgermcelldifferentiationand phagocytosis. Impairedgerm celldifferentiation results in an alteration of spermatogenesisand thedevelopment of ITGCN and testiculartumors.Impaired phagocytosis leads tothedevelopmentoftesticularmicrolithiasis. Decreased LeydigcellfunctionwillaltertheproductionofINSL3and causes cryptorchidism. It will result also in an androgen deﬁciency causinghypospadias, shortano-genitaldistance and impaired spermatogenesis. Based on the severity of the insult, testicular dysgenesis syndrome is classiﬁed as mild (impaired spermatogenesis), moderate (impaired

Figure4. Adecisiontreeforpatientshavingtesticularcancerandcontralateraltesticularmicrolithiasis.

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spermatogenesisandcryptorchidism),andsevere(impaired spermatogenesis,hypospadiasandcryptorchidism).Therisk todevelop a testicularcancer increases withthe number of features and the presence of testicular microlithiasis [61,70,71].

Management of patients with testicular microlithiasis varies signiﬁcantly amongpractitioners. According toEAU guidelines, patients with testicular microlithiasis and no testicular germ cell tumor risk factor should be encour- aged to perform self-examination [72]. Compliance is a crucialpoint.Testicularbiopsy,follow-upscrotalultrasound and routineuse of biochemicalmarkers are notjustiﬁed.

Biochemicalmarkerswerenegativeinallpatientswithtes- ticular microlithiasis in the study of Peterson et al. [11].

Insymptomaticpatientswithtesticularmicrolithiasisanda suspiciouslesion,surgicalexplorationwithtesticularbiopsy ororchiectomyshouldbeconsidered[72].Incontrast,there isnoconsensusonhowtomanagepatientswithtesticular microlithiasisandriskfactorstodeveloptesticulargermcell tumor.Atpresent,testicularbiopsyremainsthegold stan- dardtodetectITGCNandnovelimmuno-cytologicalmarkers inthesemencannotberecommendedduetotheirhighfalse negativerates[73].Someauthorsadvocateobservationwith testicularself-examinationtoearlydetecttesticulartumor whileotherspreconizetesticularbiopsytoruleoutITGCN [8,65,73—75]. The latter approach allows treating early thesepatientswithradiotherapythereforeavoidingorchiec- tomy and therisk of subsequent chemotherapy. However, suchan approachcouldalterdeﬁnitivelyspermatogenesis.

Of note, thisapproach hasno impactonoverall survival.

Anindividualizedapproachbasedontheageofthepatient, the presence of concurrentfeatures of testicular dysgenesis syndrome, the fertility of the couple, the desire of paternityandtheultrasoundpattern(bilateralandclustered vs.unilateral andlimited)is recommended(Fig.3).When biopsy is indicated for fertility purposes in patients with testicularmicrolithiasis,asearchfor ITGCNshouldbesys- tematicallyperformed. Biopsyisalsoencouragedinyoung patientswithtesticularmicrolithiasis andseveralfeatures of thetesticular dysgenesissyndrome. Observationversus testicular biopsy is also debatable in patients previously treatedbyorchiectomyforatesticularcancerandharbor- ing microlithiasis in the contralateral testis (Fig. 4). The risk in sucha patient to have an ITGCN is 20%. Observa- tionispreferredwhenfertilityisanissueinordertoallow fathering. In addition, the risk to develop metachronous tumorisreducedwhenchemotherapyisadministeredinthe adjuvant setting or in metastatic cases [76]. The advan- tage of immediatebiopsy is todetect ITGCN, acondition highlycurable withradiotherapy alone (98% success rate) [77].Therefore,orchiectomyandtheneedtotestosterone replacementtherapycanbeavoidedinthesepatients.

Conclusion

Incidentalﬁndingoftesticularmicrolithiasisintheabsence of risk factor (familial or personal history of testicular cancer,testicularatrophy,infertility,hypospadias,andcryp- torchidism) should trigger no additional interest. If the patient is at risk to develop TGCT, two options (testicular self-examinationwithan advice toseekearly medical

attention if necessary vs. immediate testicular biopsy to ruleoutITGCN/totreataccordingly)aredebatable.Several variablessuchastheageofthepatient,thedesireofpater- nity,theassociationofseveralriskfactors,thepresenceof atesticulardysgenesissyndromeandifthepatientreceived previous chemotherapy after a contralateral orchiectomy couldhelpinthedecisionmaking.

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

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