Germ cell development in the postnatal testis: the key to prevent malignancy in cryptorchidism?

1.5 MB·English

by  Hutson, John M.

REVIEWARTICLE
published:03January2013
doi:10.3389/fendo.2012.00176
Germ cell development in the postnatal testis: the key to
prevent malignancy in cryptorchidism?
JohnM.Hutson1*,RuiliLi1,BridgetR.Southwell2,BodilL.Petersen3,JorgenThorup4 andDinaCortes5
1DepartmentofUrology,RoyalChildren’sHospital,Parkville,VIC,Australia
2FDouglasStephens,SurgicalResearchGroup,MurdochChildrensResearchInstitute,Melbourne,VIC,Australia
3DepartmentofPathology,UniversityofCopenhagen,Copenhagen,Denmark
4DepartmentofPaediatricSurgeryandPathology,Rigshospitalet,FacultyofHealthScience,UniversityofCopenhagen,Copenhagen,Denmark
5DepartmentofPaediatrics,HvidovreHospital,FacultyofHealthScience,UniversityofCopenhagen,Copenhagen,Denmark
Editedby: To permit normal postnatal germ cell development, the mammalian testis undergoes a
AlbertoFerlin,UniversityofPadova, complex,multi-stagedprocessofdescenttothescrotum.Failureofanypartofthisprocess
Italy
leads to congenital cryptorchidism, wherein the malpositioned testis finds itself at the
Reviewedby:
wrongtemperatureafterbirth,whichleadstosecondarygermcelllossandlaterinfertility
DanielaPasquali,SecondaUniversità
and risk of cancer. Recent studies suggest that neonatal gonocytes transform into the
degliStudidiNapoli,Italy
LucioGnessi,UniversityofRomeLa putativespermatogenicstemcellsbetween3and9months,andthisinitialpostnatalstep
Sapienza,Italy isderangedincryptorchidtestes.Inaddition,itisthoughttheabnormalityhightemperature
*Correspondence: mayalsoimpairapoptosisofremaininggonocytes,allowingsometopersisttobecomethe
JohnM.Hutson,Departmentof
possiblesourceofcarcinomainsituandmalignancyafterpuberty.Thebiologyofpostnatal
Urology,RoyalChildren’sHospital,
germ cell development is of intense interest, as it is likely to be the key to the optimal
Parkville,VIC3052,Australia.
e-mail:[email protected] timingfororchidopexy.
Keywords:germcell,gonocyte,spermatogium,testis,cryptorchidism,orchidopexy
INTRODUCTION examine the evidence for early orchidopexy to try and prevent
The right way to treat undescended testes (UDT) remains to be abnormalgermcelldevelopment.
solved. Although much is known about the development of the
testes and sperm cells, there is a missing link in our knowl- NORMALEMBRYOLOGYANDPOSTNATALDEVELOPMENT
edge. It is not known when and how the progenitors of germ INHUMANS
cells transform from neonatal gonocytes into spermatogonia or At 5 weeks of gestation, embryonic gonocytes migrate from
spermaticstemcells.Recentresearchsuggeststhatacriticalstage the umbilical stalk into the ambisexual gonad. Human sexual
of sperm cell development may occur in the early postnatal development then begins at 7–8 weeks’gestation when the SRY
period. Germ cell development has been studied extensively in (sex-determiningregionY)geneinitiatestesticulardifferentiation
the fetus and at puberty, but not in this postnatal window. We with Sertoli cell development (Sinclair, 1994). Cords of Sertoli
will propose in this review that knowledge about early postna- cells surround the newly arrived germ cells and the interstitial
talgermcelldevelopmentiscrucialfortheoptimalmanagement cells form Leydig cells and peritubular myoid cells. Müllerian-
ofUDT. inhibiting substance (or anti-Müllerian hormone) (MIS/AMH)
Undescended testes, or cryptorchidism, is a major problem andtestosteronesynthesisbySertolicellsandLeydigcells,respec-
occurring in about 5% of neonatal boys, with surgery to pull tively, trigger regression of Müllerian ducts and preservation of
thetestesdowntothescrotum(orchidopexy), currentlyrecom- Wolffian ducts which form epididymis, vas, and seminal vesi-
mendedbetween6and12–18months(Ritzenetal.,2007;Hutson cles(Wilsonetal.,1981;LeeandDonahoe,1993;Figure1). The
etal.,2010).Ithasbeenpreviouslyshowninnumerousstudiesthat intra-abdominalfetaltestisdescendstothescrotuminacomplex,
cryptorchidisminthepastwasassociatedwitha30–60%riskof two-stage process that in humans is complete at birth, while in
infertilityorlackofgermcells,anda5-to10-foldincreaseintestic- rodentsthesecondphaseoccursinthefirstweekafterbirth(Hut-
ularmalignancy.Crucialstepsinmaturationofgonocytesintothe son etal.,1997). The regulation of this two-stage process is not
spermcelllineageandofspermcelldevelopmentcouldbeoccur- thesubjectofthisreview,butinterestedreadersshouldseesome
ringinthisearlypostnatalperiodandcouldbedependentonlow recent reviews (Ivell and Hartung, 2003; Adham and Agoulnik,
temperaturepresentinthescrotumbutlackinginUDT.Inaddi- 2004;AmannandVeeramachaneni,2007;Bayetal.,2011).
tion,massivecelldeathshouldoccurinnon-maturinggonocytes, Inbabyboys,thetemperatureoftheintra-scrotaltestesdrops
◦
clearingthetestisofanyundifferentiated,pluripotentialneonatal to 33 C at birth, with all the testicular enzyme systems read-
germcells,aspersistingcellscouldgoontoundergocelldivision justingpresumablywithinafewweekstothisnewenvironment
and become cancerous. The timing of surgery for orchidopexy (Zorgniotti, 1991). Between 2 and 4 months of age pituitary
aims to prevent these problems but lacks scientific evidence. In gonadotropins stimulate a sudden increase in testosterone pro-
thisreview,weexaminetheevidenceforearlypostnatalgermcell duction which peaks at about 3–6 months, before it wanes and
developmenttodeterminewhatcontrolsthesestepsandalsoto becomesalmostnegligibleuntiltheonsetof puberty. Thisbrief
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FIGURE1|Testiculardescent.(A)Cranialsuspensoryligament(CSL) duringmidgestationalgrowth(8–15weeks).(C)Calcitoningene-related
andgubernaculum(G)holdthetestis.Testosterone(T)andMIS/AMHact peptide(CGRP)releasedbythegenitofemoralnerve,andunderthe
onWolffianduct(WD)andMüllerianduct(MD).(B)Insulin3(Insl3)causes controloftestosterone,steersthemigratinggubernaculumtothe
thegubernacularswellingreactionthatholdsthetestisnearthegroin scrotum.
surgeofgonadotropinsandandrogensisknownas“mini-puberty” others have suggested a secondary hormonal malfunction, such
(Jobetal.,1988; HadziselimovicandZivkovic,2007). Asandro- a hypothalamic–pituitary axis deficiency (Hadziselimovic and
genlevelssubsidethereisasurgeinproductionofMIS/AMHby Zivkovic, 2007) or a placental failure to produce chorionic
Sertolicells,whichpeaksat6–12months,butremainshighthen gonadotropin (Heyns and Hutson, 1995). Based on twin stud-
untilpubertywhenserumlevelsfall(Bakeretal.,1990;Yamanaka ies,ithasalsobeensuggestedthatriskfactorsshouldbesoughtin
etal.,1991;Aksglaedeetal.,2010;Figure2). the intrauterine environment and the maternal genes. However,
another possibility first suggested in the eighteenth and nine-
ABNORMALPOSTNATALDEVELOPMENTINUDTIN teenth centuries, was that there was an anatomical defect in the
HUMANS mechanismofdescent.Withtheestablishmentofendocrinology
Failureof thefirstorsecondphaseof testiculardescentleadsto in the early twentieth century, these anatomical concepts were
congenital cryptorchidism. The causes of UDT remain largely mostlyreplacedwithexplanationsofhormonaldysfunction,such
unknown with some authors suggesting a primary testicu- asdescribedabove(HeynsandHutson,1995).However,ourown
lar hormonal malfunction (Heyns and Hutson, 1995), while research over the last 25 years, along with others, has suggested
FIGURE2|“Mini-puberty,”withtestosterone(T)andMIS/AMH formabout3–4years.Afteraperiodofquiescence,spermatidsformabout10
secretedafterbirth.Neonatalgonocytesmatureintoadultdark yearsofage,withtheonsetonspermatogenesis.Undescendedtestis(UDT)
spermatogoniabetween3and9monthsofage,andprimaryspermatocytes interfereswiththefirststep.
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thatanatomicalfaultsmaybeacommoncauseofcryptorchidism to prevent development of cancer in men (Gracia etal., 2000).
(Backhouse,1964).Cryptorchidismisassociatedwithothercon- However, the age for orchidopexy is now much younger, and it
genital abnormalities in less than 20% of the cases, but when remainstobeseenwhetherthiswillalteroutcomesinadulthood.
presentthenmostareoftenrelatedtoabnormalitiesof themid- Recentstudiesactuallyindicatethatoperationforcryptorchidism
lineandthecaudaldevelopmentfieldofthebody(Cortes,1998; at a young age lowers the risk of testicular cancer in adulthood
Jensenetal.,2010;Thorupetal.,2010). Twokeyobservationsin (Petterssonetal.,2007).
favor of this view are the failure to document convincing pri- Meanwhile,inpediatrics,itfirstbecameapparentinthe1970s
maryhormonaldefects,aswellastherealizationthatthesecond that degeneration of the UDT was occurring in early childhood
phase of descent is a very complex anatomical process, that is (Mengeletal.,1974).Initiallyitwasnotedthattherewasmacro-
likelytobepronetosubtleanomalies(AmannandVeeramacha- scopicatrophyofthetestisinearlyprimaryschoolyearsleading
neni,2007;Thorupetal.,2012).Thisisfurthersupportedbythe to the view that maybe orchidopexy should be done in 5- to
factthattheanomalymostoftenoccursunilaterally,andincases 6-year-oldboysratherthanat10–15years,basedontheassump-
whereassociatedWolffianductand/oruretericbudmalformations tionthatthismightpreventtheobviouslyvisibledevelopmentof
are present, these are predominantly found ipsilaterally (Cortes atrophy.Duringthe1970sandearly1980stherewashistological
etal.,1998a). evidenceaccumulatingofdegenerationvisibleinboysof2years
Ifsomethinggoeswrongwithmigrationofthegubernaculum of age with UDT, leading to the recommendation in pediatric
fromtheexternalinguinalringinthegroinacrossthepubisand surgerythatorchidopexymightbeoptimallydonein2-year-old
intothescrotum,theinitiallynormalpostnataltestisisretained boys (Hadziselimovic etal., 1975). It was then appreciated that
deeptotheinguinalfatpad,whichisaneffectiveinsulator,keep- there were signs of early degeneration in the testis on electron
◦
ing the UDT at 34–37 C (Mieusset etal.,1993), rather than the microscopy at about 12 months of age (Hadziselimovic, 1985;
◦
normalscrotaltemperatureof33 C,andthisisbelievedtotrigger Figure3).
theprogressivepostnataltesticulardysfunction, asthepostnatal Furthermore,itwasreportedthatallUDTharboredgermcells
◦
testis function is only optimal at 33 C (Zorgniotti, 1991). The atthetimeofbirth,butthenumberofgermcellswasdecreasedin
exquisitetemperaturesensitivityof thetestishasbeenwelldoc- aboutone-fourthof cryptorchidnewborns(Cortes,1998). Lack
umentedforalongtime,butiscurrentlynotafashionablearea of germ cells has been reported from 12, and especially from
of research in this era of molecular biology. However, the phe- 18monthsofage,andthereforesurgeryhasbeenrecommended
nomenonhasbeensolidlyprovendespitethegeneticregulationof before12or18monthsofage(Ritzenetal.,2007).
itnotbeingfullydescribed.Thisabnormalpostnataldevelopment Recentstudieshaveimplicatedtheveryfirstphases(i.e.,inthe
inthetestisalsoleadstoinhibitedpostnatalandrogenproduction first year) of postnatal germ cell development in the etiology of
(Raivioetal.,2003)andMIS/AMHproductionat6–12monthsof the subsequent infertility and risk of malignancy. However, we
age(Yamanakaetal.,1991). first need to describe normal germ cell development so that the
The net effect of cryptorchidism is germ cell loss, leading effectsofcryptorchidismcanbeunderstoodincontext.
to infertility (Mengel etal., 1974; Hadziselimovic, 1985). This
has been well described in many long-term outcome studies in NORMALGERMCELLDEVELOPMENT
men with a previous history of cryptorchidism in childhood Around4–6weeksof gestationwithintheembryonicurogenital
(Cortes, 1998; Gracia etal., 2000; Cortes etal., 2001; Vincardi ridge the primitive gonad forms on the anteromedial surface of
etal., 2001). However, the cause for this germ cell loss and the middle kidney or mesonephros. Primordial germ cells form
its timing have remained elusive until relatively recently. In the from endodermal cells in the caudal edge of the yolk sac stalk,
1950s,orchidopexywasrecommendedinboysaged10–15years and then migrate into the embryonic celom around the wall of
if the cryptorchid testes failed to descend spontaneously into the midgut and into the urogenital ridge, eventually colonizing
the scrotum at the onset of puberty (Gross and Jewett, 1956; the ambisexual gonad and differentiating into gonocytes. By 22
Vincardi etal., 2001). This recommendation was based on the weeks of gestation, these primitive germ cells mature into fetal
clearobservationthatasignificantnumberof cryptorchidtestes spermatogonia(Hadziselimovic,1983).Mesenchymalcellsinthe
descendedspontaneouslyatpuberty.Inaddition,itwasassumed 7-to8-weekambisexualgonadsurroundingthearrivinggermcells
that germ cell development was totally quiescent in childhood. form the Sertoli cells with the onset of sexual differentiation to
Indeed, it was thought that the testis was effectively in “sus- createthetesticularcords,insideabasementmembrane.Outside
pended animation” until the onset of spermatogenesis in early the cords some mesenchymal cells form Leydig cells and begin
puberty. hormonesynthesistoproduceandrogenandinsulin-likehormone
Current long-term follow-up studies of men with a previous 3(INSL3),whileothersformintomyoepithelialcellsaroundthe
historyofcryptorchidismshowa5-to10-foldincreaseinmalig- cords.
nancyrisk(Whitaker,1988;WoodandElder,2009). However,it At birth, the fetal spermatogonia or neonatal gonocytes are
iseasytoforgetthatbecauseof theverylonglag-time(i.e., 30– located in the center of the spermatic cords. Throughout child-
40years)betweeninterventionandmeasurementoftheoutcome, hooditappearsthatthegermcellsremainedinthecenterofthe
in this case development of testicular malignancy, that the age cords,andseemedtobein“hibernation”untiltheonsetofsper-
of orchidopexyinmostof thesestudiesinthecurrentliterature matogenesisatpuberty, astherewaslittlehistologicalchangein
is about 5–15 years of age. This has led to the widespread view theirappearanceorlocation.However,inrecentyears,itbecame
inadultendocrinologyandoncologythatorchidopexyisunable apparent that by 3–4 years of age the cell in the center of the
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Hutsonetal. Postnatalgermcelldevelopment
have been classified as dark type-A (Ad), pale type-A (Ap), and
type-B.Ad-spermatogoniahavenucleishowingahomogeneous,
darkstainablechromatinandoneormoreclearcavitiesofvacuole
likeappearance(Clermont,1963). Thetype-Aspermatogonium
hasbecomethelikelystemcellofspermatogenesis(deRooijand
Russell, 2000; Drumond etal., 2001; Biers and Malone, 2010).
Interestingly not all neonatal gonocytes transform into type-A
spermatogonia, so that by 1–2 years of age the total germ cell
numberislessthanhalfthatatbirth(Hadziselimovic,1983).The
remaining gonocytes are thought to undergo apoptosis, or pro-
gramed cell death, so that by 2 years of age there are none left
in the testis (Huff etal.,2001b). This process can be seen read-
ily in the postnatal rat testis, as signs of apoptosis are rare until
day3,butbyday4analysisshowsthatone-thirdofthemarelost
(Roosen-RungeandLeik,2000).
THESPERMATOGENICSTEMCELL
Asneonatalgonocytesseemtodifferentiateintounipotentstem
cellsforsubsequentspermatogenesis,theirchangeinappearance,
locationwithinthecord,andfunctionsuggestdramaticchangesin
germcellularphysiology.Thesechangesareregulatedbyaprecisely
coordinatedexpressionofkeyproteins,someofwhichareknown.
Inearlyembryos,germcellsandpluripotentembryonicstem
cellscanformanytypeofcell.However,asdevelopmentproceeds,
theabilityofgermcellstoformdifferentcellsbecomesrestricted.
In testes a subpopulation of germ cells retain the ability to dif-
ferentiate, butonlyasunipotentspermatogenicstemcell(SSCs;
Hofmannetal.,2005).
HuckinsandOakberghaveproposedawidelyacceptedmodel
for spermatogenic development which is useful to describe here
FIGURE3|Theageatwhichorchidopexyhasbeenadvocatedsincethe
(Huckins,1971;Oakberg,1971;deRooijandRussell,2000).Inthis
1950s.ReproducedwithmodificationsfromHutsonandBeasley(1992).
model,singletype-AspermatogoniaaretheputativeSSCs,which
can self-renew, while paired type-A spermatogonia are differen-
tiatingpaireddaughtercellsconnectedbyanintercellularbridge.
testicularcordsisaprimaryspermatocyte,ratherthananeonatal Pairedtype-Aspermatogoniadivideintochainsof alignedcells,
gonocyte(Hadziselimovic,1983). whichthenbecometypeA ,A ,A ,andthenA spermatogonia.
1 2 3 4
Recent studies show that the neonatal gonocyte migrates The latter cells (A ) divide to form intermediate spermatogonia
4
between the Sertoli cells to the periphery of the cord between andthetype-Bspermatogonia. Type-Bcellsthendividetoform
3and9monthsofage,or2and6daysofageinmice(Drumond primary spermatocytes that enter meiosis (Figure 4). All these
etal.,2001;Huffetal.,2001b),whereitcomesincontactwiththe steps are regulated by growth factors from Sertoli and possibly
basement membrane. These factors trigger transformation into theperitubularmyoidcells(Skinner,1991;Jegou,1993).Arecent
type-Aspermatogonia,whichlinethebasementmembrane,dis- morphologicalstudy(Drumondetal.,2001)showedthatpostna-
placingtheadjacentSertolicells.Theregulatoryfactorsinvolved taldevelopmentoftype-Aspermatogoniamayoccurmorerapidly
inthistransformationaremostlyunknown(seebelow),although thaninmaturespermatogenesis.
platelet-derivedgrowthfactors(PDGF)BandD,andalsoPDGF Thetype-AspermatogoniaandSSCshavebeenshownrecently
receptor-beta (PDGFR-β) have been implicated (Basciani etal., toexpressarangeofdifferentmarkers(Figure5).Undifferentiated
2008, 2010). Inhibition of PDGFR-β tyrosine kinase activity in SSCsexpresstheintegrinsβ-1andα-6(Shinoharaetal.,1999),and
thefirstweekpostnatallyinamousecausesaseverereductionin thereceptorsforglial-derivedneurotrophicfactor(GDNF),such
theproliferationofgonocytesandincreasestheirapoptosis(Bas- asGDNFfamilyreceptoralpha-1(GFRα-1)andreceptortyrosine
cianietal.,2008,2010).Type-Aspermatogoniamatureintotype-B kinase(RET)(deRooijandRussell,2000). Inadditionundiffer-
spermatogonia,thenmigratebackintothecenterofcordagainby entiatedSSCsexpressZbtb-16(previouslyknownasPlzf; Buaas
3–4years,tobecomeprimaryspermatocytes. etal.,2004;Costoyaetal.,2004).OnceSSCsstarttodifferentiate,
Alongside these studies of early postnatal germ cell develop- theybeginexpressingarangeofdifferentmarkers,includingc-Kit,
ment have been studies searching for the potential stem cell of thereceptorforstemcellfactor(Besmeretal.,1993;Yoshidaetal.,
spermatogenesis,withtheaimofusingthesestemcellsforrecol- 2006).TheyalsoexpressSohlh1andSohlh2,aswellasneurogenin
onizingtheinfertiletestis(Brinster,2007;WaheebandHofmann, 3(Ballowetal.,2006;Filipponietal.,2007;Haoetal.,2008).Ascan
2011). Based on morphological criteria, human spermatogonia beseenfromthisbriefoverview,mostofwhatweknowaboutSSCs
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FIGURE4|Postnatalgermcelldevelopmentinhumans.(A)Gonocytes ofgermcells/tubuleinanormaltestisandundescendedtestis(UDT)relative
migratefromthecenterofthecordstothebasementmembranearound6 toageinyears.Notethenormalfallintotalnumbersbetweenbirthand2
months,andbecometype-Aspermatogonia.By3–4yearsofagethecenter years,butfailureofthistorecoverinUDT.Theshadedareashowsthenormal
ofthecordsbecomesrecolonizedwithprimaryspermatocytes.(B)Numbers rangeandthedottedlinesshowtheaveragenumbers.
FIGURE5|Germcelldevelopmentinthefirstweekpostnatallyintherat,showingthegermcellslabeledwithMVH(mousehomologofDrosophila
Vasa),andtheSertolicellslabeledwithMIS/AMH(bar=10μm).(A)Day0,(B)Day4,(C)Day6,(D)Day10.
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comesfromstudiesofadultspermatogenesisorstemcellresearch, (HadziselimovicandHerzog,2001b). The degree of risk of sub-
ratherthanadirectstudyof thetype-Aspermatogoniuminthe sequent infertility can be quantitated, as it is almost inevitable
postnataltestis. if therearefewerthan1%of thenumberof spermatogoniaper
tubularcross-section,seeninbiopsiesfromage-matchedcontrols
ABNORMALGERMCELLDEVELOPMENT (Cortesetal.,1996). Undernormalphysiologicalcircumstances,
All cryptorchid testes of newborns contain germ cells, although thesurgeof gonadotropinsandtestosterone, andpossiblyother
in some testes the number is impaired compared to normal. as yet unknown hormones, occurs at 2–3 months of postnatal
So significant deranged germ cell development in cryptorchid age. This hormonal surge stimulates the gonocytes in the testis
testesprobablybeginspostnatally,exceptinthedysgenetictestis to develop into adult dark spermatogonia. In cryptorchidism
in disorders of sex development (DSD). The first step to fail is there has been reported evidence for a beneficial role of adju-
transformation of gonocytes into type-A spermatogonia, which vantgonadotropin-releasinghormonetoimprovefertilityinUDT
is delayed or interrupted. Evidence for this disruption is found (BiersandMalone,2010).Ithasbeenquestionedasageneralrec-
inthepersistenceoflargenumbersofgonocytesinthecenterof ommendation(Hutson,2010).Recentlytherehavebeendescribed
thetesticularcordswellbeyond6monthsofage(Figure6),and differentgroupsofcryptorchidboys,andifthepatientsatthetime
a decreased number of type-A spermatogonia (Hadziselimovic ofsurgeryhaveadecreasednumberofgermcellsand/orinhibinB
etal.,1986; Huff etal.,1989,1991). Afterthefirstyearorsothe andnocompensatoryincreaseingonadotropins,thensupplemen-
numberof spermatogoniadecrease, whilethosethatremainare taryhormonaltreatmentmaybeindicatedafterearlysurgeryfor
gonocyteswithbizarrenuclei(Hadziselimovic,1983).By3–4years UDT(Thorupetal.,2012). Ithasbeensuggestedthatantisperm
ofagetheabnormalityhasbecomeevenmoreobvious,withfailure antibodiesmaybeinvolvedinthegermcelllossincryptorchidism,
ofprimaryspermatocytestoappear(Huffetal.,1989). butthereisnoevidenceforpostpubertalantibodiesafterprevious
The abnormally high temperature of the cryptorchid human surgeryinchildhoodforcryptorchidism(Mirilasetal.,2003).All
testisisconsideredbymostauthorstobethecauseof thisgerm thesestudiessuggestthatthepostpubertalpoorfertilityislikely
cellmaldevelopment.Considerablestudieshavebeenperformed to be caused by an abnormally small pool of SSCs, the type- A
invariousanimalmodelsshowingthatheatstressleadstoacom- spermatogonia.
bination of both indirect and direct effects on the germ cells, Theriskofcanceraftercryptorchidismininfancyislesseasily
causingimpairedtransformationandmaturationaswellasinhib- correlatedwithabnormalgermcelldevelopmentafterbirth.Ithas
itedapoptosis.Thisthermalinjuryismediatedbyreactiveoxygen beenwelldescribedthattheriskof developingatesticulargerm
speciesandcertainheat-shockproteins,whichdamagethegerm cellcancerisabout5-to10-foldhigherinmenwithaprevious
cellsaswellasSertolicells(Setchell,1998; Zinietal.,1999; Ivell history of cryptorchidism compared with those with descended
andHartung,2003). testisinchildhood(Chilversetal.,1986; Giwercmanetal.,1987;
Defectivetransformationofgonocytesintotype-Adarksper- Moller etal.,1998; Wood and Elder,2009). Testicular germ cell
matogonia between 3 and 9 months of age correlates with tumorsareextremelycommon,affecting1%ofyoungmen(Rorth
abnormalspermcountsafterpuberty(HadziselimovicandHer- etal.,2000).
zog, 2001a; Huff etal., 2001a). In cases of no adult dark The common precursor of these tumors is the premalignant
spermatogonia, the age of orchidopexy has not affected a carcinomainsitu(CIS)cell,whichisproposedtobeafetalgerm
poor result for spermatogenesis in adulthood, at least so far cellthatfailedtodifferentiate,andremains,dormantinthetestis
until after puberty (Skakkebaek etal.,1982). The evidence sup-
portingthisviewcomesfromthemanysimilaritiesbetweenCIS
cells and fetal gonocytes, which share many markers and mor-
phologicalcharacteristics(HolsteinandKorner,1974;Skakkebaek
etal.,1982;Rorthetal.,2000;Rajpert-DeMeytsetal.,2003).CIS
cellsmaywelloriginateduringfetaldevelopmentinDSD,where
the germ cell physiology is deranged by the underlying genetic
anomaly.Bycontrast,thisseemslessplausibleincryptorchidism
if the maldescent is caused by extraneous mechanical defects.
In cryptorchidism, therefore, the CIS cell may arise from the
neonatalgonocytes,whichareabnormallyabundant. Thegono-
cyteshavepluripotentstemcellproperties, whichif theypersist
untilafterpuberty,withorwithoutmutation,maydevelopinto
cancer.
Carcinomainsitucellsaremorelikelytobepresentwherethere
arespecificgeneticdefects,andtheremaybedevelopmentalarrest
(Skakkebaeketal.,1987,1998;Honeckeretal.,2004).Expression
FIGURE6|Abnormalpersistenceofgonocytesbeyond6monthsof profiles of CIS cells and embryonic stem cells are very similar,
ageinaboywithcryptorchidism.ThegermcellsarelabeledwithMVH which supports the view of CIS being a multipotent stem cell
(mousehomologofDrosophilaVasa),andtheSertolicellsarelabeledwith
(Almstrupetal.,2004).Aunifyinghypothesishasbeenproposed
MIS/AMH(bar=10μm).
to link testicular maldevelopment, testicular cancer, low sperm
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counts, and cryptorchidism, known as the testicular dysgenesis
syndrome(TDS;Asklundetal.,2004).
Carcinoma in situ is more common in men with previous
cryptorchidism, and is documented in 2–3% of adult patients
(Giwercman etal.,1987,1989). However, the prevalence of CIS
ishigherinthosemenwithmacroscopictesticularatrophy(Har-
landetal.,1998)orthosewithbilateralcryptorchidism(Swerdlow
etal.,1997).Wherecryptorchidismisunilateral,thecontralateral
descended testis has a slightly increased risk of cancer (Forman
etal.,1994).Notsurprisingly,cancerriskisalsoincreasedwhere
testeswereintra-abdominal,thegenitaliawereabnormalorthere
wasaknownabnormalkaryotype(Cortesetal.,1999).
Inapediatriccollectiveseriesofsixstudies,theriskofCISin
2800 boys with cryptorchidism was 0.36% only (Cortes, 1998).
Whencomparedtohigherincidencedatafromadultsthesepedi-
atric figures support the hypothesis that the characteristics of
CIS cells and later testicular cancer develops over time, and are
not present from fetal life. Generally CIS in pediatric series is
described in later childhood (Cortes etal., 1999). However, in
thispaperwepresenta12-month-oldboywithsuspectedCISin
bilateral cryptorchid testes (Figure 7). It has to be emphasized
thatpositiveimmunohistochemicalmarkersindicatingCISinthe
adulttestisdonothavesuchpredictivevaluewhenappliedtothe
childhoodcryptorchidtestis.Positivestainingbysuchmarkersof
persistentfetalgermcellsisseeninalmosthalfofthecryptorchid
testesofboysyoungerthan5years(Thorupetal.,2012).Presence
ofplacentalalkalinephosphatase(PLAP)-positiveimmunohisto-
chemicalstainedgonocytesinbilateralcryptorchidtestesofinfant
boysindicatestheabilityofdelayedgermcelltransformationand
a preserved good fertility potential (Cortes etal.,2012). Further
researchinthisfieldisthereforeneeded.
It has been suggested that testicular biopsy itself at the time
oforchidopexyisariskfactorforpostpubertalcancer(Swerdlow
etal.,1997).InthereviewbySwerdlowetal.(1997)only9%ofthe
operatedtestesweresubjectedtobiopsy,consistentwithapossible
selectionbiasbythesurgeon,whomayhaveonlypickedthemore
atrophic testes for analysis. This view is supported by a large
study of 830 cryptorchid patients having routine biopsy, where
therewasnocorrelationbetweenthebiopsyitselfandsubsequent
malignancy(Molleretal.,1998).
Someauthorshavesuggestedthatadolescentswithaprevious
history of cryptorchidism and orchidopexy should be offered a
biopsytoidentifyif CISispresent,beforeinvasionhasoccurred
(Giwercmanetal.,1989). Alternativescreeningmethodssuchas FIGURE7|Testiculartissuefroma12-month-oldboywithbilateral
cryptorchidism.Carcinomainsitu(CIS)issuspected.(A)H&Estaining:
reliable blood or semen analysis are not yet available, although
Sertolicellsarenormalandthegermcellnumberisattheupperrangefor
testicularultrasonographymayhaveaplace(Holmetal.,2001). age.Somegermcellshavetwonuclei,andsomenucleihaveirregular
Ultrasonographyshowsarelationshipbetweenmicrolithiasisand morphologyandsomenucleolus.Amicrolithisclearlyseenwithinatubule.
CIS, but the significance of this is uncertain (Lenz etal., 1996), (B)StrongPLAPexpressionseeninallgermcells.(C)OCT4expressionin
germcellsalsointheperipheryoftubules,whichisnotoftenseenso
particularly as more recent studies of testicular microlithiasis
impressivelyinmostcryptorchidtestesatasimilarage.
showthatitisquitecommoninnormaladolescents(Goedeetal.,
2009).CISisalsoassociatedinsomepatientswithcryptorchidism
withmultinucleatedgermcells,consistentwithaberrantgermcell surgery in these follow-up studies averaged more than 2 years
development(Cortesetal.,2003). old. Inthecontextof theproposal,thatearlygermcelldevelop-
There is inconclusive evidence that an early age of surgery mentisthekey,theselong-termresultsareconsistentwitheither
leads to a reduction in risk of cancer (Pike etal., 1986; Swerd- noeffectofageatall,orwiththesuggestionthatlackofneonatal
low etal., 1997; Wood and Elder, 2009). However, because of gonocyte transformation and impaired apoptosis predisposes to
the long lag-time between treatment and outcome, the age at malignancy.
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Hutsonetal. Postnatalgermcelldevelopment
One of the problems that has bedeviled the relationship the low-temperature scrotal environment. In humans, the testis
◦
betweencryptorchidismandmalignancyisthelackofananimal is at 33 C from birth, so that congenital UDT has the potential
model, as rodents with UDT do not develop testicular tumors. todamageneonatalgonocytesbyhightemperature.Bycontrast,
Anotherproblemisthatevidenceisaccumulatingthatthereare rodenttestesonlyreachthescrotumafter12daysofage(Bergh,
some testes that become undescended after birth, and that this 1991),whichiswellafternormalgonocytetransformationand/or
group, now known as acquired cryptorchidism, have a different apoptosisiscomplete(Figure8).
riskofmalignancycomparedwithcongenitalUDT. Undescended testis in rodents, therefore, is actually a model
for acquired UDT in humans, with high temperature damaging
ACQUIREDCRYPTORCHIDISM the SSCs, but with no cancer risk as the gonocytes will have
After birth, the distance from the inguinal canal to the scrotum developed or disappeared normally. Once this key difference in
increasesfrom4–5to8–10cminearlyadolescence(Smithetal., timingoftesticulardescentisunderstood,extrapolationbetween
1989).Thismeansthatthespermaticcordmustdoubleinlength rodentmodelsandthehumansituationisstraightforward,asother
between birth and puberty (Hutson etal., 2010). We have pre- keyprocessesarethesame.Bothspeciesgroupshaveapostnatal
viously proposed that failure of this elongation is the cause of “mini-puberty”at3–6monthsinhumansand2–4daysinmice,
ascendingtestesoracquiredUDT(HutsonandHasthorpe,2005), whenthereisburstof testicularhormonesandcytokineswhich
and this is the likely explanation for many children still having are likely to be involved in gonocyte development. In addition,
orchidopexyat5–10years,despiterecommendationsforsurgery gonocytemigrationfromthecenterofthecordstothebasement
ininfancy(Donaldsonetal.,1996). membrane to form SSCs is similar in both timing and general
Realization that there are two types of UDT has triggered a morphology.
re-evaluationof thecauseandeffectof UDT.First, itisbecom- Atemperaturedifferencebetweenundescendedandnormally
ing apparent that men who had untreated, acquired UDT have descended testes in rats is not present until after 12 days of age
noincreasedcancerrisk,butstillhaveimpairedfertility(Cortes (Zorgniotti,1991),whichiswellafterthegonocytesshouldhave
etal.,1998b).Secondly,itmeansthatcurrentlong-termfollow-up transformednormallyintoSSCsorhaveundergoneapoptosis.If
studiesinadultsarelikelytocontainamixtureof patientswith excess persisting gonocytes are the cause of CIS and cancer in
bothcongenitalandacquiredUDT(Bonneyetal.,2008),making cryptorchidism,thennonewillbepresentinthetestiswhenthe
theirinterpretationdifficult. temperature becomes abnormal in rodent UDT,consistent with
Investigators have puzzled over why UDT in rodents caused thelackofcancerinthesemodels.However,thehightemperature
infertility but not cancer, as in humans. We propose that this oftheUDTwillstilldamageSSCsleadingtosubsequentinfertility
is the result of differences in timing in when the testis reaches (Figure8).
FIGURE8|Testiculartemperatureinhumansandrodents. acquiredUDTonlyinterfereswithsubsequentsurvivalofstemcells.(B)In
(A)Humangonocytesmatureinthefirstyearwhenthetesticular rodents,gonocytesmaturebeforeachangeintemperatureoccurs,sothat
temperatureis33◦C.CongenitalUDThaveabnormaltemperature gonocytedevelopmentisunaffected,similartoacquiredUDTin
early,whichinterfereswithgonocytedevelopment.Bycontrast, humans.
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Hutsonetal. Postnatalgermcelldevelopment
CONCLUDINGREMARKS Therecognitionof acquiredUDTasarealclinicalentityhas
All the evidence available points to early germ cell matura- notonlyinformedourunderstandingofthepossiblemanagement
tion being the “missing link” in the disconnection between inchildren,butalsoprovidedaninsightintowhyrodentanimal
the timing of orchidopexy and the subsequent risks of both models of cryptorchidism do not demonstrate testicular cancer.
infertility and malignancy. This suggests that infants getting Inbothcircumstances,theabnormaltemperatureaffectsthetestis
really early operation may have significantly improved out- wellaftergonocytematurationorapoptosisiscomplete, sothat
comes, although this remains hypothetical. Furthermore, in secondaryheatshockdepressesstemcellfunctionalone,leading
some cases supplementary hormonal treatment may be needed toinfertility.
to achieve the normal transformation to adult dark spermato- The next few years should help to shed light on these new
gonia. developmentsfurther,sothatwecandeterminetheoptimaltreat-
Thekeyroleofheatininterferingwiththesignalingthatcon- ment, which may include a differentiated treatment strategy for
trolsbothgonocytetransformationand/orapoptosisneedstobe different groups of cryptorchid boys. Equally, the risk of infer-
reinvestigated fully, as it is likely to lead to changes in clinical tilityandtesticularcancermaynotbethesameinallboyswith
managementofcongenitalcryptorchidism. cryptorchidism.
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