7111532 radiologia-na-neoplasia-trofoblastica-gestacional

REVIEW

Radiology of gestational trophoblastic neoplasia

S.D. Allena, A.K. Lima, M.J. Secklb, D.M. Blunta, A.W. Mitchella,*

Departments of aRadiology, and bMedical Oncology, Charing Cross Hospital, Hammersmith Hospitals NHSTrust, London, UK

Received 5 September 2005; received in revised form 26 October 2005; accepted 5 December 2005

Gestational trophoblastic neoplasia (GTN) encompasses a broad spectrum of placental lesions from the pre-malignanthydatidiform mole (complete and partial) through to the malignant invasive mole, choriocarcinoma and rare placentalsite trophoblastic tumour (PSTT). Ultrasound remains the radiological investigation of choice for initial diagnosis, and itcan also predict invasive and recurrent disease. Magnetic resonance imaging is of invaluable use in assessing extra-uterine tumour spread, tumour vascularity, and overall staging. Positron emission tomography and computedtomography undoubtedly have a role in recurrent and metastatic disease, while angiography has a place in disease andcomplication management. This review will describe the relevant pathophysiology and natural history of GTN, and theuse of imaging techniques in the diagnosis and management of these conditions.Q 2006 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction

Gestational trophoblastic neoplasia (GTN) com-prises a spectrum of placental lesions that arisefrom pregnancy and vary considerably in theirclinicopathological behaviour. Hydatidiformmoles, which often behave benignly, are bestregarded as pre-malignant because 16% of complete(CHM) and 0.5% of partial moles (PHM) can trans-form into the malignant forms of GTN, whichinclude invasive mole, choriocarcinoma and pla-cental site trophoblastic tumour (PSTT).1 The latterdisorders are also termed collectively as gestationaltrophoblastic tumours (GTT).

It is important to recognize GTN, as it is almostalways curable with preservation of fertility. Themany roles of imaging in this disease, from diagnosisto treatment, are discussed.

Background

The frequency of GTN varies tremendously withgeography. Rates of CHM are approximately

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* Guarantor and correspondent: A.W. Mitchell, Department ofRadiology, Charing Cross Hospital, Hammersmith Hospitals NHSTrust, Fulham Palace Road, London W6 8RF, UK. Tel.: C44 208846 1863; fax: C44 20 8846 1885.

E-mail address: [email protected] (A.W. Mitchell).

0.5–1/1000 and PHM are 3/1000 pregnancies inEurope, though in Southeast Asia they are highest,2

up to 8/1000 in Thailand.3 The reason for thisvariation is not understood, though genetic, as wellas socio-economic/dietary and environmentalfactors, have been implicated.3,4

Increased risk of CHM and PHM occurs at theextremes of reproductive life, with women over 40years having at least a fivefold increase in risk.5

Also, a previous molar pregnancy is a predisposingfactor.6 Choriocarcinoma and PSTT can arise afterany type of pregnancy including CHM, PHM,miscarriage and term delivery.7,8 The incidence ofchoriocarcinoma arising after miscarriage or termdelivery is estimated to be 1/50,000 pregnancies.PSTT is so rare that accurate data on its incidenceor prevalence are not available.

Clinical assessment is difficult particularly earlyin the course of the disease, as few clinicalcharacteristics are present to distinguish it from anormal pregnancy. GTN is suspected in patientswith vaginal bleeding and a clinically enlargeduterus, though these features are non-specific.The presence and course of the disease is monitoredwith quantitative levels of serum beta humanchorionic gonadotrophin (hCG), which provides avaluable evaluation of the amount of trophoblasticdisease present.9 The radiological diagnosis of CHMand PHM is also often made at an early pregnancyultrasound scan.

Clinical Radiology (2006) 61, 301–313

gists. Published by Elsevier Ltd. All rights reserved.

S.D. Allen et al.302

The majority of CHM have a 46XX diploidchromosomal pattern and occur most commonlywhen a single haploid sperm fertilizes an ovumlacking maternal genes, and then undergoes dupli-cation. Macroscopically CHM classically resembles abunch of grapes, due to generalized swelling ofchorionic villi, and pathologically, is composed ofsyncytiotrophoblastic and cytotrophoblasticcells.10 These are usually intrauterine in site,though may contain some foetal tissue if coexistentwith a normal foetus and placenta in a dizygotictwin pregnancy. This can be a cause of pathologicalmisdiagnosis, as they may be classified as PHMs.11

PHMs are genetically triploid, most commonlythe result of fertilization of a normal egg by twosperm.12 Villous swelling is less intense, and anembryo is usually present, which may live into theearly second trimester. However, the villousswelling and trophoblast may be so subtle, thatmany PHM are missed during evacuation for a“miscarriage”, or during spontaneous abortions.10

Flow cytometry can be useful to distinguish thesefrom hydropic abortions and other non-molarchromosomal duplication syndromes.13

A CHM or PHM that invades the myometrium istermed an invasive mole and can be diagnosed onultrasound and on a rising hCG after uterineevacuation. Choriocarcinoma encompasses manyabnormal karyotypes and can arise following anypregnancy, including PHMs. It is highly malignant,necrotic and haemorrhagic, microscopically resem-bling an implanting blastocyst containing cytotro-phoblastic elements and absent chorionic villi. It islocally angio-invasive.10 Choriocarcinoma arisingafter a miscarriage or term delivery may notpresent for many years, can be normal on pelvicultrasonography and simply display as distantmetastatic disease with an elevated hCG. It istypically highly vascular and patients may presentwith signs of haemorrhage at any involved sites.14

Rarely patients may present with concurrentmetastatic disease, most commonly in the lungand vagina, but this can occur anywhere, includingthe liver and brain.

PSTT is the rarest form of GTN, but deservesseparate consideration, as it behaves in a distinctfashion.15 This represents a neoplastic prolifer-ation of intermediate trophoblasts that invade themyometrium at the placental site after preg-nancy.16 They may develop from an antecedentnormal pregnancy, abortion or after either a CHMor PHM,8 though the foremost is the commonestscenario.17 Clinical presentation is often withirregular vaginal bleeding but may be a conse-quence of metastatic disease.18 Unlike otherforms of malignant GTN, PSTT is often more

slow growing, tends to spread locally through theuterus and can involve lymph nodes (a very rarefinding for choriocarcinoma) before metastasizingelsewhere. PSTT also tend to be relatively poorlyvascularized tumours.17,19 Due to the lack ofsyncytiotrophoblastic tissue, serum hCG levelsare often only modestly elevated, although wehave never had a case at our institute where thehCG was not elevated. PSTT are also relativelychemoinsensitive, so when the disease is localizedto the uterus hysterectomy is recommended.However, women with metastatic disease canstill be cured with aggressive chemotherapy. Themain factor in determining outcome is theduration from the causative pregnancy: thosetreated within 4 years are nearly always curedwhilst those diagnosed beyond this time have sofar had a 100% death rate.

Several systems have been used to classify theseverity of GTN, including the Bagshawe scoringsystem,20 WHO score,21 and Charing Cross Hospi-tal prognostic scoring system.22 These all usefactors that have long been recognized aspredictive of poor outcome. More recently anew International Federation of Gynaecologistsand Obstetricians (FIGO) scoring system has beendeveloped and most centres use this to enablebetter comparison of patient response andoutcome (Fig. 1).23

The scoring systems have enabled simple strati-fication of patients into two therapeutic groups.Those with a low FIGO score (%6) have a low risk ofdeveloping disease resistant to single drug therapy(methotrexate or actinomycin D) whilst those witha high score (O6) require multi-agent combinationchemotherapy (Table 1 and Fig. 1). The FIGOstaging carries little prognostic significance and isnoted but not used to determine therapy. It shouldbe noted that PSTT are not classified under thisscoring system and those patients with metastaticPSTT require very aggressive multi-agentchemotherapy.

Approximately 84% of patients with CHM and99.5% of patients with PHM will be cured aftersuction evacuation of the uterus.7,24 Other surgi-cal techniques such as hysteroscopy and hyster-ectomy are not favoured as they significantlyincrease the likelihood of the need for chemother-apy, thought to be due to the uterine manipu-lation. Second evacuation is only rarely successfulat reducing the risk for chemotherapy and isgenerally not recommended.10 Patients withmalignant disease following CHM or PHM areusually at low risk of developing disease that isresistant to treatment with a single drug (metho-trexate or actinomycin D) and overall have an

Figure 1 Algorithm for the management of gestational trophoblastic neoplasia.

Radiology of gestational trophoblastic neoplasia 303

almost 100% cure rate.25 However, patients withhigh scoring disease that receive multidrugcombination chemotherapy with etoposide, meth-otrexate, adriamycin, alternating weekly withcyclophosphamide and vincristine (Oncovin)(EMA–CO) have an 80–90% cure rate.25–27

Table 1 The revised FIGO 2000 scoring system.

FIGO score 0 1Age (years) !40 R40Antecedent pregnancy Mole AbortioInterval months from index pregnancy !4 4–6Pre-treatment hCG (mIU/ml) !1000 1000–10Largest tumour size including uterus (cm) !3 3–5Site of metastases Lung Spleen,Number of metastases – 1–4Previous failed chemotherapy – –

FIGO staging for gestational trophoblastic neoplasia 2000. FIGO Oncopatients scoring 6 or less receive single drug therapy with either mwith multi-agent EMA/CO chemotherapy.

Imaging features

Ultrasound

Ultrasound is the radiological investigation of choicefor initial diagnosis of GTN. As well as identification

2 4– –

n Term –6–12 O12

,000 10,000–100,000 O100,000O5 –

kidney Gastro-intestinal Liver, brain5–8 O8Single drug Two or more drugs

logy Committee. Int J Gynaecol Obstet 2002;77:285–7. Low riskethotrexate or actinomycin D and those scoringO7 are treated

Figure 2 An axial image from a transabdominalultrasound image showing an enlarged uterus with amarkedly heterogeneous echo texture. A large complexmass is present centrally, with the endometrium notidentified separately. These are features of a molarpregnancy with probable endometrial encroachment.

Figure 3 A longitudinal image from a transabdominalultrasound image with power Doppler interrogation.Marked myometrial power Doppler signal surrounds anechogenic endometrial mass of molar tissue in anenlarged uterus.


of a mole, ultrasound should also be obtained toexclude an intrauterine pregnancy before initiatingchemotherapy. The most frequent transabdominalsonographic appearance of a CHM in the firsttrimester is that of an enlarged uterus containing apredominantly echogenic endometrial mass(Fig. 2).28 Unfortunately this appearance is non-specific and an incomplete miscarriage may appearidentical. The presence of a gestational sacsurrounding the echogenic oval-shaped mass, hasbeen reported.29 In these cases, only a significantclinical concern and correlation with a high hCGlevel will facilitate correct diagnosis. Transvaginalsonography (TVS) will demonstrate more findings,however, at our centre patients coming for assess-ment pre-chemotherapy do not normally undergoTVS as this might trigger bleeding from a possiblevaginal metastasis. This technique will show theinterface between abnormal trophoblastic tissueand normal myometrium with higher resolution, andhence may allow the diagnosis of myometrialinvasion. This is particularly relevant, as thisinvasive disease may remain after surgical evacua-tion.30 It also may show the characteristic patho-logical molar vesicles. These typically punctuate thelesion and appear as multiple small anechoic spaces,ranging from 1–30 mm in diameter.31 Within thesecond trimester a CHM will further expand theuterus, and the anechoic spaces will become morenumerous and visible, even transabdominally.

There can be diagnostic difficulty in distinguish-ing a PHM from a CHM and practically, thedistinction is usually made histopathologically

after evacuation of the molar tissue. However,this distinction does not affect the management asboth need to be evacuated. Classically with PHM,the placenta is enlarged and thickened and containsmultiple diffuse anechoic lesions consistent withcystic degeneration.32 The mole itself tends to beless advanced than a complete mole of a compar-able gestational age, hence “partial”. It can beassociated with amniotic membranes, a functioningcirculation and even an embryo (usually nonviable).33 It may also occur as a tubal pregnancy,appearing similarly as a heterogeneous adnexalmass containing numerous hypoechoic structuresconsistent with cysts.34 Naumoff et al.,35 estab-lished ultrasound criteria for the diagnosis of PHM,stating that first the placenta should be enlargedwith numerous cysts, second there should be agestational sac present, and third any foetalmaterial present is growth retarded. However,these criteria are not specific. Sebire et al.,36,37

reviewed 155 histologically proven CHM or PHMwhom had had a preceding sonographic diagnosis. Inonly 34% was the diagnosis made of a molarpregnancy, with the remainder misdiagnosed asmiscarriages. Accuracy was higher in CHM (58%)compared with PHM (17%). Although ultrasound isvery useful to raise the suspicion of CHM/PHM thefinal diagnosis rests with the pathology.36,37

Although uterine disease is sometimes absent inpatients presenting with choriocarcinoma, likeinvasive moles they may appear as heterogeneous,echogenic masses characterized by necrosis andhaemorrhage. They are markedly hypervascular onDoppler interrogation, though in some cases endo-metrial, myometrial and parametrial invasion canbe difficult to demonstrate (Fig. 3). In such cases,

Figure 4 (a) A normal pulsed wave Doppler interrog-ation of the right uterine artery in a patient with treatedGTN. This shows normal high impedance flow waveformswith a uterine artery pulsatility index (UAPI) of 2.88(minimum normal UAPIO1.5).46 (b) An abnormal pulsedwave Doppler interrogation of the right uterine artery in apatient with active GTN. This shows low impedancewaveforms with a UAPI of 0.56. Note is also made ofmarked myometrial colour flow Doppler signal.


magnetic resonance imaging (MRI) can play animportant role, although it is rarely clinicallynecessary.30 Choriocarcinoma is distinguished his-tologically from an invasive mole by absentplacental villous structures, but this distinction isseldom possible sonographically.

PSTT may also appear as a heterogeneous,hyperechoic mass with multiple cystic spaces withinthe myometrium of an enlarged uterus.38 Thesefeatures alone do not allow distinction from otherforms of GTN, though on Doppler both hypervas-cular and hypovascular forms of the disease havebeen described with or without cystic masses, butnone of these features are diagnostic of PSTT.39,40

After treatment some patients may retainvascular abnormalities associated sometimes withresidual heterogeneous scaring but this is of nosignificance providing the serum and or urine hCGlevels remain normal and there is no associatedblood loss. These appearances may normalize withtime. Recurrent disease always manifests itselfwith a rising hCG and this should prompt repeatwhole-body imaging including a Doppler ultrasoundof the pelvis.41

As well as assessing the molar tissue present,an accurate measurement of uterine volumeshould be obtained. The uterine volume is knownto correlate with tumour burden and is usedamongst other factors to determine the riskstratification of the disease.20 At Charing Crosswe have preferred three-dimensional assessmentby volume as this is more accurate, but inter-nationally, most centres rely on a single measure-ment to determine the FIGO score (Fig. 1).Endometrial encroachment can also be assessed,but this has not yet been shown to correlate withthe degree of endometrial bleeding.

The use of colour flow and spectral Doppler hasincreased the sensitivity of ultrasound in theprimary diagnosis of GTN as well as having arole in monitoring disease response to treat-ment.42 The uterine vessels can be sampled, andwaveform patterns, peak velocities, resistiveindex (RI) and pulsatility index (PI) determined.Both RI and PI are indices that quantify resistanceto flow, with high resistive flow producing anincreased RI and PI, and vice versa.43 During anormal pregnancy, in the first trimester, Dopplerinterrogation of the intrauterine arterial systemshows high impedance waveforms with lowdiastolic velocities. At the implantation site, lowimpedance flow may be present due to physio-logical vascular invasion of trophoblastic tissue.Vascular impedance may reduce further in thesecond and third trimesters, as physiologicaltrophoblastic arterial invasion continues.44 In a

molar pregnancy, similarly arterial trophoblasticinvasion occurs, but at an abnormal rate. As aresult, high velocity, low impedance waveformson Doppler interrogation occur prominently in thefirst and early second trimesters, far earlier thanin a normal pregnancy (Fig. 4).45 The uterineartery PI as an indirect in vivo measure offunctional tumour vascularity, has been shown toindependently predict response to chemotherapy(more specifically methotrexate resistance), inGTN.42,46 Thus patients with a low PI indicatingincreased arteriovenous shunting, probably associ-ated with neovascularization found in GTN, aresignificantly more likely to become resistant tosingle drug therapy with methotrexate. If aprospective study confirms these retrospectiveresults, it is likely that PI assessments will needto be included in the GTN scoring system.46


Computed tomography (CT)

The role of CT in GTN is principally in the detectionof metastatic disease, and is discussed in a latersection. Although ultrasound is a more suitabletechnique for evaluation of the primary disease, anenlarged uterus with focal irregular low attenuationlesions are typical appearances.47 When visualizedextrauterine pelvic disease appears as bilateralovarian enlargement with multilocular theca luteincysts. Enhancing parametrial soft tissue is charac-teristic of local spread.

MRI

MRI does not have a role in routine assessment ofpersistent disease following a CHM or PHM, and isonly indicated in our practice in difficult cases suchas in relapsed patients, suspected PSTT, or veryadvanced disease. The MRI findings in GTN can berelatively non-specific, and it may be difficult todistinguish GTN from an incomplete miscarriage oran ectopic pregnancy.48

In CHM and PHM in the first trimester, little or noabnormality may be present, though primary molartissue may be visualized as heterogeneously highsignal intensity tumour on T2-weighted imaging(Fig. 5).48–50 Molar tissue may be seen to slightlydistend the endometrium and enlarge the uterus,with a “cluster of grapes appearance”.49 Thisfeature reflects the vesicular nature of the tumour,but is not usually present until the second

Figure 5 A sagittal T2-weighted MRI image in a patientwith known GTN. This shows a heterogeneous high signaluterine mass, with endometrial encroachment, butappears confined to the uterine corpus.

trimester. A focal rim of hypointense myometriummay surround this.

In the second trimester CHM and PHM aretypically of similar or higher signal intensity thanthe adjacent myometrium on T1-weighted imaging.Focal signal hyperintensity may reflect areas ofhaemorrhage within the lesion. Numerous cysticspaces may also be present within the mass and maybe characteristic.51 On T2-weighted imaging,tumours typically have a heterogeneous high signalintensity, with an indistinct boundary between theendometrium and myometrium.52 Diffuselyincreased myometrial signal with obliteration ofthe normal zonal architecture on T2-weightedimaging may reflect diffuse myometrial involve-ment by tumour, but this is not specific.50 This alsohas been shown to occur with missed and incom-plete miscarriage, and in patients who have had arecent diagnostic currettage.48,53 After treatmentthis appearance returns to normal, parallelingdecreasing hCG levels as disease load decreases.The converse has also been shown to apply, withpatients with a rising hCG having a continuedarchitectural disruption and a large tumour load.50

There appears to be correlation of uterine findingsat levels of hCG O1500 mIU/ml, but at levels !500 mIU/ml there is usually no MRIabnormality.48,50

Using contrast-enhanced dynamic MRI, areas offocal enhancement are visualized that relate to theamount of active trophoblastic tissue and alsocorrelate to hCG levels.54 Marked enhancement inthe early dynamic phase indicates active disease inthe form of viable trophoblastic cells with sur-rounding inflammatory response, and in patientswith markedly elevated hCG levels, there is strongenhancement. Non-dynamic post-contrast-enhanced T1-weighted imaging is not of similarvalue, as tumour–myometrial contrast is muchdecreased (normal myometrium is also enhancing).

Features to indicate high tumour vascularity, aretortuous flow voids consistent with vessels, passingthrough the tumour and within the adjacentmyometrium, parametrium and adnexae on bothT1 and T2-weighted imaging.55,56 Internal iliac andarcuate vessel engorgement, especially withrespect to the external iliac vessels are also afeature.52

As patients respond to chemotherapy, theuterine volume and the tumour vascularitydecrease. As normal uterine zonal anatomyreappears on T2-weighted imaging, signal hetero-geneity usually decreases, though intra-lesionalhaemorrhage may develop. At an interval of 6–9months after treatment, the majority of patientshave normal uterine appearances on both T1 and

Figure 6 An axial T2-weighted MRI image showing aheterogeneous high signal mass, arising from the uterus.There is clear extrauterine extension and probable pelvicside wall involvement (arrow). This lesion was histologi-cally a choriocarcinoma.


T2-weighted imaging, though incidental adnexalcysts of 2–4 cm in size were shown to be a commonfinding.52,57 Residual tortuous and coiled vesselswithin a thickened myometrium are a hallmark of auterine vascular malformation, a well-recognizedsequelae of treated GTN.58

Invasive moles have parametrial involvementthat can be readily visualized and appear as anenlarged high signal mass on T2-weighted imaging,within the parametrium and beyond the confines ofthe uterus (Fig. 6). This is identified better on MRIthan ultrasound. Vaginal involvement appears as abulbous wall of the fornix with indistinct marginsand an abnormally high signal intensity.52 Contrast-enhanced dynamic MRI, has potential for earlydemonstration of invasive disease in post molarGTN. Invasive GTN typically manifests as focalhyperintense areas within the myometrium, on T2-weighted imaging.51 The tumour may be hypervas-cular, and it may distort uterine zonal structures.The boundaries between the tumour and themyometrium are typically indistinct. Haemorrhageand necrosis are more common with this type ofdisease, which can be difficult to distinguish fromviable tumour, though this is easier with contrast-enhanced dynamic MRI.51,54 The MRI features ofhaemorrhage are of course quite variable depend-ing on the age, but are often manifest by high signalintensity on T1-weighted imaging.

Few studies have described the MRI features ofPSTT. As with ultrasound, two different MRIappearances undoubtedly correspond to the hyper-vascular and relatively hypovascular tumourtypes.39 The hypervascular type is described as an

isointense mass on T1-weighted imaging andslightly hyperintense on T2, relative to normalmyometrium.59 Numerous signal voids are visual-ized on all sequences, and marked dilatation ofgonadal vessels may be present. After the admin-istration of intravenous gadolinium, avid tumourenhancement is shown.60 The hypovascular tumourtype is described as being typically smaller in size,hyperintense to normal myometrium on both T1 andT2-weighted sequences, with some enhancementafter gadolinium administration. There is anabsence of signal voids or prominent vascular-ity.60,61 MRI allows more accurate tumour localiz-ation, clarifies vascularity, and shows extensionthrough the myometrium (if present), thus allowingmore appropriate surgical planning. However, theappearances described are not specific, and do notallow definitive distinction from other forms ofGTN.39

MRI is also employed to assess pelvic lymph nodestatus, however, this is only relevant in PSTT as theother forms do not tend to metastasize to lymphnodes.

Metastatic disease

Metastatic disease has been reported in up to 19% ofall GTN, but the vast majority of these cases occurin choriocarcinoma.62 Principally the route ofspread is haematogenous,63 and most commonlymetastases occur in the lungs; in up to 87% in oneseries.64 With the exception of vaginal disease, it isin fact rare to have other metastatic disease in theabsence of lung metastases.65

Pulmonary metastases occur due to embolizationof trophoblastic tissue that has escaped from theuterus into the venous outflow. Usually the amountof tissue that has entered the bloodstream is toosmall to block the pulmonary vasculature, andinvades the pulmonary parenchyma, establishingparenchymal metastases. Typical lesions arerounded, and are of soft tissue density, measuringusually up to 3 cm in diameter, and may rarelycavitate.64,66,67 They usually number less than 10,but can be solitary or even miliary.68 However, if asignificant amount of tissue enters the blood-stream, it can block the pulmonary vasculatureand will produce symptoms and signs of acutepulmonary embolism.69 On CT this may appear as alarge intravascular tumour, though pulmonaryinfarction may also result.68 On MRI high signalintravascular tumour may occlude the pulmonaryartery on the T1-weighted sequence, with wedge-shaped infarctions and parenchymal metastases


also visualized.70 Both pulmonary emboli andparenchymal disease are highly vascular, so analveolar airspace shadowing may be the predomi-nant pattern, if there is extensive parenchymalhaemorrhage.66,71 Other reported findings includepleural effusions, presumed to occur when meta-static nodules bleed into the pleural space.72 Alsoendobronchial tumours have been reported, pre-senting with features of bronchial obstruction.73

The recommended radiographic staging forpatients with malignant GTN includes an initialchest radiograph, but in high risk patients, a CTexamination is advisable, as up to 41% of patientshave lung metastases that are not detectable on theplain film.74,75 However, the clinical importance ofsolitary pulmonary micrometastatic disease has notyet been fully evaluated.74–76 In fact FIGO stillrecommend a chest radiograph rather than a chestCT to assess the number of metastatic lesions, asalthough CT detects more metastases than a plainfilm, that has not been shown to affectmanagement.23,75

Liver metastases occur later in the course of thedisease and are markers of a prognostically pooroutcome. Liver ultrasound can be carried out at thesame time as the pelvic assessment, but in high riskpatients or patients with known vaginal or lungmetastases, abdominal CT is recommended.23

Lesions are typically multiple, heterogeneous,usually hypointense masses, that avidly enhanceafter intravenous contrast medium administration.Contrast medium enhancement is typical in thearterial phase, and haemorrhagic transformation isfrequent. These lesions are not readily distinguish-able from other hypervascular hepatic tumours onCT alone, although a couple of angiographic specificabnormalities have been reported. A hypervascularmass with aneurysmal dilatation of the peripheralend of the hepatic arteries in the arterial phase,and persistent vascular lakes in the venous phaseare characteristic.77 These lesions may be amen-able to selective chemoembolization and shouldnever be biopsied because of the risk of fatalhaemorrhage.78 On MRI, the appearances areessentially identical to other hypervascular livermetastases.

Central nervous system disease is present in up to15% of patients with metastatic GTN, but has beenreported as even more prevalent on autopsystudies.79,80 Clinical presentation includes head-aches, seizures and motor and sensory deficits. Themajority of lesions are multiple, occur at the grey–white matter junction, and are most commonlylocated in the parietal lobe. Surrounding oedemaand secondary haemorrhage are occur frequently,with many lesions hyperintense on unenhanced CT.

Recommended staging of the brain is with MRI,where signal characteristics are widely variabledepending on the age of associated haemor-rhage.23,81 Enhancement with gadolinium is usual.At Charing Cross all patients with lung metastasesundergo MRI brain imaging as these patients are atsignificant risk of CNS involvement.

Metastatic vaginal disease is common though itusually occurs through continuous spread from theprimary uterine lesion. MRI is preferred forradiological evaluation, though if vaginal diseaseis the isolated region of metastasis, selectiveembolization may be effective management.65

A variety of other sites of metastatic diseasehave been reported, including the kidneys, gastro-intestinal tract and skin.82–84 Another rare site ofmetastatic disease is to the neonate, which hasbeen reported when choriocarcinoma is concurrentwith a normal pregnancy.85

PET and PET/CT

There are limited data on the efficacy of PET andPET/CT in the evaluation of recurrent and meta-static GTN, with studies to date limited to casereports and small case series. 2-[F-18]fluoro-2-deoxy-D-glucose (FDG)-PET has been shown to beeffective in the identification of malignant tissue inmany different primary and metastatic tumourtypes.86 A study by Grisaw et al. in which 53patients underwent PET/CT for staging of primaryor recurrent pelvic malignancy, showed the tech-nique to be both sensitive and specific for assessingextent of disease, however, only one patient in theseries had GTN.87 In patients with GTN it has beenshown to identify occult disease when ultrasound,CT and MRI are equivocal, at sites including the lungparenchyma, pulmonary artery, liver and broadligament.88–90 In our own experience at CharingCross, nine patients have undergone FDG-PET aspart of their restaging for relapsed malignant GTN.This investigation has been helpful in assessinguterine scar versus recurrence, and in locating thesite of active disease in six of the patients, one ofwhich had no other abnormality on all other imagingtechniques (CT, MRI and ultrasound).

Complications

GTN is often highly vascular and is the commonestcause of uterine vascular malformations.91 Despitecomplete tumour response to chemotherapy, thesevascular malformations persist in up to 15% of


patients.92 A complication of these malformationsis haemorrhage in up to 2%, which is usually vaginal,but may be intraperitoneal and can be life-threatening, requiring massive blood transfusion.93

Traditionally, surgical management has been themainstay of treatment in these cases, with uterineartery ligation or even hysterectomy required.94

However, the majority of these lesions are

Figure 7 (a) A digital subtraction angiogram showing auterine vascular malformation in a patient with previousGTN. This procedure was performed via a right commonfemoral artery approach, with subsequent selectivecatheterization of the uterine arteries bilaterally, usinga 5 F glide catheter. (b) A digital subtraction angiogram inthe same patient after embolization, demonstratingcomplete obliteration of the vascular malformation.Embolization was carried out with polyvinyl alcohol gelfoam slurry, with a particle size of 355–500 mm.

predominantly supplied by the uterine arteries,and are amenable to endovascular management.95

Uterine artery embolization is a safe alternativetreatment, performed via a common femoral arteryapproach, with aortograms to outline the mainblood supply to the vascular malformation from theuterine arteries (Fig. 7).91 After selective uterineartery catheterization, the embolic agent isemployed, which is ideally polyvinyl alcohol par-ticles. When stasis is visualized within the system,embolization is considered complete and theprocedure terminated following a final “check”aortogram, to assess for any residual disease. Areduction in 80% or more in size of the malfor-mation has a proven therapeutic benefit.91 As withother indications for uterine artery embolization,side effects include pain, which is usually respon-sive to opiates and non-steroidal analgesics.96

Otherwise side effects are rare and relate to thepreviously employed embolic agents, such ascyanoacrylate.97,98 Uterine infarction does notoccur, due to the extensive pelvic vessel collater-alization. Subsequent conception in these patientsafter embolization is now being increasinglyreported.99,100 Another indication for selectiveembolization is isolated vaginal metastases.101

Theca lutein cysts develop due to hyperstimula-tion of the ovaries, by high levels of hCG in up to37% of patients with GTN.102 Usually patientscomplain of only mild discomfort, though theyoccasionally rupture and presentation may be withan acute abdomen. Transvaginal sonography or MRIwill readily demonstrate these cysts.

Hyperthyroidism is a rare association, due tocross-reaction of hCG with thyroid stimulatinghormone as a consequence of their shared alphasubunit. Thyroid function tests will show sup-pressed thyroid stimulating hormone (TSH) andboth an I123 scan and a Tc99 scan will show diffuselyincreased uptake within the thyroid gland.

Post-treatment surveillanceand follow-up

After surgery the vast majority of patients with non-invasive molar disease are cured. However, per-sistent disease will develop in a minority, virtuallyall of which will be cured with further treatment,but these need to be identified. Since 1973, allpatients with GTN are registered at one of threenational follow-up services.11 After treatment,patients will have an hCG level taken initially at48 h post-evacuation.11,103 When registered, 2weekly blood and urine samples are sent to one of


the reference laboratories until the levels havenormalized. Follow-up continues for a further 6months, and assuming the levels have remainednormal, patients are allowed to proceed with afurther pregnancy.11,104 If patients have hadchemotherapy, conception is not advised for 12months after completion because the greatest riskof relapse is within this period and a pregnancywould mask early detection. Furthermore, it ispossible that the preceding chemotherapy mayhave damaged ova and the 12 month period allowstime for such eggs to either undergo repair or dieoff. Despite this advice, 230 women have becomepregnant within the first year of follow-up, andfortunately, there does not appear to be anyincreased risk of relapse for the mother orteratogenecity in the resulting offspring.105

The vast majority of patients with previous molarpregnancies, even if they undergo multiagentchemotherapy, can still anticipate normal repro-ductive function.106 With subsequent pregnancies,an early ultrasound is advised to confirm normality,and after the pregnancy, an hCG level at 6 and 12weeks is also recommended.107 Those patients whohave had chemotherapy require hCG follow-up forlife as we are currently uncertain when it is safe tostop.

Conclusion

Although hCG levels may be abnormally high duringearly pregnancy affected by molar disease, this isnot diagnostic. Transabdominal ultrasound is theexamination of choice for initial radiologicaldiagnosis, which may show molar tissue, myome-trial invasion, and also have the capability ofpredicting which patients will develop resistanceto chemotherapy, and hence provide valuableprognostic information. It also has a role inassessment for residual and recurrent disease.

MRI is useful in assessing myometrial andparametrial tumour extension, tumour vascularityand is an accurate tool in tumour staging. There iscurrently insufficient data evaluating the use of PETand PET/CT in GTN, despite their use in othermalignant pelvic pathologies. They are used toassess for recurrent and metastatic disease on acase to case basis, where other techniques haverevealed equivocal results.

In the diagnosis and evaluation of metastaticdisease, body CT imaging remains the technique ofchoice for assessing disease in the thorax andabdomen, though MRI is more sensitive for evaluat-ing pelvic metastatic disease and also brain and

other CNS pathology. Patients with heavy bleedingcan be cured by angiographic embolization of themain feeding blood vessels to the tumour.

The radiologist plays an essential role in thediagnosis and management of GTN. Knowledge ofthe spectrum and course of the disease, andcapabilities of the different techniques will allowappropriate technique selection and interpretationof the imaging findings.

Acknowledgements

The authors thank the Department of Health fortheir continued support and NTRAC.

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