Clinical Radiology (2009) 64, 857e871

REVIEW

Cancer presenting during pregnancy: radiologicalperspectives

S. Doylea,*, C. Messioub, J.M. Rutherfordc, R.A. Dineena

aDepartment of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, UK, bSection ofClinical Magnetic Resonance, Institute of Cancer Research and Royal Marsden NHS Foundation Trust,Sutton, Surrey, UK, and cFoetomaternal Medicine, Nottingham University Hospitals NHS Trust,Nottingham, UK

Received 22 May 2008; received in revised form 22 July 2008; accepted 25 August 2008

Malignancy presenting during pregnancy is rare. When it does, there are important considerations and challenges for

the radiologist. The physiological changes of pregnancy may mask signs and symptoms of malignancy leading to de-layed presentation. Endocrine and physiological changes during pregnancy can interact with tumour biology to alterthe behaviour and patterns of growth of certain tumours. The timing and choice of imaging technique pose potentialrisks to the foetus, but this must be weighed against the risks to both mother and foetus of inadequate investigation ormisdiagnosis. This review outlines the general principles and approach to imaging the pregnant patient with suspectedmalignancy, following which there is a more detailed discussion of the effects of pregnancy on tumour biology andpresentation of specific tumours. Imaging strategies are discussed for the different entities, and where possible,evidence-based imaging recommendations are made.ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction

Although rare overall, malignancy accounts for upto one-third of maternal deaths during gestation.The incidence of cancer in pregnancy has been es-timated as affecting 1 in 1000 pregnancies,1 and 1in 3000e6000 live births.2e4 This is less than innon-pregnant women of the same age,5 which ismultifactorial. Much of the reduction in incidenceis likely due to infertility associated with the un-derlying diagnosis/treatment and women withknown cancer avoiding pregnancy. Delays or misdi-agnosis of cancer in pregnancy may also be a con-tributory factor. The latest triennial report ofmaternal deaths in the UK by the ConfidentialEnquiry into Maternal and Child Health (CEMACH)

* Guarantor and correspondent: Department of Radiology,Nottingham University Hospitals NHS Trust, Queen’s MedicalCentre, Derby Road, Nottingham, NG7 2UH, UK. Tel.: þ447976979094.

E-mail address: SDoyle76@aol.com (S. Doyle).

0009-9260/$ - see front matter ª 2009 The Royal College of Radiolodoi:10.1016/j.crad.2008.08.020

found a significant number of cases of delayed di-agnosis of malignancy in pregnancy, despite overtsymptoms.6 This is of relevance to radiologistswhen making decisions about the appropriatenessof radiological investigations during pregnancy.

In this review we consider the biological factorsthat may alter tumour behaviour and diagnosis oftumours presenting in pregnancy, and where pos-sible, imaging strategies are presented. Thecommonest cancers diagnosed during pregnancy(Table 1) are reviewed, along with selected tu-mours of the brain and spine, which can behavedifferently during pregnancy. The gestational tro-phoblastic tumours, which can coexist with viablepregnancy, are also discussed.

Clinical considerations

A common cause of delay in the diagnosis of cancerin pregnancy is the mistaken attribution ofsymptoms to the pregnancy itself (Fig. 1). The

gists. Published by Elsevier Ltd. All rights reserved.

Table 1 Commonest cancers in pregnancy.

� Cervix� Breast� Melanoma� Lymphoma� Leukaemia� Thyroid� Ovary

858 S. Doyle et al.

physiological changes in pregnancy includeincreased breast density and size, altered biome-chanical stress on the spine, and abdomino-pelviccompression, all of which increase as the pregnancyprogresses and can cause maternal symptoms.Other common features of pregnancy include nau-sea and vomiting, particularly in the first trimester.Therefore, many symptoms are common to bothpregnancy and malignancy, such as vomiting, ab-dominal pain, back pain, urinary symptoms, andbreast masses, and adequate clinical assessmentand investigation as appropriate are required to dis-tinguish these. Based on analysis of mis- or delayeddiagnosis of malignancy in pregnancy, the latestCEMACH report highlights concerning symptomsthat were under-investigated or erroneously attrib-uted to other causes (Table 2).

Figure 1 Malignancy masquerading as a complicationof pregnancy. A 35-year-old women presenting at 31weeks of gestation with seizures and raised liver en-zymes, presumed to be due to eclampsia. (a) Enhancedcranial CT performed following an emergency Caesareansection showed multiple brain metastases. Whole-bodyCT demonstrated a T4 left upper lobe mass (b), subse-quently confirmed by biopsy as an adenocarcinoma,and multiple liver metastases.

Imaging considerations

Ionizing radiation and the foetus

Deterministic effects in the foetus (those resultingfrom cellular damage occurring when a certaindose threshold is exceeded) include death, mal-formation, growth restriction, and severe mentalretardation. The predicted thresholds for theseeffects are all over 50e100 mGy and typically inthe order of hundreds of Gray. This is well abovethe usual doses for most diagnostic radiologicaltests (Table 3), and therefore, the advice is thatthere is no significant risk of diagnostic medical ex-posures causing these complications.7,8 Only whenthe foetal dose approaches the much higher radia-tion doses used in therapeutic radiotherapy aredeterministic effects a real concern (Table 4).

Stochastic effects in the foetus result fromradiation-induced modification of cells, and in-clude induction of cancer and hereditary disease.These are considered to have no dose threshold.Current guidelines7 calculate the number of excesscancer cases (both leukaemias and solid tumours)up to age 15 years following irradiation in uteroas 1/13,000 per mGy for x-rays and gamma rays,

from 5e6/52 post-last menstrual period (LMP).This is on a background of a natural baseline UKrisk of childhood cancer of 1/500. The risk of her-itable effects from foetal irradiation is thought tobe the same as that after birth, at 1/200,000 per

Table 2 Worrying symptoms in pregnancy which requireadequate investigation.

� Severe abdominal or back pain� Sciatica� Urinary incontinence� Haematuria� Unexplained breathlessness� Significant weight loss

Table 4 Radiation dose thresholds for foetal deterministiceffects.7,8

Weeks post-LMP Foetal dose Potential deterministiceffects

2e4(Pre-implantation)

>50e

100 mGySpontaneous abortion

but not malformation2e8

(Organogenesis)>200 mGy Malformations

8e15 100e

1000 mGySevere mental

retardationAfter 15th week >1000 mGy Mental retardation

Cancer presenting during pregnancy 859

mGy for x-rays and gamma-rays. The natural inci-dence of heritable disease manifesting at birth isestimated to be at least 1e3%. The predicted sto-chastic foetal effects from certain imaging testsare listed in Table 5. The potential stochasticeffects on a pregnancy of up to 5e6/52 post-LMP,although not zero, are judged much less.

Most radiological examinations in which thefoetus is not exposed directly to the primary x-raybeam incur a foetal dose of less than 1 mSv, which ismainly from internal scatter within the patient andfrom leakage from the x-ray tube housing. For ex-ample, the mean foetal dose from chest computedtomography (CT) is 0.06 mGy (with a possible max-imum of 0.96 mGy), the average foetal dose is,therefore, less than half the dose from an abdomi-nal radiograph.7 Abdominopelvic shielding witha lead-rubber apron equivalent to 0.5 mm leadcan significantly reduce dose from leakage radia-tion, but not the dose from internal scatter.8,10

In essence, the advice is that the majority ofdiagnostic ionizing radiation exposures are unlikelyto increase the childhood risks of malignancy orheritable disease significantly when comparedwith the natural risk, and foetal exposure wouldnot justify the greater risks of invasive foetaldiagnostic procedures to the mother or foetus, ortermination of pregnancy to the mother.7,9 Thisshould be borne in mind if there is clinical need

Table 3 Maternal and foetal radiation doses from commonimaging tests.7,8,109

Imaging test Maternal radiationdose (mean effectivedose mSv)

Foetal radiationdose (mGy)

Mean Maximum

Chest radiograph 0.2 <0.01 <0.01Abdominal

radiograph1.7 1.4 4.2

Barium enema 9.0 6.8 24CT head 2.0 <0.005 <0.005CT chest 9.1 0.06 0.96CT abdomen 8.0 8.0 49CT pelvis 9.4 25 7999mTc bone

scintigram5.0 3.3 4.6

CT, computed tomography.

for maternal imaging using ionizing radiation, insituations where alternative imaging methods willnot suffice. Obviously the choice of investigationshould be the lowest radiation dose test to ade-quately answer the clinical question. Most workto date on 2- [18F]-fluoro-2-deoxy-D-glucosepositron-emission (FDG-PET)eCT has excludedpregnant patients, and although this technique isbeing increasingly shown to be valuable in the as-sessment and staging of some cancers, currentlyit has no established role during pregnancy.11

In cases where there is clinical need for imaginginvolving direct irradiation of the foetus, currentadvice for the radiologist includes taking allpossible technical measures to reduce the dose,asking a medical physicist to make a preliminaryevaluation of the dose to the foetus, and giving themother all available information about the corre-sponding risk from that dose. If the mother is toounwell to participate fully in this consentingprocess, but urgent imaging is required, therisk:benefit decision must be taken in consultationwith the referring physician. In such cases, re-cording the examination dose and performing andrecording an estimation of consequent risk isrecommended.8

Magnetic resonance imaging (MRI) and thefoetus

Although no definite adverse outcomes have beenestablished from MRI in pregnancy, there are some

Table 5 Risk of stochastic foetal effects from commonimaging tests.7

Mean foetalradiation dose (mGy)

Risk of stochastic foetal effects

Childhoodcancer

Hereditarydisease

0.005 (Chest radiograph) <1 in a million <1 in a million3.3 (99mTc-bone scintigram)1 in 4000 1 in 60,0008 (CT abdomen) 1 in 1600 1 in 25,00025 (CT pelvis) 1 in 500 1 in 8000

860 S. Doyle et al.

MRI-specific concerns that currently mean theexisting advice is to use MRI only in cases wherecertain conditions are met; namely that theclinical question cannot be answered by ultra-sound; that patient management is likely to bealtered, and that the imaging cannot wait untilafter birth.12e14 Despite the current lack of evi-dence of mutagenic risk in human foetuses, manyadvise avoiding MRI exposure, if possible, duringthe first trimester of pregnancy, the period offoetal organogenesis.

One concern is over the potential for foetaltissue heating, resulting from radiofrequency pulseenergy deposition. The specific absorption rate(SAR), a measurement of energy deposition in thepatient during MRI examination, increases with thestatic magnetic field strength, the number ofradiofrequency pulses, and the flip angle. How-ever, it has been noted that foetal MRI has widelyused spin-echo sequences, which have a high SAR,compared with low SAR gradient-echo sequences,without proven detriment.15

Contrast media and the foetus

Another issue of potential safety concern withboth CT and MRI is that of foetal exposure tocontrast media. Both intravenously administratediodinated contrast agents and gadolinium chelatesare predominantly distributed in extracellularwater and rapidly excreted via the maternalkidneys, but small amounts can cross the placenta.Excretion is via the foetal urinary tract into theamniotic fluid, which can then be ingested.Although there is little available safety informa-tion currently, to date no adverse foetal effectshave been observed following maternal exposureto iodinated contrast media or gadolinium che-lates. However, foetal abnormalities have beenobserved in rats after maternal gadolinium chelateadministration,16 and due to the paucity of humansafety data, exposure to these agents is avoided, ifpossible, during pregnancy.17 No adverse effectshave been seen in infants after gadolinium chelateexposure during pregnancy. Maternally adminis-tered iodinated contrast media containing freeiodide can potentially cause foetal or neonatalhypothyroidism, hence current advice is to checkneonatal thyroid function during the first week oflife in infants exposed in utero.

Minimization of risk of aortocaval compres-sion during imaging

An important consideration for any imaging tech-nique in pregnant patients is correct positioning to

avoid aortocaval compression, a common phenom-enon, particularly in the third trimester. Supinepositioning leads to compression of the inferiorvena cava and lateral displacement of the infrare-nal aorta by the gravid uterus,18 which can lead toa reduction in cardiac output by up to 24%.19 Thiscan manifest as the supine hypotensive syndrome,with hypotension causing dizziness, pallor, sweat-ing, tachycardia, and faintness. This can beavoided by positioning the patient in a 5e10� leftlateral tilt, for example, using a foam insert orpillow under the patient’s right side.

Tumours in pregnancy

Cervical

Tumour behaviourInvasive cervical cancer is the commonest malig-nancy to occur during pregnancy, accounting forup to 50% of pregnancy-related cancers, occurringin around 1/2200 pregnancies.20 Histologicallythere is no difference between the cancers ofpregnant versus non-pregnant women, with themajority (90%) being squamous cell carcinomas.The majority of women with cervical cancer areasymptomatic, but can present with pain, vaginalbleeding, or discharge. Therefore, if present,symptoms can be masked by pregnancy, leadingto potential delay in diagnosis.21 Most reportshave found that cervical cancer in pregnancy wasmore likely to be of lower stage, likely due topatients undergoing cervical examination duringroutine obstetric review.22 The weight of evidencesuggests that maternal survival is not adverselyaffected by pregnancy.23

The effect of the cancer on the pregnancydepends on whether the pregnancy can be contin-ued without excessively delaying definitive treat-ment, which in turn depends on the stage ofpregnancy and cancer stage at diagnosis. Cervicalcancer spreads by local extension into adjacentstructures including uterus, vagina, and distalureters, and via the parametrium towards thepelvic side wall. Lymphatic spread is initially tothe regional pelvic lymph nodes (parametrial,obturator, iliac). Distant nodal involvement (e.g.,para-aortic, inguinal) is a late feature, and distantvisceral metastases are uncommon.

Imaging strategyStaging is required to plan treatment, which canrange from a watch-and-wait approach until afterbirth for early stage disease, to radical surgery,

Cancer presenting during pregnancy 861

such as hysterectomy and pregnancy termination inthe first trimester, or radical Caesarean hysterec-tomy in the third trimester, with or without radio-therapy. Abdominopelvic staging is optimally doneusing MRI, which can be used to assess the size ofthe primary tumour and identify local invasion ornodal disease, as well as identify distant metastaseswithin the abdomen and complications such ashydronephrosis (Fig. 2). T2-weighted sequencesare most useful for delineating local extent andnodal involvement.24 The commonest sites of dis-tant metastases other than nodes are the lungsand bones. Chest imaging options include a chestradiograph or CT chest with abdominal shielding,with other centres instead advocating the use ofa pulmonary-nodule sensitive MRI sequence suchas turbo spin-echo (TSE) or short tau inversionrecovery (STIR).25 CT is more sensitive than chestradiography and MRI for detecting lung metastases,but again the likelihood of findings changing

Figure 2 Cervical cancer presenting in pregnancy. A24-year-old woman presented at 30/40 gestation withvaginal bleeding. A suspicious cervical lesion, seen atcolposcopy, was biopsied, histology showed adenocarci-noma. MRI showed widening of the cervical canal butpreservation of the cervical stromal layers, and no localextension or lymphadenopathy (radiologically FIGOstage IB1), and the 31/40 fetus in a cephalic presenta-tion (sagittal T2-weighted images shown). At 35/40 thepatient underwent a Caesarean section with subsequentexamination under anaesthesia, radical hysterectomy,and pelvic lymph node dissection. Histology showeda 20 mm moderately-differentiated cervical adenocarci-noma with negative nodes and no paracervical involve-ment (surgically FIGO stage 1B1).

management during pregnancy versus the risks ofradiation to both foetus and mother should be con-sidered. If a whole-body skeletal survey formetastases is required, a whole-body MRI withturbo-STIR sequence has been advocated as an ef-fective technique, with better sensitivity for bonemetastases than bone scintigraphy while avoidingfoetal radiation dose.26,27

Breast

Tumour behaviourPregnancy-associated breast cancer is commonlydefined as that diagnosed during pregnancy orwithin 1 year postpartum, as the physiologicalchanges in breast tissue beginning in pregnancycontinue into the subsequent period of lactation.Three percent of breast cancers present in womenwho are either pregnant or lactating.28 Breast can-cer is the second commonest cancer in pregnancyafter cervical cancer, affecting approximately1/3000e10,000 pregnancies,29 and is the common-est cause of cancer death in women who are preg-nant or lactating.30 It is currently seen mainly inthe 32e38 year age group of pregnant patients,but as the average age at which women conceivetends to increase, both the incidence and the aver-age age at diagnosis are likely to rise.31,32

Histologically, pregnancy-associated breast can-cers are similar to those in non-pregnant women ofreproductive age, with the majority being invasiveductal carcinomas. The weight of evidence does notsupport previous studies showing an excess of in-flammatory breast cancer,33,34,30 with an incidenceof 2e4% being found in both populations. In preg-nancy there are a relatively high proportion ofoestrogen-receptor negative (54e80%) and proges-terone-receptor negative tumours,35 which is simi-lar to the non-pregnant young female population,although some studies suggest that the number ofoestrogen-receptor negative tumours is higher inpregnancy than in age-matched controls.33 The rela-tionship between hormonal factors in pregnancypromoting or inhibiting tumourigenesis is complex,and, as yet, incompletely understood. Raised serumlevels of oestrogen, progesterone, and prolactinhave been proposed as potential contributory fac-tors,36,37 whereas some other pregnancy-relatedhormones (human chorionic gonadotrophin, relaxin)may inhibit tumour growth.38,39 A Swedish study ofbreast cancer cases in women under 40 years sug-gested that BRCA1/2 mutation carriers were at in-creased risk of breast cancer during pregnancy,possibly indicating a role for circulating oestrogensin accelerating malignant transformation.40

Although some propose a hypothetical increase in

862 S. Doyle et al.

tumour aggressiveness in pregnancy, no survivalbenefit is seen in those terminating the pregnancy.41

Breast imaging of the pregnant patient occursmost frequently for evaluation of a palpable lump(Fig. 3).42 This, combined with the potential mask-ing of breast carcinoma by physiological breastchanges, results in pregnancy-associated cancersoften being larger and of later stage than mammo-graphically detected cancers in the screeningpopulation. Axillary lymph node involvement ismore likely at diagnosis (68 versus 40e50% inthe non-pregnant population).23 However, whenmatched for stage and patient age, the overallsurvival is similar.43

Figure 3 A 39-year-old woman presented at 27/40 with abreast. Clinical examination revealed a 10 mm category B (inTargeted ultrasound of the right breast revealed a 15 mm caopsied under ultrasound guidance. (b) Bilateral mammographcer was confirmed at biopsy, provisionally classified as gradprone imaging. Wide local excision with axillary node sampliThe mass was radiologically visible on the excision sample. Hinvasive ductal carcinoma, with extensive surrounding ductasurgical margins. Axillary nodes were negative for tumour (stto induce at 37e38/40, followed by chemotherapy and subs

Imaging strategyHistorically there have commonly been delays indiagnosing breast cancer in pregnancy, presumablylargely due to the masking of cancers by physiolog-ical changes in breast tissue. In certain series thisdelay has been significant, averaging 10 months.44

The physical alterations in breast tissue during preg-nancy include proliferation of ductal and glandularbreast tissues, leading to increased breast clinicaland radio-density, breast enlargement, and later,milk production. The increased breast density per-sists post-partum until cessation of lactation, witha radiological return to near the pre-pregnant ap-pearance from 1e5 months post-lactation. Another

3 month history of a breast lump in the upper outer rightdeterminate) mass centrally in the upper right breast. (a)tegory A (sonographically malignant) mass, which was bi-y was normal (bilateral cranio-caudal views shown). Can-e 2. MRI was not performed in view of the difficulty ofng and sentinel node biopsy was performed at 30 weeks.istology showed clear margins around a 22 mm, grade 3,l carcinoma in situ (DCIS) measuring 50 mm extending toage 1). A joint decision was made with the obstetric teamequent mastectomy.

Cancer presenting during pregnancy 863

factor delaying diagnoses may be reluctance to per-form breast biopsy during pregnancy because of theincreased risk of bleeding, infection, and milk fistu-lae.45,46 There is evidence that this delay is nowshorter, but remains common.47,48

The differential diagnosis of breast lumps inpregnancy and lactation is wide, with benignlesions such as abscesses, galactoceles, and fibroa-denomas common. Indications for imaging andbiopsy of pregnancy-associated breast lumps arethe same as for non-pregnant women of the sameage. However, there are some pregnancy-specificconsiderations regarding choice of imaging tech-nique. The initial imaging of a palpable breastlump should be targeted ultrasound, which reliablydistinguishes cystic lesions, such as galactoceles,from solid lesions. The commonest causes of a solidbreast mass in pregnancy or lactation are fibroa-denomas and lactating adenomas, but if ultra-sound demonstrates a solid lesion, this should bebiopsied without delay to exclude malignancy.Core-biopsy is preferred to fine-needle aspiration(FNA), as the hyperproliferative cellular state ofbreast tissue in pregnancy can cause misinterpre-tation on FNA evaluation.49 The sensitivity ofbreast ultrasound for malignancy in pregnancyhas generally been found to be better than thatof mammography, approaching 100%.50 However,one small series found that sonographic appear-ances of breast cancer in pregnant women couldbe atypical, for example, featuring cystic compo-nents and posterior acoustic enhancement.51

After ultrasound of a suspicious lesion, mammog-raphy has a role in assessing for synchronous lesionsand the presence of calcifications. There are fewdata on the foetal dose received from modernmammography systems. Older work widely quotesan estimated foetal dose of 4 mGy from bilateraltwo-view mammography, but recent work has founda significantly smaller dose of less than 0.06 mGy,which can be further reduced by between two toseven times by the use of abdominopelvic shield-ing.52,53 However, mammography is often less usefulthan ultrasound in pregnancy-associated breastcancer, with a significantly higher false-negativerate. The predominantly glandular backgroundparenchymal pattern on mammography in this youn-ger population, in addition to the pregnancy-relatedadditional glandular proliferation, hyperaemia, andoedema is more likely to obscure a cancer (Fig. 3b).Reports of mammographic sensitivity for cancervary from only 25% up to 87% in pregnantpatients,54e56 but usually less than 70%.57,58 A smallseries found that although the mass itself was notvisible on mammography in more than half of cases,there were often secondary signs suggestive of

malignancy, such as axillary lymphadenopathy, sus-picious calcifications, or skin thickening.51 In manycases, the main role of mammography is to excludediffuse malignant-type micro-calcifications whichwould preclude breast-conserving surgery. In thisscenario, a single projection instead of the standardtwo views may be adequate.59

Contrast-enhanced MRI has reduced sensitivityand specificity for cancer detection in densebreast tissue, limiting the diagnostic value inpregnant and lactating women.60 In addition, MRIof the breasts is optimally performed with the pa-tient lying prone, and therefore, is often impracti-cal in the second half of pregnancy (see case).

Routine staging of asymptomatic patients has notbeen shown to improve prognosis and is, therefore,not indicated routinely. Further imaging is dictatedby symptoms, such as chest radiography for breath-lessness. If liver metastases are suspected, ultra-sound is an appropriate first investigation withoutthe safety issues of MRI, although MRI has bettersensitivity for liver metastases and may be requiredif ultrasound is negative in cases with strong clinicalsuspicion. Bone metastases in breast cancer tend topredominate in the axial skeleton, and inpregnancy, are optimally imaged with MRI. Brainmetastases are also optimally imaged by MRI.

Melanoma

Tumour behaviourMelanoma is one of the commonest cancers inwomen of reproductive age and its incidence isincreasing.61 Melanoma comprises 8% of malignan-cies diagnosed during pregnancy.62 A recent reviewarticle63 attempted to debunk several widely heldbeliefs about the relationship between melanomaand pregnancy, including the beliefs that mela-noma is commoner in pregnancy and has a worseoutcome in pregnant patients. This presumed asso-ciation appears largely based on work from the1950s, which did not use a control group or analyseprognosis relative to disease stage.64 Since then,the weight of evidence indicates that incidenceis unchanged between pregnant and non-pregnantwomen,65 and that stage-for-stage the prognosis isalso unchanged.66 Melanomas in pregnant womenhave been found in some series to be thickerthan in non-pregnant women66; one theory is thatfalse beliefs about hormonal effects on nevi resultin delayed investigation of an enlarging nevus. Al-though pregnancy and oral contraceptives oftencause increased skin pigmentation,67 it is a myththat they commonly cause nevi to grow ordarken.68 Several series have shown an increasedincidence of lymphatic metastases in pregnant

864 S. Doyle et al.

patients compared with non-pregnant con-trols.69,70 Although the incidence of distant metas-tases and overall survival does not seem to besignificantly different between the twogroups,71,66 there are a limited number of long-term follow-up studies.

Imaging strategyStaging of melanoma (American Joint Cancer Com-mission staging system) depends on the depth of thelesion and the presence of regional lymph node ordistant metastases.72 In terms of imaging pregnantpatients with melanoma, the need for whole-bodyradiological staging during pregnancy is a concernonly for the minority of patients. Around 85% of mel-anomas are stage I at diagnosis, with treatment oflocalized disease (stages I and II) comprising surgicalexcision� local lymph node dissection. Dependingon local practice, chest radiography and liver ultra-sound may be used to screen for clinically unsus-pected metastases. Stages IIIþ IV requireexamination of the chest, liver, and regional lymphnodes. In the first instance chest radiography and ul-trasound of the liver and regional lymph nodes mayprovide sufficient initial information to enable dis-cussion of prognosis with the patient and to aidtreatment planning. Some patients given a diagnosisof advanced metastatic melanoma, which has a verypoor prognosis, may decide to terminate the preg-nancy. If the primary lesion is on the lower body orlower extremities, ultrasound may be insufficientto assess for pelvic nodal disease, in which caseMRI of the abdomen/pelvis would be preferable toCT to avoid foetal ionizing radiation exposure. In ad-dition, MRI can be helpful due to the characteristichigh T1, low T2 signal of paramagnetic melanin.The considerations of best investigation for pulmo-nary metastases are as previously discussed.

Lymphoma

Tumour behaviourLymphoma is rare in pregnancy despite being thefourth most frequent diagnosis of malignancymade in pregnant women.73 Although less commonthan non-Hodgkin’s lymphoma (NHL) in the generalpopulation, the incidence of Hodgkin’s disease(HD) peaks in young adults and is, therefore,more frequently associated with pregnancy thanNHL, which is commoner in the older population.HD most commonly presents with peripherallymphadenopathy, particularly cervical, and withnon-specific systemic symptoms such as nightsweats, weight loss, and malaise. The clinicalcourse and long-term survival rates in HD

(dependent on stage, but often above 80% inyoung patients) do not significantly differ inpregnancy.74,75

The incidence of NHL has increased over the lastfew decades, in part due to the association withhuman immunodeficiency virus (HIV) infection.NHL tends to be at a higher stage when diagnosedand have a worse prognosis than HD.76 Approxi-mately two-thirds of NHL cases during pregnancyare aggressive subtypes and disseminated (stage4) disease. Burkitt’s lymphoma, an uncommon sub-type usually occurring in childhood, can occur inpregnancy. It has been theorized that hormonalchanges and increased blood flow in pregnancymay aid dissemination of aggressive forms, suchas Burkitt’s lymphoma, with increased incidenceof breast, uterine, and ovarian involvement.75

An unusual presentation of lymphoma, which isassociated with pregnancy, is bilateral breastlymphoma, primary or metastatic, most commonlyhigh-grade/Burkitt’s lymphoma. Bilateral breastinvolvement with acute lymphoblastic leukaemiahas also been documented.77 Breast lymphoma canpresent with uni- or bilateral breast enlargement.Although this is usually clinically gross, far beyondwhat might be expected as physiological duringpregnancy, this can initially be misdiagnosed asmastitis.78,79

Imaging strategyThe staging of lymphoma in the non-pregnantpopulation is most commonly with CT of the chest,abdomen, and pelvis� neck depending on the clin-ical site of disease, although PET-CT is being in-creasingly used in the staging and follow-up oftreatment response in lymphoma. In the pregnantpatient, the method and timing of staging dependson whether there is an intention to continue thepregnancy and the treatment strategy to beused. A strategy to minimize foetal radiationdose may include a chest radiograph or chest CTwith abdominopelvic shielding, and MRI withoutcontrast media of the abdomen and pelvis.

Thyroid

Tumour behaviourThyroid cancer is the commonest endocrinemalignancy, with an increasing incidence in thegeneral population over recent decades.80 Previ-ous neck irradiation and a family history of thyroidcancer are risk factors. It is approximately threetimes commoner in women than men,81 and the in-cidence in pregnancy has been reported as up to9e14 per 100,000 live births.82 The majority (upto 80%) of thyroid cancers are well-differentiated

Cancer presenting during pregnancy 865

papillary cancers, which have an excellent progno-sis with a 30-year survival of approximately 95%.90

Thyroid nodules occur in approximately 2% ofpregnant women, most benign in nature.88 Boththe development of new benign thyroid nodulesand the enlargement of pre-existing benign thyroidnodules have been observed in pregnancy.83 It hasbeen proposed that thyroid tissue growth is stimu-lated during pregnancy due to close similarity be-tween the beta subunit of hCG and that ofthyroid-stimulating hormone (TSH).84 The effectsof pregnancy on thyroid malignancy are not fullyunderstood. Some studies have suggested an accel-eratory effect of pregnancy on the growth of thy-roid cancer,85 whereas other series have notfound any such effect.83 The overall prognosis forthyroid cancer diagnosed during pregnancy hasbeen shown to be not significantly altered fromcases diagnosed in age-matched, non-pregnantcontrols.86,87

Imaging strategyApproximately 5e13% of thyroid nodules will bemalignant. The prevalence of malignancy is similarfor patients with a solitary nodule as for those withmultiple nodules.89 Ultrasound of both the thyroidand the cervical lymph nodes is the usual first-lineimaging investigation, with FNA biopsy of lesions asappropriate. There are no diagnostic sonographicfeatures of malignancy, but certain features, par-ticularly in combination, increase the likelihoodof malignancy. These include calcifications, solidrather than cystic composition, hypoechogenicity,irregular margins, absence of a benign-type‘‘halo’’, cervical lymphadenopathy, and predomi-nantly central rather than peripheral vascularity.90

Nodule size is not predictive of malignancy, and if10 mm is used as the threshold before biopsy isperformed then some cancers will be missed. How-ever, this must be balanced with the knowledgethat the majority of thyroid cancers are indolentin nature, and that the treatment of subcenti-metre cancers currently has an unproven effecton life expectancy.90

Management of thyroid nodules is usually basedon the clinical, sonographic, and cytological find-ings. Other imaging methods have only a limitedrole. Thyroid scintigraphy is contra-indicated inpregnancy. In the rare cases of poorly differenti-ated aggressive thyroid cancers in pregnant pa-tients, further radiological staging may be required,usually comprising chest imaging as the lungs arethe commonest site of metastases. The diagnosis ofan aggressive-type tumour in pregnancy may lead toelective termination in order to begin aggressivetreatment. The more usual treatment of well-

differentiated papillary thyroid cancer ofteninvolves total thyroidectomy, followed by 131I abla-tion of any residual thyroid tissue. If diagnosed dur-ing pregnancy, surgery is either performed in theearly-mid second trimester or delayed until afterdelivery depending on the particular clinicalcircumstances and local practice. 131I ablation isdelayed until after delivery and breast-feeding ifsurgery is performed during pregnancy; it can begiven 3e6 months after delivery if the thyroid can-cer is a typical low-grade papillary malignancy.91

Ovarian

Tumour behaviourAlthough the second commonest gynaecologicalcancer encountered in pregnancy, ovarian canceris rare, occurring in the range of 1/9000 to 1/25,000 pregnancies.92 This is in contrast to the fre-quent finding of adnexal masses during pregnancy,commonly during routine obstetric imaging; oneseries reported this finding in up to 1/190 pregnan-cies.93 The vast majority of these prenatallydiscovered adnexal masses prove benign, mostbeing corpus luteum or other functional cyststhat usually resolve by 16 weeks gestation.94 Only3e5% of adnexal masses are subsequently foundto be malignant.95 Adnexal masses before 16weeks are usually asymptomatic and found on rou-tine ultrasound; after 16 weeks with the enlarginguterus adnexal masses are more likely to becomesymptomatic, presenting with torsion (15%), pain,or haemorrhage.94 CA125 levels are not reliablein pregnant patients for diagnosis or follow-up ofovarian cancer.

Imaging strategyUltrasound, including the use of Doppler, may bethe only required imaging method in the investi-gation of adnexal masses. Benign characteristicsinclude asymptomatic unilocular unilateral cystsunder 6 cm in size, which are often physiologicaland usually resolve by the end of the first trimes-ter. Worrying features include solid components,size over 6 cm, bilaterality, ascites, and a low re-sistive index to blood flow on Doppler assessment,whereas masses with a high resistive index are verylikely benign even if persisting into the second tri-mester.96 MRI may be helpful in further character-ization in cases where ultrasound is equivocal, butin the presence of these concerning features ex-amination at laparoscopy or laparotomy is usuallyrequired. In cases with features suspicious for ma-lignancy, initial staging is usually surgical. The ma-jority of ovarian malignancies diagnosed duringpregnancy are at an early stage (FIGO stage I).

Figure 4 Meningioma presenting during pregnancy. A25-year-old woman with headaches in the third trimesterdeveloped acute deterioration of visual acuity in theright eye at 35 weeks of gestation. A pituitary cause ofthe visual loss was suspected and MRI was performed.Contrast-enhanced, T1-weighted, (a) coronal and (b)sagittal images show a meningioma arising from the re-gion of the tuberculum sellae and planum sphenoidale,with normal appearances of the pituitary gland (shortblack arrow). The tumour abuts the optic chiasm (shortwhite arrow) and displaces the cisternal portions of theoptic nerves superiorly and laterally (long white arrows).

866 S. Doyle et al.

The prognosis is similar to that in non-pregnantwomen.94

Brain and spine

Tumour behaviourTumours of the brain and spinal cord are rare inpregnancy, with an estimated incidence of 3.6cases of primary malignant brain tumours permillion live births (a figure that excludes meningi-omas, vestibular schwannomas, and pituitary neo-plasms).97 The relative frequency of differenttypes of intracranial tumours is unchanged in preg-nancy compared with age-matched non-pregnantwomen.98 Thirty-two percent of brain tumours inpregnancy are gliomas, 29% meningiomas, 15% ves-tibular schwannomas, and other rarer types (suchas cerebellar astrocytoma and medulloblastoma)account for 6% or less each. Spinal tumours diag-nosed in pregnancy are even rarer, the majority(61%) of these are benign vertebral haemangio-mata, with spinal meningiomas second commonest(18%).99

Pregnancy can cause rapid enlargement of tu-mours, particularly meningiomas, pituitary adeno-mas, vestibular schwannomas, and cerebellarhaemangioblastomas. Proposed mechanisms includevascular engorgement and increased fluid content,as well as hormonal effects. Approximately 90% ofmeningiomas have high-affinity progesterone recep-tors and 30% have oestrogen receptors, which mayexplain their propensity to grow during pregnancy(Fig. 4). Postpartum improvement in symptoms hasespecially been described in association with menin-giomas and spinal vascular tumours,98 although neu-rological deficit may persist beyond delivery.100

Thirty percent of pituitary macroadenomas enlargein pregnancy to the extent that medical or surgicalintervention is needed, either treatment duringpregnancy, or treatment after induction of an earlydelivery. In one series 17% of pregnant women withvestibular schwannomas developed new or worsen-ing symptoms during the last month of pregnancy.101

Small studies have found oestrogen receptors in44e100% of vestibular schwannomas.102,103

Gliomas most commonly present in the thirdtrimester of pregnancy. Although the prognosisstage for stage is similar to non-pregnant patients,symptoms can be dangerously exacerbated atbirth, with raised intracranial pressure causingbrain herniation (Fig. 5).104 Clinical features ofbrain tumours include headache, nausea, and vom-iting due to raised intracranial pressure, neurolog-ical deficits, and fits. Constant or daily headacheshould not be attributed to pregnancy, particularlyin patients with no past history of headache.

Nausea and vomiting in pregnancy can be mistakenfor morning sickness, although this usually pre-dominates in the first trimester and then tends toremit, unlike tumour-related sickness. Seizures inpregnancy, particularly in the second half of preg-nancy, are more likely to be due to eclampsia than

Figure 5 Glioma presenting in pregnancy. A 23-year-old presented at 19 weeks gestation with headachesand a single seizure. MRI was performed to excludevenous sinus thrombosis, but showed a large, bland,left frontal tumour felt to be consistent with a low-gradeglioma. Coronal T1 images at 31 weeks showed a signifi-cant mass effect with midline shift and tumourdisplacing the optic chiasm (white arrow), althoughthis had not changed significantly from the initial MRI.Following consultation between the neurosurgical andobstetric teams, elective Caesarean section wasperformed at 36 weeks.

Cancer presenting during pregnancy 867

brain tumour. As a guide, intracranial tumourshould be considered as a cause for seizureswhen seizures are focal or when there are no otherfeatures of eclampsia.100

Vertebral haemangiomas can become symptom-atic in pregnancy, most commonly in the thoracicregion.100 Spinal meningiomas are also commonerin the thoracic region, and like intracranial menin-giomas may rapidly grow during pregnancy. Bothsymptomatic vertebral haemangiomas and spinalmeningiomas most commonly present in the thirdtrimester with painless leg weakness and paraes-thesia, and later with sphincter disturbance.Back pain is not typical, but if a pregnant patientdoes present with thoracic back pain, this shouldnot be confused with common pregnancy-relatedmechanical lower back pain.

Imaging strategyMRI is the method of choice for imaging suspectedcentral nervous system (CNS) tumours in pregnancy,predominantly for its ability to characterize tu-mours, showing greater sensitivity and specificityfor brain tumours than CT. Contrast-enhanced MRI,

diffusion-weighted imaging, perfusion MRI, andmagnetic resonance spectroscopy can aid tumourcharacterization, and should not be withheld if theinformation gained from these techniques couldpotentially influence treatment decisions.

CT has a valid role for urgent cases in which raisedintracranial pressure is suspected. The averagefoetal dose from a CT brain is less than 0.005 mGy,7

which has minimal detrimental implications for thefoetus. Hence for urgent investigation of worryingneurological symptoms there should be no delaydue to concerns about foetal radiation exposure.

For spinal compression symptoms, again MRI isthe technique of choice. In this context the needto urgently assess for a remediable cause would, inpractice, outweigh the general advice to avoid MRIin the first trimester of pregnancy.

Gestational trophoblastic tumours

Tumour behaviourThe gestational trophoblastic tumours (GTT) rep-resent a unique group as they are the only tumoursto arise as a direct consequence of pregnancy. GTTalmost always develops with or following a preg-nancy, 50% following a molar pregnancy, 25% aftera pregnancy not carried to term, and 25% after anapparently normal pregnancy. This equates to an8% risk of GTT after a complete molar pregnancy,0.5% risk after a partial molar pregnancy, and1/50,000 risk after a full-term pregnancy.105

Pathologically the group comprises invasivehydatidiform mole, placental site trophoblastictumour, and choriocarcinoma.106 GTT commonlypresent with persistent vaginal bleeding post-par-tum, but not uncommonly present with metasta-ses, and are usually diagnosed by persistentlyhigh serum b-hCG.

Choriocarcinoma is the most malignant formwith early blood-borne metastases. The incidenceis 0.02e0.2/1000 pregnancies. Vaginal bleeding ispresent in only 50e60% of cases. Presentation iscommonly with metastatic symptoms usually in thelate post-partum period, but can be delayed formonths to years following the pregnancy. Metas-tases are typically hypervascular/haemorrhagic,with commonest sites being lung (75e87%) andvagina (50%), with other common sites includingvulva, kidneys, liver, ovaries, brain (3e20% willhave brain metastases at diagnosis), and bowel.The diagnosis of metastatic choriocarcinomashould always be considered in women recentlypost-partum presenting with cough or haemopty-sis, but also in any woman of reproductive age withhaemorrhagic lesions or widespread metastaticdisease of unknown cause.

868 S. Doyle et al.

Imaging strategyUltrasound with colour Doppler is widely used toassess GTT for location and degree of myometrialinvasion, although in some centres transvaginalultrasound is avoided in known GTT because of thepotential risk of causing bleeding from vaginalmetastases.106 Trophoblastic tumour nodules tendto be surrounded by neo-vasculature, commonlywith arterio-venous anastomoses. Characteristi-cally on ultrasound the appearance is of hypoechoicblood lacunae surrounded by irregular echogenictrophoblastic nodules with multiple intramyome-trial vascular shunts. These intramyometrial vesselstypically have low resistive index and high peak sys-tolic velocities.107 These features can also be usedto monitor response to treatment, with the resis-tance to flow usually inversely proportional to theserum b-hCG level. Uterine volume can also be mea-sured on ultrasound, which is related to tumour bur-den and used to aid staging (FIGO 2000). MRI doesnot have a routine role in imaging local GTT, butcan be useful in assessing parametrial or other localinvasion, and is the preferred technique for assess-ing vaginal metastases.106

Further investigation for suspected metastasis isrequired following primary treatment if there arepersistently raised b-hCG levels or symptoms ofconcern. In the absence of lung or vaginal metas-tases, other metastatic disease is unlikely, andtherefore, chest imaging either with chest radio-graph or CT is an appropriate first investigation formetastases. In choriocarcinoma, the commonestcause of metastatic GTT, the haematogenouspulmonary metastases are typically multiplerounded soft-tissue densities measuring up to3 cm in diameter, usually less than 10 in number.Less common thoracic manifestations includemiliary metastases, intravascular tumour causinginfarction, and airspace opacification due to hae-morrhage. Although CT detects more pulmonarynodules than a chest radiograph, it is not estab-lished whether this affects management.106 If CTis used, low-dose lung CT protocols have shownadequate levels of detection for accurate stagingpurposes, despite not detecting as many smallnodules as standard thoracic CT.108 Imaging ofthe brain, chest, abdomen, and pelvis may berequired depending on symptoms. In practice, aspatients found to have lung or vaginal metastasesare at high risk of metastases at other sites,usually further imaging is appropriate in thesepatients, including abdominal CT to assess for livermetastases, and brain MRI. Liver metastases aretypically multiple hypodense masses on non-contrast CT, which enhance avidly in the arterialphase. Brain metastases are typically multiple,

most commonly occurring at the greyewhite mat-ter junction in the parietal lobe.106

Conclusion

Pregnancy should not preclude investigation ofserious symptoms. Investigating pregnant womenfor cancer requires careful consideration of thepotential risks and benefits of various imagingmethods. In many cases the pregnant woman canbe adequately investigated and staged withoutsignificant risk to the foetus. This is essential notonly for treatment planning, but also to provideprognostic information to inform the clinician andwoman’s decision making.

Effective communication between members ofthe multidisciplinary team is critical in the care ofthese women. As a key member of this team, theradiologist has a vital role in communicating thepotential risks and benefits of the various imagingmethods to other professionals, and when appro-priate, directly to the patient.

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