Table Of ContentKatalinicetal.WorldJournalofSurgicalOncology2013,11:14
http://www.wjso.com/content/11/1/14 WORLD JOURNAL OF
SURGICAL ONCOLOGY
CASE REPORT Open Access
Symptomatic cardiac metastases of breast cancer
27 years after mastectomy: a case report with
literature review - pathophysiology of molecular
mechanisms and metastatic pathways, clinical
aspects, diagnostic procedures and treatment
modalities
Darko Katalinic1*, Ranka Stern-Padovan2, Irena Ivanac3, Ivan Aleric4, Damir Tentor5, Nora Nikolac6, Fedor Santek1,
Antonio Juretic1 and Stjepko Plestina1
Abstract
Metastases to theheart and pericardium are rare but more common thanprimary cardiac tumours and are
generally associated with a rather poor prognosis. Most cases are clinically silent and are undiagnosed in vivo until
theautopsy.We present a female patient witha 27-year-oldhistory of anoperated primarybreast cancer who was
presented withdyspnoea, paroxysmal nocturnaldyspnoeaand orthopnoea. The clinical signs and symptoms
aroused suspicion of congestive heart failure. However,the cardiac metastases were detected during a routine
cardiologic evaluation and confirmedwith computed tomography imaging. Additionally, this paper outlines the
pathophysiology of molecular and clinical mechanisms involved in themetastatic spreading, clinical presentation,
diagnostic procedures and treatment of heart metastases.The present case demonstrates that a complete surgical
resection and systemic chemotherapy may result in a favourable outcome for many years. However,a lifelong
medical follow-up, withthe purpose of a detection of metastases, is highly recommended. We strongly callthe
attention of clinicians to thefact that during thefollow-upof all cancer patients, such heart failure may be a
harbinger of thesecondaryheart involvement.
Keywords: Heartmetastases, Breast cancer,Pathophysiology, Symptoms, Treatment
Background various cardiacsymptoms. Common primary tumours to
Metastases to the heart assume greater diagnostic and metastasise to the heart are mediastinal tumours, lung
therapeutic importance as the incidence ofdifferent can- cancer, melanoma, breast cancer and esophageal cancer
cer types rises. The condition was first described by [4]. Intracavitary growth of secondary heart tumours,
Theophy Boneti in 1700 [1]. Primary tumours of the however, is quite unusual. Therefore, despite their fre-
heart are rare, occurring at a frequency of <0.02% in dif- quency,metastasestothe heartrarelygainclinicalatten-
ferent autopsy series [2]. However, secondary or meta- tion. The signs of cardiac involvement are often
static tumours of the heart are more common than overlooked, since the symptoms of a metastatic disease
primary tumours [3] and patients may present with prevail. We present a case of breast cancer with symp-
tomatic heart metastases and heart chambers involve-
*Correspondence:[email protected] ment 27 years after mastectomy and discuss the
1DepartmentofOncology,UniversityHospitalCentre(KBCZagreb), pathophysiology of molecular mechanisms of cardiac
UniversityofZagrebSchoolofMedicine,Kispaticeva12,HR-10000,Zagreb,
Croatia
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Katalinicetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
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metastases, metastatic pathways, clinical manifestations, since the hymoptysis and a solitary metastatic tumour in
diagnostic proceduresandtreatment. the distal left lung were diagnosed. She underwent a left-
sided pulmectomy and mediastinal lymphadenectomy
Case presentation (PHD:Metastaticadenocarcinomaofthebreast)withgood
The patient’s past medical history was significant for a clinicaloutcomeandthediseasewasstabileforthefollow-
right-sided total mastectomy for carcinoma in 1984 (PHD: ing6years.In2005,atregularoncologicfollow-up,thepa-
Adenocarcinomaofthebreast)(Figure1Aand1B).Thepa- tientwasdiagnosedwithatumourformationundertheleft
tientwasstagedasT2N0M0.Atthattime,shehadnoradi- scapula which was surgically removed (PHD: Metastatic
ation or chemotherapy. All lymph nodes were negative. In adenocarcinoma of the breast, ER+, HER-2/neu +++)
1992, the patient was diagnosed with lung metastases and (Figure 1C and 1D). After that, she was treated with ana-
treated withCMF regimen(cyclophosphamide, methotrex- strosol and trastuzumab with regular medical follow-up
ate and fluorouracil), with a partial tumour regression. In andshefeltquitewell.
1995, she underwent the ablation of solitary metastasis in In 2011, 27 years after mastectomy, a 64-year-old white
the left lung lobe (PHD: Metastatic adenocarcinoma of the womanwasadmittedtoourhospitalwitha2-weekhistory
breast).In1999,acompleteclinicalre-evaluationwasmade of shortness of breath, dyspnoea, paroxysmal nocturnal
Figure1Histopathologicalevaluation.Hematoxylinandeosin(HE)histologicanalysisrevealedahighlycellularmalignanttumourwithsolid
clustersofatypical,polymorphicepithelialcells(imageA,high-powerphotomicrograph,originalmagnification,×400;HEstain).Thetumourwas
partiallynecrotic(imageB,low-powerphotomicrograph,originalmagnification,×100;HEstain).Immunohistochemicalstudyshowsthatthe
tumourcellsstainedpositiveforestrogenereceptors(ER)(imageC,low-powerphotomicrograph,originalmagnification,×200)andHER-2/neu
receptors(imageD,low-powerphotomicrograph,originalmagnification,×200)consistentwithdiagnosisofbreastadenocarcinoma.
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dyspnoeaandorthopnoeawithoutchestpain.The clinical enhanced multislice computed tomography (MSCT) of
presentation aroused suspicion of a congestive heart fail- the chest confirmed and demonstrated a large metastatic
ure. The Karnofsky’s index of performance status (KPS) massthatinvolvespredominantlythepericardiumandthe
was 20% and the Eastern Cooperative Oncology Group left ventricle with the extension into the left atrium
PerformanceStatusScale(ECOGPS)wasgrade4.Onad- (Figure 3A-3E). The patient was treated with corticoster-
mission,thepatientwasafebrileandinamoderatedegree oids, amynophilline, digitalis, beta-adrenergic antagonists,
of respiratorydistress. Therewasnoclinical or laboratory analgetics,low-molecular-weightheparinandoxygenation.
evidence for any kind of inflammation or pulmonary em- The palliative radiation therapy was initiated, but because
bolism. Her pulse was 140 beats per minute and regular, ofpatient’sseveregeneralcondition,atotaldoseofonly6
and her blood pressure was 130/90 mmHg. The heart Gy/day was delivered as a palliativethoracic radiotherapy.
sounds were distant and faint, there were no heart mur- Unfortunately, soon after hospital admission, the patient
murs. Chest radiography revealed an increase in cardiac died. The immediate cause of death was cardiorespiratory
silhouetteandthelungcongestion.Theelectrocardiogram arrest due to massive involvement of the heart by meta-
showed sinus tachycardia and low voltage without other staticmalignancy.
abnormalities. All cardiac enzymes were negative.
However, the high values of carbohydrate antigen 15–3 Discussion
(Ca15–3)(335.2kIU/L,normalrate<25)andcarcinoem- Malignant tumours metastasizing to the heart are one of
bryonicantigen(CEA)(380.8μg/L,normalrate<3.4)sug- the least investigated topics in clinical and experimental
gested clinical relapse. Two-dimensional transthoracic oncology. In the past, the low incidence of cancer to the
echocardiography (2D-TTE) revealed cardiac involvement heart has been explained on the theory that the heart
with metastatic tumour mass (Figure 2). A contrast- was not receptive to tumour cells. Prichard mentioned
Figure2Echocardiographicevaluation.Four-chamber2-dimensionaltransthoracicechocardiogramshowsalarge,irregularmetastaticmass
(2.3×1.1cm),whichinfiltratedpericardiumandmyocardium(predominantlyanteroapicalandlateralwallsoftheleftventricle)withintracavitary
propagation(arrows).
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Figure3Radiologicalevaluation.Contrast-enhancedaxial(Figures3A-3C),coronal(Figure3D)andsagittal(Figure3E)multislicecomputed
tomographyscanofthechestrevealedmassive,predominantlynecroticmetastatictumourmass(13×10cminsizeonaxialview)withpericardial
andheartinvolvement(arrows).Thetumourwaspartiallynecroticandinfiltratedthethoracicaortaandthepulmonarytrunkwithextensioninto
theleftatrium.
the kneading action and metabolic peculiarity of the the gradual improvement in surgery, chemotherapy,
heart muscle, and the rapid blood flow as factors radiotherapy, biotherapy and molecular targeted therapy,
accounting for the low incidence [5]. Other authors con- life-threatening sites of metastases are more commonly
sidered that the low incidence was more likely the result receiving intensive local therapy for palliation. Such
of inadequate observation. Until the 1960s, primary and tumoursare frequently highly responsiveto radiotherapy
especially secondary cardiac tumours were merely a or chemotherapy, and premortem diagnosis may be crit-
curiosity and the diagnosis was academic. Generally, ical in the clinical management. Although no malignant
they have devastating consequences given that they in- tumours are known which diffuse preferentially to the
volve such an important organ and present in very heart, some do involve the heart more often than others,
subtle ways causing a subsequent delay in clinical diag- for instance lung cancer, breast and esophageal cancer,
nosis. In the past two decades, imaging has improved lymphoproliferative malignancies, as well as melanoma
detection, with 2D-TTE, 2-dimensional transesophageal [5,7-12]. Metastasis is cancer’s most deadly aspect and it
echocardiography (2D-TEE), computed tomography is affected by several interconnected processes. There-
(CT) and magnetic resonance imaging (MRI) being the fore, tumour’s ability to spread to the heart tissue
mainstay of clinical evaluation [6]. Because of its easy depends on many different factors, not only the molecu-
availability, 2D-TTE, 2D-TEE and radiology procedures lar, biological and pathophysiological characteristics of
such as CT or MRI are complementary techniques, and the primary tumour, but also the specific structural and
are all used in the evaluation of cardiac deposits. With functionalcharacteristics oftheheart[5].
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Pathophysiologyofcardiacmetastases,metastatic wererightandthatthetwotheoriesarenotmutuallyex-
pathwaysandcascades:frommoleculartoclinicalaspects clusive. Additionally, organ-specific anatomic considera-
Although primary cardiac tumours are extremely rare tions also influence the metastatic process. These include
(different postmortem studies reported rates between blood-flow patterns from the primary tumour and the
0.001% and 0.28%), secondary tumours are not, and the homingabilityofcancercellstocertaintissuesandorgans.
heart can be metastasised by any sort of malignancy Typical environmental barriers in a metastatic event in-
[13,14]. Only tumours of the central nervous system have clude physical (a basement membrane - BM), chemical
not been proven to develop heart metastases. The exact (lowpH, reactiveoxygenspecies, hypoxia,andsoon)and
incidence of cardiac metastases is unknown. Indeed, sec- biological (immune surveillance, inhibitory cytokines and
ondary deposits are considered rare, but when sought for, regulatory extra-cellular matrix peptides) components
theincidenceseemstobenotaslowasexpected[15]and [22]. During tumour invasion, malignant cells penetrate a
they exist usually in the setting of a widely disseminated variety of extracellular matrices (ECM), including BMs
disease[12].Reflectingtheagedistribution,heartmetasta- andinterstitialstromathroughmultiplestepsinthemeta-
sespredominantlyoccurinpatientsbetweenthesixthand static cascade. To be completely successful, a tumour cell
eighth decades of life and there is no gender preference. must invade and degrade connective host tissue (invasion
Theywerefoundin1.23%of12,485consecutiveautopsies, of the primary tumour border - BM and the tissue sur-
compared with a 0.056% prevalence of primary cardiac rounding the tumour by the cell) and subsequently intra-
tumours[12].Inautopsiesatwhichamalignantneoplasm vasate (the bloodstream or lymph channels), survive the
was diagnosed, cardiac metastases were found in 9.7% to transitintothenewenvironment,arrestindistantvascular
10.7% of cases [4,16,17]. According to Bussani et al., the bed, extravasate to a distant site (the tumour cell than
highest rates of heart metastasis were found in patients invades into the BM of the targeted tissue interstitium),
diagnosed with pleural mesothelioma (48.4%), melanoma initiateamicrometastasisandproliferatetometastaticcol-
(27.8%), lung cancer (21%) and breast cancer (15.5%). ony [21,22].The initial partof this cascade also known as
High rates have also been found in patients with ovarian ‘epithelial to mesenchymal transition’ (EMT) was first
cancer (10.3%) and lymphoproliferative malignancies conceived by Krug et al. in 1987 and described by Hay in
(9.4%). About two-thirds of all heart metastases involved 1995 [23,24]. It is defined as the switch from non-motile,
thepericardiumandonlyone-thirdtheepicardiumorthe polarized epithelial cells to motile, non-polarized mesen-
myocardium [18]. Some tumours colonize a wide variety chymal cells, with the potential to migrate from primary
of organs and the first site encountered will be the most tumoursitestodistanttissuesandorgans,wheretheycan
commonsiteofmetastaticformation.Othersaremorese- proliferate [23-25]. There are several EMT components,
lective, they bypass some organs and selectively colonize and the most important are E-cadherin, N-cadherin, and
specific distal tissues. Interestingly, for reasons which are transforming growth factor-β (TGF-β) [26]. A ringleader
not clear, melanoma has a particular predilection for of EMT is a process named the ‘cadherin switch’, defined
metastasising to the heart and brain and a half of all cases by a decrease in E-cadherin, the component of adherent
of disseminated melanoma patients will have cardiac junctions, and a simultaneous increase of mesenchymal
depositsatnecropsy[19].However,breastcancerprimarily N-cadherin.Thisswitchallowscellstoloseadhesiveaffin-
metastasizestothebone,lungs,regionallymphnodes,liver ity for other surrounding cells and become more migra-
andbrain,withthemostcommonsitebeingthebone. toryandinvasive[26-29].Anothermostpotentinducerof
In 1889, Stephen Paget noticed that metastases in EMT is the TGF-β, a known pluripotent growth factor,
breast cancer were not random. He postulated ‘seed and able to induce EMT in mammary and other cell types
soil’ hypothesis claiming that a metastatic cells arose [26,30,31]. As we know, the process of metastatic spread-
from the proliferation of a few tumour cells (the seeds) ing is a complex series of different steps. Malignant cells
in the favourable tissue environment provided by certain break away from the primary tumour and degrade
organs (the soil) [20]. According to the ‘seed and soil’ proteinsthatmakeupthesurroundingECM,whichsepa-
theory, it is difficult for cancer cells to survive outside rates the tumour from adjoining tissue. Cell-ECM adhe-
their region of origin, so in order to metastasize they sion, motility, and localised proteolysis are mediated
must find a location with similar characteristics [20]. For mainly by matrix metalloproteases (MMPs). The tumour
instance,melanoma spreadstothebrain,presumablybe- cell develops structures called invadopodia, which are
cause neural tissue and melanocytes arise from the same highly concentrated in several MMPs [32,33]. Therefore,
cell line in the embryo. A few decades later, in 1928, op- the degradation of ECM is facilitated by MMPs, and
posite to Pageth’s opinion, James Ewing challenged the tumour cells can move across tissues into nearby stroma.
‘seed and soil’ theory and proposed that metastasis ECM-tumour cell interactions play a critical role in each
occurs purely by anatomic and mechanical routes [21]. oftheeventsofthemetastaticcascade.Interactionsofthe
Today, it is widely known that both Paget and Ewing breast cancer cells with integrins, fibronectin, tenascin C,
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laminins, collagens, endoglin, hyaluronan, heparanase and heart tissue, but these tumours predominantly attain to
proteoglycans can contribute to the metastatic process. the heart by the lymphatics. Via mediastinal lymph
The ECM protein Tenascin C (TNC) is an adhesion- nodes, tumour cells intially invade the epicardial, and
modulating extracellular matrix glycoprotein and it is then the myocardial lymphatic system [45]. As in our
upregulated in metastatic breast cancer. TNC is highly case, secondary heart tumours that have partial or total
expressed in tumour stroma and stimulates tumour-cell intracavitary growth are rare; when they do occur, they
proliferation. Endoglin is a cell-surface disulfide-linked areoftenaccompaniedbythrombosis[46-51].
homodimericglycoproteinwhichbindstointegrinsandis Thestructureofthelymphaticsystemintheheartmight
a co-receptor for TGF-β. For instance, brain and heart- explain the low incidence of secondary deposits in the
metastatic breast-tumour cells also express endoglin in heart compared with other tissues and organs [18]. As a
large amounts [34,35]. Heparanase expressed by breast particularity of lymphatics in the heart, the flow in the
cancer cells participates in angiogenesis and neovasculari- capillaries is high, determined by the effects of heart
sation by degrading the polysaccharide scaffold of the pressure. If lymphatics are obstructed by tumour cells,
endothelial BM, thereby releasing angiogenic growth fac- lymphwillstagnateinthemyocardialregionsupstreamof
tors from the ECM [36]. There are also several different the obstruction, and endocardial to epicardial drainage by
celltypescriticalfortumourgrowth.Gaoetal.andNolan the lymphatics will be inhibited. This in turn leads to tis-
et al. demonstrated that endothelial progenitor cells are sue damage duetolymphstasis, and favoursanincreased
critical for metastasis and angiogenesis [37,38]. Further- proliferation of neoplastic cells in undrained regions and
more, the ablation of endothelial progenitor cells in the retrograde lymph flow, which might disseminate malig-
bone marrow leads to a significant decrease in tumour nant cells to the more internal parts. As a result of
growth and vasculature development [39]. Metastatic increased pressure, the lymphatic wall may also break,
spreading is also mediated by numerous growth factors leading to interstitial tumour spread. The blockade of the
and cytokines, operating through different cell signalling common lymphatic node by neoplastic cells coming from
pathways. To initiate transcriptional responses, these sig- metastasised mediastinum lymph nodes is a key event
nalling moleculesmustenterthenucleus throughthe nu- leading to the formation of metastases. The penetration
clear pore complex (NPC). The NPCs are made of intothemyocardiumisfavouredbythestasisofthelymph
proteinsnamednucleoporins(Nups)andthereareseveral flow, and most importantly by the damage to the
Nupsthat are often abnormal in cancer patients. Some of epicardial plexus caused by the stasis in part, but also by
them are Ribonucleic acid exports 1 (Rae1) linked to thedirecteffectofthetumorcells[18,52].
breast cancer pathophysiology [40] and Nup88 which is Interestingly,metastaticcelldoesnotdisseminateneces-
overexpressedinovarian cancer [41]as well as in a broad sarily from the primary tumour. The first step in this
spectrum of sarcomas, lymphomas and mesotheliomas process is metastasis to a ‘generalizing site’such as lungs,
[42,43]. The transport of different cytokines, transcription liver, and so on (primary level of dissemination). This key
factors (HER2, TGF-β, galectin-3, NF-κB and other), or disseminating site is the first filter encountered by blood-
metastasis activators across the nuclear envelope com- borne or lymph-borne metastases once they are released
monly requires transporters (karyopherins) that bring from the affected lymph nodes. For a given primary
them to the nuclear pore. Finally, these molecules are tumour,morethanonesuchkeymetastaticsitemayexist.
translocated into the nucleus, where they can bind to tar- Dissemination of malignant cells then proceeds via sec-
get genes to initiate transcription and consequently cell ondary metastases from the generalising sites (secondary
migration and proliferation. For the metastasis to occur, levelofdissemination)[53].
allstepsinthemetastaticcascademusttakeplace.There- Finally, more recent molecular studies have shown that
fore, the blockade of any single step in the metastatic some forms of malignant tumours, including breast can-
pathwayshouldslowdownmetastasisprogression[44]. cer, arise from a small subset of cancer stem cells (CSCs),
Heartmetastasesareusuallysmallandmultiple;infre- which are often marked by the cell surface antigens
quently, single large tumour lesions are also observed. CD133,CD144andCD24.Thesecellsinducetumourfor-
Clinically, they occur by four main routes: transcoelo- mation and are often resistant to conventional anticancer
mic, lymphatic, haematogenous and thru implantation. treatments. TheCSCsexpressesspecific repertoireofsur-
Metastases may reach the heart via the hematogenous face markers, which allows their differential purification,
or lymphatic route, or by direct or transvenous exten- selectivelyendowedoftumorigeniccapacityasopposedto
sion. Lymphatic spread is most important and tends to all other subsets. They sustain the growth of heteroge-
give rise to pericardial metastases, while hematogenous neous cancer tissues, which recreate the full repertoire of
spread preferentially gives rise to myocardial metasta- tumour cell populations observed in the primary tumour,
ses. Tumours such as the breast cancer, which develop and most importantly, they display the main functional
near the heart, may expand by direct extension into the hallmarks: self-renewal and differentiation. However, the
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roleofCSCsinmultistagecancerprogression,particularly often thefirstmanifestation ofaheart metastasis[61].
with respect to metastasis, has not been well-defined and Inallcasesofarapidincreaseinpericardialfluid,
it has remained partially understood [54-57]. Obviously, cardiactamponade canresult andnecessitate
better understanding of CSCs as a fundamental compo- immediatepericardiocentesis [4,8].Slateretal.even
nent of the metastatic cascade may lead to novel thera- reportedacaseofconstrictive pericarditisfrom
peuticstrategies[58]. metastaticbreastcancertothepericardium[62].
Hypotension, dyspnea,venous congestion, peripheral
Clinicalmanifestationsanddiagnosticprocedures cyanosis,pulsusparadoxus andfallinQRSvoltageare
There is no strong correlation between the extent of car- allhallmarksofdiagnosis.ChestX-raymay revealan
diac metastases and clinical symptomatology. Some increaseincardiacsilhouette. Theelectrocardiogram
tumours, even with extensive spreading to the heart, pro- (ECG) maybehelpfulindemonstratingpericarditis,
ducenosymptomsandbecomeevidentbyincidentalfind- butasLamberta etal.concluded:‘The
ings. Usually, heart involvement is not noticed until after electrocardiographicchangesillustrativeofpericarditis
death. In some retrospective studies, only about 10% of areminimalinsubjectswith malignancies ofthe
patients who died of metastatic disease presented with pericardiumunless there issuifficientinvolvement’
symptoms or signs related with heart failure [9,59]. The [63].Tumour-inducedpericardialeffusionand
symptomatologyandclinicalpresentationvary,depending pericardialmassescanbebestviewedbymeansof
more on location than on size and can be classified as 2D-TTE and2D-TEEimaging,CTscan,highresolution
extracardiac (constitutional and mechanical), cardiac CTand MRI. Moreover,thepericardiocentesis
(pericardial, myocardial and intracavitary) or combined. specimen canbesubmitted tocytologicalanalysisto
Constitutional symptoms of pyrexia, arthralgias, rash and typify the tumourcells andhelpidentify theprimary
so on are mostly caused as a result of cytokine release. tumourorigin.
Mechanical symptoms (dyspnea, orthopnoea and chest
discomfort) result from compression of cardiac chambers Myocardialinvolvementmayoccurfrom encroachment
or coronary arteries or from pericardial irritation or tam- onthepericardium, orconductionsystembysecondary
ponade caused by growthor effusion/haemorrhagewithin deposits.Tumourtissueinthemyocardial massis
the pericardium. Myocardial symptoms are caused by usually asymptomatic anddoesnotproduceany
arrhythmias due to compression or encroachment on the characteristicECGsigns,butthereare many
conduction system. Intracavitary symptoms are caused exceptions.Generally, the clinicalpatternis
due to secondary deposits that obstruct valvular function, proportionalto thedegreeofmyocardialinfiltration,or
bloodfloworcombined,ortotumoursthatcausetumour relatedtothewallinfiltrationsite. Whenevertheright
fragmentstoembolizeintothesystemiccirculationorthe heart isinvolved,the interventricularseptum islikely
lungs [18,51]. Intracavitary symptoms may also vary with toshareinthe process,andthe conductionsystem may
body position, which can alter haemodynamics. Most be compromised.Arrhythmiasmay occur,however,
patients show symptoms of congestive heart failure, without septal invasion,andthey areimportantfor
superior vena caval obstruction or embolization [60]. antemortemdiagnosis.Different ECG changesare
According to the anatomic location of the tumour, some extremelycommonincardiacmetastasisand ECGhas
special symptoms and physical findings can be grouped been ofsomehelp[64,65].Typicalpresentation
together with regard to pericardial, myocardial and includesatrial flutterorfibrillation,prematurebeats
endocardial/heartchamberinvolvement[61-71]. and paroxismalsupraventricularand ventricular
arrhythmias(commonlytachycardias)conduction
Pericardialinvolvementmayoccuralone ormaybe disturbancesand atrioventricular blocks[64].Tumour
associated with metastaseselsewhere inthe heart. emboli occasionallyplugavesseland produce coronary
Intrathoracicgrowths,usuallycarcinoma ofthebreast insufficiency, symptomsofanginapectoris or
and lungs,may extend directlyinto thepericardium myocardialinfarction[3].Association between tumour
wherethetumourmay further invadeother partsof infiltrationofthe heart andcardiacrupture hasbeen
theheart.Themostfeared complications areneoplastic reportedonlyinisolated cases. Metastasesto theheart
pericardialeffusionswhichcanbeserous, may affectthemusclesufficientlytoproduce
serosanguineousorbloody,andmaylack congestiveheart failure.ScottandGarvinconcluded
haemodynamiccompromise.Theymay bemild thatthe development ofcongestivefailure without
(and resultinnosymptoms;incasesofa slowincrease apparentcauseinpatientswith malignantdiseaseraises
inpericardialfluid,thepericardium maystretchand thepossibility ofcardiac metastases.[8].Ceardic
thepericardialeffusioncanremain asymptomaticfor metastasesmayalso causeT-wave changes,S-T
some time)butthey are commonly symptomaticand deviationsand Qwaves[9].Displacement ofthe RS-T
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segment,invertedTwavesandisoelectricS-Tsegments andpatient’sgeneralcondition(correlationwithKarnofsky
inallleads may alsobefound [66,67]. andECOGperformancescores),andmayincludedifferent
systemic chemotherapy or palliation [51]. However, the
Heart chambersinvolvement isuncommonand the treatment is usually palliative because the prognosis is
symptomsof venous and intracardiacinvolvementare poor,butradiationtherapycansuccessfullypalliatecardiac
often minimal inrelation totheextensiveinvolvement metastases while preserving quality of life. In the specific
seen.Tumourembolireachingthe chambersmay cases where secondary cardiac involvement leads to the
implantontheendocardiumdirectlycausing valvular initialdiagnosisofprimarytumour,oristhefirstevidence
stenosis,valvularinsufficiency orheart failure. of metastatic recurrence, aggressive management may re-
Murmurstypical ofstenosismay be causedby sult in long-term survival [18,74]. Surgery would be only
metastaticdepositsand may changewith position. considered in patients whose primary tumour is under
Syncopeandsuddendeathhavealsobeen reported control and who have a significant disease-free interval.
[47,68].Furthermore,intracavitaryright-sidedheart Surgery is also indicated in exceptional cases of solitary
metastasescanleadtopulmonaryembolism,andleft- intracavitary growth, leading to obliteration of heart
sidedheartmetastasestosystemicembolism[50,69,]. chambersor valveobstruction,and the patient appears to
Most oftheendocardialgrowths causelittle disability have a good prognosis [75]. However, in both cases, the
and, likemostmetastaticdepositsoftheheart,are postoperative mortality is significant [76,77]. This poor
usually unexpectedand incidentalnecropsyfindings. prognosis points to the importance of selecting an appro-
Endocardialmetastasesmayalsomimicbacterial priatemodeoftherapy,takingintoconsiderationeachpa-
endocarditiswhich isrelevantfordifferentialdiagnosis. tientindividually[78].
Tumourcells thatinfiltratethelumenofagreatvein
may initiate thedepositionoffibrinuponthem. The Conclusion
fibrin,inturn, servesasaframeworkforcontinued Progressincancerbiologyhasexpandedourunderstanding
tumourgrowth.Thethrombosismay alsoextend along of the molecular and cellular mechanisms of cancer devel-
the veintothe heart chambers,hinderingbloodflow opment,metastaticspreadingtotheheartandothertissues,
and effectiveheart function.Theleftatriummaybe as well as resistance of cancer cells to chemotherapy and
invaded fromthe extensionoftumourthrombosisof radiotherapy. This manuscript has reviewed some of the
thepulmonary veins. 2D-TTE and 2D-TEEwithCTor key pathways that have been shown to play an important
MRIare valuableindelineatingthe presence or role in the process of breast cancer spreading to the heart
absenceofintracardiactumourmasses [6,50,69]. anddifferentdiagnosticandtreatmentmodalities.However,
Nuclearmedicinetechniquespreviouslyemployedto breast cancer and other malignant tumours, as a result of
detect secondaryheartdepositsincludebloodpool their genomic instability, have tremendous redundancy in
imagingand gallium orthallium scintigraphy [70]. their ability to maintain growth and to spread into sur-
Positron-emissiontomography computed tomography rounding tissues and distant organs. As such, this remark-
([18F]FDG-PET/CT)hasalreadybeen provenbemore able level of complexity makes successful treatment of
accuratethan CTintheevaluation ofmetastaticheart breast cancer metastases all the more challenging. Accord-
tumours,especiallyinthefollow-upofpatients ing to some reports, an average survival period after the
previouslytreatedwithchemotherapyand/or diagnosis ofcardiacmetastases hasbeenapproximately5.5
radiotherapy[71].[18F]FDG-PET/CT,positron- months [77]. Obviously, it is very important to know that
emissiontomographyMRI(PET-MRI) and 3- in cancer patients with symptoms of heart failure, meta-
dimensionalechocardiography mayhavetheadvantage static cardiac deposits must always be considered in the
ofdetecting themetastasesincomparison withother differential diagnosis, even in the subjects with a distant
conventionalimagingmodalities[71-73]. positive medical history. Clinicians should be alert to the
possibility of cardiac metastasis in a patient with and even
Treatment without clinical symptoms. 2D-TTE and 2D-TEE, which
The pathophysiological and clinical aspects of cardiac are easy, fast and sensitive techniques for detection of
metastases are intriguing, but, whatever the treatment, cardiac metastasis, and CT, MRI, [18F]FDG-PET/CT and
their clinical evolution is usually disappointing. In many PET-MRI as confirming methods should always be per-
cases, secondary deposits manifest in patients with formed when any suspicion exists in order to exclude car-
advanced cancer disease, with the heart being involved in diacinvolvementduringclinicalfollow-up[65,67,71-73,77].
the generalised cancer spread. Most patients will already Thiscasealsodemonstratesthatcompletemastectomyand
have undergone surgical treatment for the primary other oncological and surgical procedures may result in a
tumour, or chemotherapy and/or radiation therapy. The favourable outcome for many years, but regular medical
treatment of heart metastases depends on tumour origin lifelongfollow-upismandatory.
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