Tumours of the Heart - IARC · Tumours of the Heart ... Left atrial tumours, especially those that ... Rarely, tumours such as myxoma, cause systemic symptoms,including anorexia,

CHAPTER 4

Tumours of the Heart

Although tumours of the heart do not contribute significantly tothe overall tumour burden, they may cause a variety of cardiacand systemic symptoms. Clinical features depend not only onthe size, but, to a significant extent, on the anatomic location.Small, benign neoplasms may have devastating clinical conse-quences if in a critical location.

Progress in imaging and cardiac surgery have considerablyimproved the prognosis. However, cardiac sarcomas are stilllife-threatening diseases.

Due to the low frequency, there is no specific garding schemefor malignant heart tumours. This volume largely follows theprinciples of classification and grading detailed in the WHOClassification of Tumours of Soft Tissue and Bone.

BB10_interieur:- 1A lung intro 14/09/10 14:53 Page 249

250 Tumours of the heart

WHO histological classification of tumours of the heart

__________1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {6} and the Systematized Nomenclature of Medicine (http://snomed.org).

Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.

Benign tumours and tumour-like lesionsRhabdomyoma 8900/0Histiocytoid cardiomyopathyHamartoma of mature cardiac myocytesAdult Cellular Rhabdomyoma 8904/0Cardiac myxoma 8840/0Papillary fibroelastomaHaemangioma 9120/0Cardiac fibroma 8810/0Inflammatory myofibroblastic tumor 8825/1Lipoma 8850/0Cystic tumour of the atrioventricular node

Malignant tumoursAngiosarcoma 9120/3Epithelioid haemangioendothelioma 9133/3Malignant pleomorphic fibrous histiocytoma(MFH)/Undifferenciated pleomorphic sarcoma 8830/3Fibrosarcoma and myxoid fibrosarcoma 8840/3Rhabdomyosarcoma 8900/3Leiomyosarcoma 8890/3Synovial sarcoma 9040/3Liposarcoma 8854/3Cardiac lymphomasMetastatic tumours

Pericardial tumoursSolitary fibrous tumour 8815/1Malignant mesothelioma 9050/3Germ cell tumoursMetastatic pericardial tumours


251Introduction

Epidemiology

The estimated frequency of cardiactumours ranges from 0.0017-0.33%{2165}. In a review of 22 autopsy-basedseries of primary cardiac tumours a fre-quency of 0.021% was identified among731,309 patients {1656}. In one 20-year(1972-1991) review of 12,485 autopsycases, there was a 0.056% incidence ofprimary tumours and a 1.23% incidenceof secondary tumours {1116}. However,these data may have a high referral biasand may not reflect population-basedincidence rates {2079}. At the MayoClinic, the autopsy incidence of primarycardiac tumours from 1915 to 1931 was0.05%, but more than tripled to 0.17%between 1954 and 1970 {2165}; again,referral bias may have played a role inthis change.When most cardiac tumours were diag-nosed at autopsy, myxomas and sarco-mas were reported at a similar frequency.With the utilization of cardiopulmonarybypass and surgical excision, the report-ed frequency of myxomas as opposed tocardiac sarcomas has increased sub-stantially {249,1568}. In a review of surgi-cal series, cardiac myxomas constitute77% of surgically excised tumours, andcardiac sarcomas, 10% {249}.In children, cardiac tumours are not com-mon and most are benign {249}. Themost common pediatric tumours includerhabdomyomas, fibromas, myxomas,and teratomas {249,356}.Secondary cardiac tumours, eithermetastatic or by direct invasion, outnum-ber primary cardiac neoplasms {1116}. Areview of 3,314 autopsies found a 2.9%frequency of metastatic tumours involv-ing the heart {12}. The most common pri-mary sites are lung, breast, and cuta-neous melanoma.

Clinical features

Cardiac neoplasms may cause a varietyof signs and symptoms {1225,1791,2079}. The clinical presentation dependson the size of the tumour and its anatom-ic location. Growth rate, friability, andinvasiveness are also important factors

that determine clinical features {737}.Large tumours may be relatively silent,whereas small tumours in a critical loca-tion may give rise to devastating clinicconsequences. Left atrial tumours, especially those thatare mobile or pedunculated, may lead tosystemic embolism involving the coro-nary, cerebral and peripheral circulations{737,1568,2077}, resulting in myocardialinfarction, stroke or ischemic viscera orlimbs. Left atrial tumours may also inter-fere with mitral valve function resulting inmitral stenosis or regurgitation. Cardiacmurmurs and a characteristic tumour“plop” may be auscultated. Valve dys-function manifests as left-sided heart fail-ure with shortness of breath, orthopnea,paroxysmal nocturnal dyspnoea, pul-monary edema, fatigue, cough, andchest pain {356}. Intramural left ventricular tumours maybe asymptomatic or present with a masseffect. With protrusion into the cavity,hemodynamic compromise may result{1225}. Local extension of the tumourmay cause conduction or coronary arterycompromise with chest pain, myocardialinfarction, arrhythmia, heart block or sud-den death {356,737,1225,1791}. Right atrial or right ventricular tumoursmay result in right heart failure from atri-oventricular or pulmonary outflowobstruction, resulting in peripheraledema, hepatomegaly, ascites, short-ness of breath, syncope and sometimes,sudden death {737}. If the tumours inter-fere with valve function they may result inregurgitation or stenosis {1791}. Right-sided cardiac tumours mayembolize to the lungs and present as pul-monary emboli with chest pain, pul-monary infarction and haemoptysis{1634,1791}. Chronic embolization mayalso mimic chronic thromboembolic dis-ease with signs and symptoms of pul-monary hypertension.Pericardial tumours may cause chestpain typical of pericarditis {1225,1568}.The tumours may be haemorrhagic andcause pericardial effusion and tampon-ade {1634}. However, constrictive peri-

carditis may also result from tumour infil-tration.Rarely, tumours such as myxoma, causesystemic symptoms, including anorexia,weight loss, fatigue and malaise whichmay mimic a variety of systemic disor-ders {356,737,1774,2077}. Interestingly,they may also cause haematologicabnormalities, including anemia, poly-cythemia, leukocytosis, thrombocytosisand elevated sedimentation rate {1225}.Tumour production of mediators, includ-ing interleukins, has been reported{1774}.

Imaging

Primary tumours of the heart and peri-cardium may be detected as an abnor-mal finding on a chest radiogram oranother imaging test obtained for anunrelated reason. Once detected car-diac imaging is needed to define (1)tumour location, extent and boundaries;(2) relationships with adjacent key car-diac structures such as valves and coro-nary arteries; (3) tumour type; and (4)presence and degree of functionalimpairment. The main non-invasive imag-ing modalities for evaluating primary car-diac tumours each have advantages anddisadvantages. They are often usedtogether in a complementary manner fordiagnosis and surgical planning.

EchocardiographyThe primary advantage of echocardiog-raphy is that it has the best spatial andtemporal resolution and provides excel-lent anatomic and functional information{492,705,1070,1162,2104,2215}. It is theoptimal imaging modality for small mass-es (<1 cm) or masses arising fromvalves. A second major advantage ofechocardiography is the ability to imagevelocities with Doppler, which allows forassessment of presence, degree, andlocation of obstructions to blood flow orvalve regurgitation. Echocardiography istypically the modality used for the initialevaluation of cardiac tumours and maybe the only diagnostic test required insome patients. Disadvantages include

Tumours of the heart: Introduction A.P. BurkeJ.P. VeinotR. LoireR. Virmani

H. TazelaarH. KamiyaP.A. Araoz

G. Watanabe



suboptimal image quality in patients withpoor acoustic windows, inability to imageextent of disease outside of the medi-astinum, and relatively low soft tissuecontrast, which limits detection of tumourinfiltration and characterization of tumourtissue. Also, intravenous contrast agentsare not routinely used with echocardiog-raphy, which limits the ability to charac-terize tumour vascularity.

Magnetic Resonance Imaging (MRI)The primary advantage of MRI is itsexcellent soft tissue contrast whichmakes it the most sensitive modality fordetection of tumour infiltration. MRI hasmore manipulable imaging parametersthan other imaging modalities. Becauseof this, MRI is the best modality for char-acterizing tumour tissue {1003,1768,1831,2156}. For example, a T2-weightedstandard or fast spin echo sequence dis-tinguishes tumours with high water con-tent, such as haemangioma, fromtumours with low water content, such asfibroma. A third advantage of MRI is theability to characterize tumour vascularitywith intravenous contrast. Though not asflexible as echocardiography, MRI doesallow assessment of wall motion andassessment of velocities through largevessels. This allows for characterizationof ventricular function, inflow or outflowobstruction and valve regurgitation. Theprimary disadvantage of MRI is longexamination times, which translates intothe need for sedation in children, and theneed for reliable ECG gating. MRI shouldbe considered when the tissue type,exact location, or the relationships of thetumour with neighbouring structures arenot completely defined by echocardiog-raphy or when surgical resection of thetumour is considered.

Computed Tomography (CT)ECG gated CT scans with the latest gen-eration of multidetector scanners or withelectron beam scanners are also veryuseful for cardiac imaging {65,275}. Inmany ways, the advantages and disad-vantages of CT are intermediate betweenthose of echocardiography and MRI.Modern CT scanners have excellent spa-tial resolution, which is better than that ofMRI, but not as high echocardiograpy.CT has better soft tissue contrast thanechocardiography, and can be used todefinitively characterize fatty content andcalcifications; however, the overall soft

tissue contrast and ability to characterizetumour infiltration and tumour type is lessthan that of MRI. Intravenous contrastcan provide information about tumourvascularity, an advantage CT shares withMRI. CT may be used as an adjunct toboth echocardiography and MRI.

Cardiac Catheterization This is seldom required for diagnosis ofcardiac tumours, but may be performedin adults to exclude coronary artery dis-ease. Angiography provides indirect andnonspecific imaging based on fillingdefects within the cardiac chambers anddisplacement of the coronary arteries{347,1840}. Two exceptions are worthnoting. First, endomyocardial biopsy fortissue typing may be considered inselected patients. Second, selectivecoronary angiography is helpful whenplanning surgical resection of anintramyocardial tumour.

Tumour grading and staging

Given the low frequency of malignantcardiac tumours, there is no gradingscheme specifically referring to malig-nant heart tumours. This volume uses thecriteria published in the recent WHO

Classification of Tumours of Soft Tissueand Bone {590}. The concept of gradingsarcomas was first introduced in 1977{1712}. Several grading systems havesince been proposed which have shownto correlate with prognosis {412,1247,1418,2031,2070}. The two most impor-tant parameters in non-cardiac soft tis-sue seem to be the mitotic index andextent of tumour necrosis {1793,2031,2070}. Most pathologists recognize threegrades of malignancy: G1, low grade;G2, intermediate grade; and G3, highgrade. Some use a 4-tiered system.The two most widely used systems arethose of the NCI (U.S. National CancerInstitute) {412,413} and the FNCLCC(Fédération Nationale des Centres deLutte Contre le Cancer) {387-389,748,2031}.According to the methodology defined in1984 {412} and refined in 1999 {413}, theNCI system uses a combination of histo-logic type, cellularity, pleomorphism andmitotic rate for attributing grade 1 or 3.All the other types of sarcomas are clas-sified as either grade 2 or grade 3depending on the amount of tumournecrosis, with 15% necrosis as thethreshold for separation of grade 2 andgrade 3 lesions.The FNCLCC system is based on a scoreobtained by evaluating three features:tumour differentiation, mitotic rate andamount of tumour necrosis {2031}. Ascore is attributed independently to eachparameter and the grade is obtained byadding the three attributed scores.Tumour differentiation is highly depend-ent on histologic type and subtype. Thereproducibility of this system has beentested by 15 pathologists: the crude pro-portion of agreement was 75% for tumourgrade, but only 61% for histologic type{748}.Because of the limitations and pitfalls ofgrading, the following guidelines havebeen suggested to improve reliablility:> Grading should be used only foruntreated primary soft tissue sarcomas.> Grading should be performed on rep-resentative and well-processed material.> Grading is not a substitute for a histo-logic diagnosis and does not differentiatebenign and malignant lesions. Beforegrading a soft tissue lesion, one must besure that one is dealing with a true sar-coma and not a pseudosarcoma.> Parameters of grading must be carefullyevaluated, particularly the mitotic rate.

Tumour differentiation Score 1: Sarcomas closely resembling

normal adult mesenchymal tissue (e.g., low-grade leiomyosarcoma).

Score 2: Sarcomas for which histologicaltyping is certain (e.g., Myxoid Fibrosarcoma)

Score 3: Undifferentiated, angiosarcoma

Mitotic countScore 1: 0-9 mitoses per 10 HPF*Score 2: 10-19 mitoses per 10 HPFScore 3: ≥20 mitoses per 10 HPF

Tumour necrosisScore 0: No necrosisScore 1: <50% tumour necrosisScore 2: ≥50% tumour necrosis

Histologic gradeGrade 1: Total score 2,3Grade 2: Total score 4,5Grade 3: Total score 6, 7, 8

Modified from Trojani et al {2031}.*A high-power field (hpf) measures 0.1734mm2

Fig. 4.01Parameters of the grading system for sarcomas ofthe Féderation Nationale des Centres de LutteContre le Cancer (FNCLCC).


253Introduction

The WHO Classification of Tumuors ofSoft Tissue and Bone {590} offers addi-tional information on the grading of softtissue sarcomas.There is no TNM classi-fication for cardiac malignancies.

Treatment and prognosis

In general, surgical resection, when pos-sible, is the treatment of choice for pri-mary cardiac tumours in symptomaticpatients. It is also highly desirable forpatients whose tumours are identifiedincidentally because of the ever-presentrisk of sudden death, embolism, obstruc-tion, or arrhythmia {307,952}. In patientswith rhabdomyomas and so called histio-cytoid cardiomyopathy, predominantlychildren, there are some who suggestthat surgical intervention is only neces-sary in the face of life-threatening symp-toms, as these tumours are benign andknown to regress with age {1880}.

Surgical strategy varies by tumour type.Cardiac myxomas arise mainly from theleft atrial septum, and the surgical strate-gy usually includes complete tumourresection with underlying stalk.Sometimes reconstruction using a pros-thetic patch is necessary {952}. Theprognosis of patients with cardiac myxo-mas is excellent. They may occasionallyrecur, especially in patients with Carneycomplex, an autosomal dominant syn-drome characterized by associated skinlesions, endocrine abnormalities andother unusual tumours {1018}. It is diffi-cult to suggest a regular surgical strate-gy for other cardiac tumours as theyarise in various locations. The prognosisfor other benign tumours is generallyfavourable with low recurrence, and it isquite good even if incompletely excised{307,952,1880}. Orthotopic heart trans-plantation is an option if tumour resection

and reconstruction would be expected tocause irreparable damage to essentialcardiac structures {731}.For malignant cardiac tumours, completeresection is often impossible because oflocal spread {2071}. The prognosis ofpatients with primary malignant cardiactumours is very poor even if complete re-section is attempted {952,2071}. Adjuvantchemotherapy and irradiation are usuallyalso given, but these are not effective inmost cases {2071}. Favourable results ofheart transplantation for primary malig-nant cardiac tumours have been reporteddespite immunosuppression {731,733,1962, 2071}.


254 Tumours of the heart - Benign tumours with myocyte differentiation

Rhabdomyoma

Definition

A benign tumour of the cardiac myocyte,which can be solitary or multiple. Thecells typically contain large glycogenfilled vacuoles.

ICD-O code 8900/0

Epidemiology

Cardiac rhabdomyoma is commonlyassociated with tuberous sclerosis, anautosomal dominant disorder with a highmutation rate. It involves multiple organsincluding brain, kidney, pancreas, retinaand skin. In autopsy series, patients withtuberous sclerosis have a 30% incidenceof cardiac rhabdomyoma {571}.However, the actual incidence is likelyhigher since series that have evaluatedpatients with echocardiography havefound an incidence between 40% and86% {119,492,777}. The presence ofmultiple cardiac rhabdomyomas prena-tally may be the earliest manifestation oftuberous sclerosis.

Localization

Rhabdomyomas are firm, white, well-cir-cumscribed lobulated nodules that occur

in any location in the heart, but are morecommon in the ventricles. In patients withtuberous sclerosis, tumours are usuallymultiple (> 90%) and can consist ofnumerous miliary nodules measuring lessthan 1 mm; in this instance, the term“rhabdomyomatosis” has been used. Themost common locations are the left ven-tricle and ventricular septum, although30% will have atrial wall or right ventricu-lar involvement {1602}. In contrast topatients with tuberous sclerosis, approxi-mately 50% of sporadic rhabdomyomasoccur singley.

Clinical features

Signs and symptomsRhabdomyomas are the most commontumours in the pediatric age group. Theyare also the tumours most commonlydiagnosed during the prenatal period byfoetal echocardiography. Intrauterine aswell as sudden death after birth hasbeen attributed to these tumours.Clinical and hemodynamic findings arerelated to the number, position, and sizeof the tumours. For instance large intra-mural or intracavitary tumours mayobstruct valvular orifices, or occludeintracavitory spaces {1254}. Foetal dys-rhythmias or non-immune hydrops may

be identified as early as 21 weeks byultrasound {863}. The tumours maycause infant respiratory distress, con-gestive heart failure, or low cardiac out-put. Right-sided tumours that causeobstruction may cause cyanosis, or fea-tures suggestive of tetralogy of Fallot orpulmonary stenosis {41,583}. Left-sidedtumours may present as subaorticobstruction, or hypoplastic left heart syn-drome {2068}. Rarely they can be asso-ciated with structural cardiac defects{2113}. Patients with “rhabdomyomato-sis” or diffuse microscopic involvementof the myocardium may present asthough they have a cardiomyopathy.Spontaneous regression is a commonfeature {1254,1840}.Electrocardiographic abnormalities willvary depending on location, but evi-dence of ventricular hypertrophy and ST-T wave abnormalities consistent withischemia and/or strain are common. Theconduction abnormalities consist of bun-dle branch block, preexcitation, and firstto third degree atrioventricular block.

ImagingAt echocardiography rhabdomyomasappear as homogeneous, well-circum-scribed echogenic masses in the ventric-ular myocardium, possibly protrudinginto the ventricular cavity. Althoughuncommon, extensive rhabdomyomascan be associated with ventricular dys-function. Given that the finding of multi-ple cardiac masses is diagnostic of rhab-domyoma, especially in patients withtuberous sclerosis, and that the tumoursare not infiltrative, echocardiographyusually provides adequate informationfor diagnosis and clinical management. Ifthere is question of tumour type or oftumour invasion, MRI or CT may be usedto further define the tumours. At MRI,rhabdomyomas appear as well-circum-scribed masses with signal characteris-tics similar to that of normal myocardium{155,737,1003}. Compared with the sig-nal from uninvolved myocardium, themasses are hypointense on post-gadolinium imaging. At CT, rhabdomy-

Benign tumours with myocyte

differentiation A.P. BurkeH. TazelaarC.R. Patel

B.M. ShehataT. Geva

G. TornambeneD.J. Radford

R. Virmani

BAFig. 4.01 Rhabdomyoma. A Echocardiogram of an infant who presented with supraventricular tachycardia.There are multiple rhabdomyomas. These eventually regressed and the arrhythmias resolved.B Echocardiographic imaging from the apical chamber view, showing multiple cardiac rhabdomyomasinvolving the left (LV) and right (RV) ventricles.


255Rhabdomyoma

omas also appear as multiple nodules,which may be hyper or hypoattenuatingcompared to normal myocardium. WithMRI or CT, the rest of the body can beimaged for signs of tuberous sclerosis.However, because rhabdomyoma hasmany imaging features similar to normalmyocardium, echocardiography, MRI,and CT may be complementary as rhab-domyomas that are not visible by onemodality may be visible on another {737}.

Macroscopy

Single or multiple, they are well-circum-scribed, non-capsulated white or greywhite nodules which may vary in sizefrom millimeters to several centimeters.Tumours can become quite large, espe-

cially in sporadic cases. In one series of14 cases, the range was 0.3-9.0 cm, witha mean of 3.4 cm {248}. They most oftenoccur in the ventricle, but can be foundin the atria, at the cavoatrial junction andon the epicardial surface. Large tumoursmay obliterate and distort a ventricularcavity.

Histopathology

Cardiac rhabdomyomas are well-demar-cated nodules of enlarged cardiacmyocytes with cleared cytoplasm. Insome cells, strands of eosinophilic cyto-plasm stretch from a central nucleus tothe cell membrane giving rise to cellsthat resemble a spider (“spider cells”).The majority of cells show vacuolization

with sparse myofilaments. There is astrong reaction with periodic acid-Schiffreagent, reflecting the presence of abun-dant intracellular glycogen.

ImmunoprofileImmunohistochemical studies documentthe striated muscle characteristics ofrhabdomyoma cells, which express myo-globin, desmin, actin, and vimentin.Tumour cells do not express cell prolifer-ation markers such as Ki-67 and PCNA,indicating that the lesions are more likelyhamartomas as opposed to neoplasms{248}.

Electron microscopy

By electron microscopy, the cells resem-ble altered myocytes. They possessabundant glycogen, small and sparsemitochondria, and cellular junctionsresembling intercalated disks surroundthe cell periphery. In contrast, the inter-calated disks of differentiated myocytesare located exclusively at the poles of thecell. Intercalated discs and myofibrils orcollections of Z band material are pres-ent. Rarely one may observe there primi-tive T-tubules. Leptomeric fibers close tothe sarcolemma may also be identified.

Differential diagnosis

The diagnosis of cardiac rhabdomyomain infants and young children is straight-forward. In patients with multiple non-cal-cifying masses, especially with othermanifestations of tuberous sclerosiscomplex, a tissue diagnosis is unneces-sary. However, because the tumourshave been shown to regress with ageand multiple biopsies do not allow forevaluation of the morphologic changesthat characterize this process, the rela-tionship between persistent rhabdomy-omas and so-called adult rhabdomy-

DCFig. 4.02 Cardiac rhabdomyoma. A Multiple rhabdomyomas in an infant with tuberous sclerosis complex(courtesy of William D. Edwards, M.D.). B Intraoperative photograph. The tumour nearly fills the ventricu-lar cavity, and is glistening and polypoid. C Stillborn child with a ventricular rhabdomyoma. D Subaorticrhabdomyoma in an 5 months old child.

BA

BAFig. 4.03 Rhabdomyoma. A The subendocardium shows a poorly demarcated area of cellular vacuolization.B A higher magnification note "spider" cells, several vacuolated tumor cells, and cells with abundanteosinophilic cytoplasm , which is more typical for rhabdomyomas in older children.

Fig. 4.04 Cardiac rhabdomyoma with classic spidercell.



omas and hamartomas is not clear. In therare examples of rhabdomyomas in olderchildren, there is often a paucity of spidercells, resulting in a tumour with somecharacteristics of adult rhabdomyomas,but without the proliferative activity.Hamartoma of mature cardiac myocytes,which, like rhabdomyoma, is a non-prolif-erative hamartomatous lesion, occurs inadults. These tumours lack circumscrip-tion and spider cells.

Genetic alterations

The familial form of tuberous sclerosis,which is present in up to 50% of patientswith cardiac rhabdomyoma, exhibitsautosomal dominant inheritance. Twodisease genes have been identified:TSC-1 at chromosome 9q34, and TSC-2at chromosome 16p13 {1613}. The TSC-1 gene encodes hamartin, and TSC-2tuberin, proteins involved in tumour sup-pression. Loss of heterozygosity is oftenfound at these loci in tumours frompatients with tuberous sclerosis. The pre-cise roles of TSC-1 and TSC-2 in thedevelopment of cardiac tumours andregulation of embryonic and neonatalcardiomyocyte growth remain to be elu-cidated.

Treatment and Prognosis

Rhabdomyomas have a natural history ofspontaneous regression {204,556,1840}.However, serious symptoms may precip-itate the need for surgical resection.When arrhythmias are the presentingsymptom, treatment with anti-arrhythmicdrugs is commenced. If control isachieved by that means, then drugs can

be continued until the arrhythmias ortumours regress. If drugs fail to controlarrhythmias, surgical resection is indicat-ed. When a tumour is causing intracar-diac obstruction, surgery is necessary{180,525,538,1289}.

Histiocytoid cardiomyopathy

Definition

Histiocytoid cardiomyopathy is a rare,but distinctive arrhythmogenic disordercaused by a neoplastic or hamartoma-tous proliferation of cardiac cells withsome Purkinje cell characteristics.

Synonyms

Purkinje cell hamartoma, arachnocytosisof the myocardium, infantile cardiomy-opathy, infantile xanthomatous cardio-myopathy, oncocytic cardiomyopathy,focal lipid cardiomyopathy, isolated car-diac lipidosis, infantile cardiomyopathywith histiocytoid changes, myocardial orconduction system hamartoma, foamymyocardial transformation, and congeni-tal cardiomyopathy.

Epidemiology

Histiocytoid cardiomyopathy occurs pre-dominantly in the first two years of life;20% of cases are diagnosed in the firstmonth, 60% in the first year, and lessthan 3% after two years of life. The preva-lence of this disease may be higher thanthe reported cases would suggest, sincesome cases are undoubtedly diagnosedas Sudden Infant Death Syndrome(SIDS).

The female preponderance is 3:1. Inapproximately 5% of cases there seemsto be a familial tendency.

Clinical features

Histiocytoid cardiomyopathy is anarrhythmogenic disorder; 70% of pub-lished cases the patients present with aspectrum of arrhythmias and electricaldisturbances including: paroxysmal atrialtachycardia, atrial fibrillation, ventricularfibrillation, ventricular tachycardia, pre-mature atrial contractions, prematureventricular contractions, Wolff-Parkinson-White syndrome, and right or left bundlebranch block. Approximately 20% of patients presentas sudden death and often such caseshave been misclassified as SuddenInfant Death Syndrome (SIDS). Otherinfants experience flu-like symptoms pre-ceding or accompanying the cardiacmanifestations. The majority of patients(95%) display cardiomegaly, but mayalso have a number of associated anom-alies, including cardiac malformation(16%): ventricular and atrial septaldefects, hypoplastic left heart syndrome;and endocardial fibroelastosis. Extra-cardiac anomalies occur in 17% ofpatients including corneal opacities,microcephaly, cataract, aphakia, hydro-cephalus, agenesis of the corpus callo-sum, cleft palate, laryngeal web, and lin-ear skin defect. Combined cardiac andextracardiac anomalies occur in 4%, and7% show extracardiac histiocytoid cellsin exocrine and endocrine glands {1794}.

Fig .4.05 Histiocytoid cardiomyopathy. A Gross picture of the heart, showing multiple histiocytoid nodules in the aortic valve leaflets, endocardium, and papillarymuscles (arrows). B Macroscopic photograph of a heart demonstrating the left ventricle and portion of the mitral valve. Note pale tan endocardial nodules at thelevel of the annulus.

BA


257Histiocytoid cardiomyopathy

Etiology

Many theories of the etiopathogenesishave been proposed, including viralinfection, myocardial ischemia, toxicexposure, and metabolic disorders suchas glycogen storage disease, cardiaclipidosis, and various mitochondrialmyopathies. However, the clinical, gross,microscopic, and ultrastructural findingsshow clear differences between theabove-mentioned disorders and histiocy-toid cardiomyopathy. The clinical presen-tation (arrhythmia), the distribution of his-tiocytoid cells, and their ultrastructuraland immunohistochemical characteris-tics, all point to the cardiac conductionsystem as playing a key role. The primi-tive Purkinje cells of the developing heartshow a striking resemblance to histiocy-toid cells. Both types of cells show strongpositivity for cholinesterase by frozensection histochemistry and for neutrallipids with the Sudan Black stain.Cholinesterase is present only in the con-duction tissue of the heart; it is not pres-ent in contractile myocytes {1794}.

Macroscopy

Single or multiple subendocardial yellow-tan nodules or plaques ranging from 1-15 mm may be seen in both ventricles,the septum, and on all four cardiacvalves. Although these nodules are main-ly seen beneath the endocardium follow-ing the distribution of the bundle branch-es of the conduction system, they canalso be seen in the inner myocardiumand subepicardial areas. Lesions may begrossly inapparent as nodules, but multi-ple cross sections of the myocardium

may show a mottled appearance withirregular ill-defined yellowish-tan areas.

Histopathology

Histiocytoid cardiomyopathy lesionsappear as multifocal, ill-defined islandsof large polygonal cells with granulareosinophilic cytoplasm, small round tooval shaped nuclei containing occasion-al nucleoli. The cytoplasmic appearanceis due to extensive accumulation of mito-chondria. The cells are distributed alongthe bundle branches of the conductionsystem. The sinoatrial and atrioventricu-lar nodes are involved in 28% of cases;however, these areas are not sampledroutinely {1794}.

ImmunoprofileHistiocytoid cardiomyopathy cells reactwith anribodies to desmin, myoglobin,myosin, and muscle specific actin. Thereis no expression of macrophage or histi-ocyte antigens (CD68, CD69, MAC 387,LN3, HAM-56). The cells also fail to reactwith antibodies to vimentin and cytoker-atin (CAM-5.2), whereas S-100 proteinreactivity is variable. Cell proliferationmarkers (Ki-67 and MIB-1) are usuallynegative {682,1713}.

Electron microscopy

Ultrastructurally, the cells of histiocytoidcardiomyopathy show poorly developedintercellular junctions. Their cytoplasmcontains a superabundance of swollenmitochondria with disorganized cristaeand dense membrane bounded gran-ules, which push the diminished myofib-rils to the periphery of the cell. The cyto-plasm also contains lipid droplets of vari-

able size, scattered desmosomes, inter-calated discs, and leptometric fibers.


The disease has been confused with mito-chondrial cardiomyopathy. However, thereare major gross, light microscopic, andultrastructural differences between the twodiseases. Mitochondrial cardiomyopathyshows no discrete nodules as present inhistiocytoid cardiomyopathy. Additionally,in mitochondrial cardiomyopathy, allmyocytes are affected, but to a variabledegree, whereas in histiocytoid cardiomy-opathy, only focal areas of the heart areinvolved, but the affected cells are affect-ed totally. The ultrastructural changes inhistiocytoid cardiomyopathy cells consistof increased numbers of mitochondria withand without structural changes andreduced myofibrils. In mitochondrial car-diomyopathy, the mitochondria are consis-tently abnormal in a varitey of ways. Theyare enlarged, show variation in size andshape, contain occasional glycogen parti-cles, and have cristae which areincreased in number and on cross section,are arranged in a concentric circular fash-ion (like growth rings of a tree) surroundingoccasional dense bodies.

Genetic susceptibility

Familial recurrence of histiocytoid car-diomyopathy in 5% of cases has led toseveral proposals of a genetic mecha-nism. The female preponderance ofcases suggests an X-linked mutationcausing prenatal lethality in the homozy-gous male {168,234,1898}. A femaleinfant with “oncocytic cardiomyopathy”and microphthalmia with linear skin

Fig. 4.06 Histiocytoid cardiomyopathy. A Discrete, circumscribed nodule of pale cells, superficially resembling foamy macrophages in the subendocardium.B Subendocardial histiocytoid nodule. Note the ill-defined border with adjacent myocardial fibers.

BA



defects showed monosomy for Xp22{1543}. Biochemical {1543} and molecu-lar (mitochondrial DNA) {57} evidencesuggest a defect of complex III (reducedcoenzyme Q-cytochrome c reductase) ofthe respiratory chain in cardiac mito-chondria. Such a mechanism could beresponsible for the mitochondrialchanges observed by light and electronmicroscopy, and the systemic involve-ment in some patients. It has been sug-gested that the disease is due to a muta-tion in Sox6 gene (p100H), which is asso-ciated with widespread myopathies{385}. From reported cases with knownethnic background, histiocytoid car-diomyopathy appears to be more com-mon in Caucasian (80%) followed byAfrican-American (15%), and Latin-American infants (3%); it is rare in Asianinfants {1794}.

Prognosis and predictive factors

Histiocytoid cardiomyopahty causesincessant ventricular tachycardia in smallchildren and can result in sudden death.Surgical excision or direct-vision cryo-ablation of the multiple small nodulartumours is required for long-term cure{665}. Surgical intervention, electrophys-iologic mapping, and ablation of thearrhythmogenic foci result in a survivalrate of approximately 80%. Some authorshave found that aggressive anti-arrhyth-mic treatment may allow the tumours toregress without subjectiing patients tosurgery. A few patients with extensivedisease have undergone cardiac trans-plant {664,678,984,1286}.

Hamartoma of mature cardiacmyocytes

Definition

The term “hamartoma” has been looselyapplied to several cardiac tumours, mostcommonly histiocytoid cardiomyopathy(“Purkinje cell hamartoma”). The termhas also been applied to lesions or mal-formations composed of a variety of car-diac elements, and other tumours com-posed primarily of a single cell type (e.g.,rhabdomyoma). The term hamartoma ofmature cardiac myocytes is used for adistinct tumour in adults, composed ofcardiac myocytes. This lesion may besingle or multiple.

Etiology

The etiology of cardiac hamartoma isunknown. Some have suggested thatthese tumours may represent maturingcongenital rhabdomyomas. However,there has been no association of hamar-toma of mature cardiac myocytes withother syndromes including the tuberoussclerosis complex, making this unlikely.

Localization

Hamartomas of mature cardiac myocytesmay occur in the ventricles or atria, andmay be single or multiple {243}. Unusualexamples of diffuse multiple tumourletssimilar to so-called rhabdomyomatosis,have also been described.

Clinical features

As is the case with most cardiactumours, the clinical features depend onthe location. Tumours in the atria mayresult in supraventricular arrhythmiasand Wolf Parkinson White syndrome, andthose in the ventricles sudden death, orno symptoms at all.

Macroscopy

They are usually poorly demarcated firmwhite masses and range in size from 2mm to 5 cm in greatest dimension. Theyresemble normal myocardium, but thebundles of muscle may appear disorgan-ized and associated with bands of con-nective tissue.

Histopathology

They are composed of enlargedmyocytes with obvious cross striations,and contain enlarged, irregular nuclei.They are poorly demarcated and mayinterdigitate with normal myocytes at theedges of the tumour. The interstitium

demonstrates increased collagen.Interspersed fat cells may be present insmall numbers.

ImmunoprofileThe tumours are similar to normal car-diac myocytes, and express actin andmyosin. Abnormal accumulations ofthese intermediate filaments may beappreciated, particularly of actin. Thereis no evidence of proliferation byimmunohistochemical stains for Ki-67 orPCNA.

Electron microscopy

The cells show features of myocytes, butabnormal accumulations of actin andmyosin may be identified.


The disorganized hypertrophied musclefibers of a hamartoma are also reminis-cent of the disarray characteristic ofhypertrophic cardiomyopathy, but withrare exception (apical variant), hyper-trophic cardiomyopathy is not associatedwith a focal mass lesion.


These tumours are benign neoplasmsand can be excised, resulting in cure.However, arrhythmias and sudden deathmay be the initial presentation.

BAFig. 4.07 Histiocytoid cardiomyopathy. A Electron microscopic illustration showing histiocytoid cells packedwith mitochondria. The diminished myofibrils are displaced to the periphery of the cell (arrows). B Highermagnification showing abundant swollen mitochondria with disorganized cristae and dense membranebounded granules.


Adult cellular rhabdomyoma

Definition

Adult cellular rhabdomyoma is a benignneoplasm of striated myocytes. A similartumour frequently occurs in the head andneck region (extracardiac rhabdomy-oma).

ICD-O code 8904/0

Epidemiology

The adult form of extracardiac rhab-domyoma occurs primarily in the headand neck region of men and women over40 years. Four cases of “extracardiac”rhabdomyomas have been described inthe heart {241,2226}.

Clinical features and localization

Three of the four reported cases of adultcellular rhabdomyoma have occurred inthe atria, and all have occurred in adultsfrom 35-55 years of age. Common to anyheart tumour, the mode of presentation isoften electrical disturbance such assupraventricular tachycardia or nonsus-tained ventricular tachycardia. Themasses may be identified incidentally.

Macroscopy

They range in size from 2–5 cm. Thetumours are soft, bulging, tan to brownand have a pseudocapsule. These fea-

tures distinguish these tumours fromother cardiac tumours with muscle differ-entiation.

Histopathology

These tumours are histologically distinctfrom cardiac rhabdomyomas, and arecomposed of tightly packed, round topolygonal cells with eosinophilic, finelygranular cytoplasm, occasional vacuolesand occasional spider cells. Conversely,cardiac rhabdomyomas are composedof large cells with clear cytoplasm con-taining abundant glycogen and manyspider cells.


In contrast to congenital rhabdomyomas,adult cellular rhabdomyomas occur inadults, demonstrate evidence of cellularproliferation e.g. by expression of Ki-67antigen, and contain relatively few vac-uolated or spider cells. Unlike hamar-toma of mature cardiac myocytes, thetumours are well circumscribed, andalthough not as frequent as in congentialrhabdomyoma, some vacuolated cellsare usually present. Furthermore, the dis-organized masses of myofilaments char-acteristic of hamartoma of mature car-diac myocytes are not seen. Rhabdo-myosarcoma shares some features withadult cellular rhabdomyoma. Despite theevidence of cell proliferation in the latter

tumours, the absence of tumour necro-sis, mitotic figures, myogenin expression,and the presence of a well-definedpseudocapsule help to distinguish it fromrhabdomyosarcoma.

Histogenesis

The lesion is believed to be a true neo-plasm of striated muscle origin.

Somatic genetics

Due to the rarity of these lesions, molec-ular and genetic characterization has notbeen undertaken. In extracardiac rhab-domyoma, a reciprocal translocationbetween chromosomes 15 and 17 andabnormalities of the long arm of chromo-some 10 have been described {680}.


The prognosis of adult cellular rhab-domyoma is unknown, but presumed tobe benign, based on the biologic behav-iour of extracardiac rhabdomyomas inadults. Late recurrences have beendescribed in extracardiac rhabdomyoma{680}.

BAFig. 4.08 Hamartoma of mature cardiac myocytes. A The tumour was circumscribed, with the appearanceof muscle. B The tumour cells are hypertrophic, forming disorganized bundles with interstitial fibrosis.

Fig. 4.09 Adult cellular rhabdomyoma. Note themonomorphic, bland spindled cells; their myogenicnature is not clearly evident on routine stains.

259Adult cellular rhabdomyoma


260 Tumours of the heart - Benign tumours of pluripotent mesenchyme

Cardiac myxoma

Definition

Myxoma is a neoplasm composed ofstellate to plump cytologically blandmesenchymal cells set in a myxoid stro-ma.

ICD-O code 8840/0

Epidemiology

Cardiac myxoma represents one of themost common benign cardiac tumours{2013,2165}. In most surgical series, theyaccount for almost 80% of cases{249,1986}. In large registries and repos-itories with significant referral bias myxo-mas represent between 20 and 40% ofprimary cardiac tumours {249,1338}.Patient age ranges from 2-97 years.Mean age at presentation is 50 years{1133}. About 90% of individuals arebetween the ages of 30 and 60 years{2165}. A recent analysis of 1,195 indi-viduals with myxomas revealed that 67%were female and 33% were male {2212}.Patients with the myxoma (Carney) com-plex are generally younger and moreoften male than patients with sporadicmyxomas.

Clinical features

Clinical presentation is diverse anddependent upon tumour location and toa lesser extent morphology {175,643,1598,1616}. About 20% of cardiac myxo-mas are asymptomatic; they are usuallysmaller than 40 mm {722,736}.

Cardiac symptomsIn over 50% of patients left atrial myxo-mas cause symptoms of mitral valvestenosis or obstruction (dyspnoea andorthopnoea from pulmonary oedema orheart failure). Right atrial myxomas mayobstruct the tricuspid valve and causesymptoms of right-sided heart failure.The majority of patients have an abnor-mal physical examination, most charac-teristically a diastolic or systolic murmur.A “tumour plop” may be occasionallyheard in early diastole {722,1598,1616}.Abnormal, but nonspecific electrocardio-graphic changes may be identified in 20-40% of patients and include atrial fibrila-tion or flutter and left and right bundlebranch block {643,1616}. Chestroentgenograms also show only nonspe-cific findings, including cardiomegaly,chamber enlargement, and pulmonaryoedema {1616}.

EmbolismEmbolic phenomena are the secondmost common manifestation (30-40% ofpatients). Frequent sites of embolizationinclulde the central nervous system, kid-ney, spleen and extremities. Coronaryembolism may result in myocardialinfarction {524,1542}. There is some evi-dence that fibrous lesions are more likelyto produce valvular obstruction whilepolypoid and myxoid ones are more like-ly to embolize {722,736}.

Systemic symptomsThese are possibly related to IL-6 pro-duction by tumour cells. They are seen inapproximately 20% of patients andinclude myalgia, muscle weakness,arthralgia, fever, fatigue and weight loss.Although infection of a myxoma is rare,when present the initial manifestationsmimic those of infective endocarditis,and can include fever, chills, petechiae,subconjunctival haemorrhages, Oslernodes and positive blood culture. Anaemia, leukocytosis and elevated ery-throcyte sedimentation rate are the mostcommon laboratory findings {175,1616}.Most myxomas are sporadic, althoughsyndromic and familial cases (Carney ormyxoma complex) are well recognised.In familial cases, the patients present ata younger age, they occur in unusuallocations and have a higher recurrencerate than in non-familial cases{296,2114}.

Imaging

At echocardiography carciac myxomastypically appear as a mobile massattached to the endocardial surface by astalk, usually arising from the fossaovalis. Myxomas with this appearancecan be confidently diaganosed byechocardiography and further imaging isnot necessary {1298}. In fact, becausethe tumours are usually small andmobile, myxomas are typically betterdefined by echocardiography than byeither MRI or CT, because echocardiog-

Benign tumours of pluripotent

mesenchyme

A.P. BurkeH. TazelaarJ.J. Gomez-RomanR. LoireP. ChopraM. TomsovaJ.P. VeinotT. Dijkhuizen

C.T. BassonR. Rami-Porta

E. MaiersA.E. Edwards

P. WalterJ.R. Galvin

S. TsukamotoD. Grandmougin

P.A. Araoz

BAFig. 4.10 Cardiac myxoma. A Long axis MRI view of the left ventricle demonstrating a well-circumscribedmyxoma (T) centered in the left atrium. The inferior portion of the mass abuts the tricuspid valve. B Themass seen in the previous figure (T) originates from the atrial septum and is best demonstrated on the axialview. The right-sided effusion and consolidation (E) are unrelated to the myxoma (the patient had metasta-tic malignant melanoma, with an incidental cardiac myxoma).


261Cardiac myxoma

raphy has the best spatial and temporalresolution. If the narrow stalk is not visi-ble, the diagnosis cannot be made byechocardiography and further imaging,usually MRI, is necessary to show thetumour’s margins and to exclude tumourinfiltration. At MRI and CT myxomaappears as an intracavitary heteroge-neous, lobular mass. As with echocardio-graphy, if the narrow stalk is visible, myx-oma can be diagnosed by MRI or CT{66}.

Macroscopy

Cardiac myxomas are intracavitarymasses that occur most often in the leftatrium {361}. They arise from the endo-cardium of the atrial septum near thefossa ovalis in 85-90% of cases. Most ofthe remainder are located in the right atri-um. Rarely, they arise in the ventricles.

Multiple tumours occurring at sites otherthan fossa ovalis and ventricles are gen-erally found in the inherited form of car-diac myxoma. Very rarely, cardiac myxo-mas have also been documented tooccur on valves and chordae tendineae.

The external appearance, consistency,size and weight are extremely variable.They may be as small as a few millime-ters and as large as 14 cm in diameter.The weight ranges from 2-250 gm. Tinycardiac myxomas may be totally asymp-tomatic and discovered incidentally atsurgery for another purpose or autopsy.Larger ones are either sessile or pedun-culated, but the site of attachment isalways discrete and usually in the regionof the fossa ovalis. Occasionally, thestalk may be long, resulting in free mobil-ity of the tumour within the atrial cavity.

Myxomas are ovoid, globular, lobulatedor polypoid. They may be smooth andglistening or have multiple papillary, vil-lous, finger-like projections. They may begrey white and fibrous, gelatinous andmyxoid, or a combination of both. Thepapillary structures may be quite friableincreasing the risk of embolisation.Superficial thrombi also embolize.Marked variation in colour is characteris-tic. Pale grey, pearly white or yellowbrown areas are frequently admixed withhaemorrhagic dark brown or red areas.Tumour consistency depends on thequan tity and distribution of fibrous tissue,and calcification. Rarely, the bulk of thetumour becomes calcified {120,1180}.

Histopathology

The myxoma cells may be arrangedsingly, in cords, or in vasoformative ringstructures {245,361,1625}. The cells canbe elongated, fusiform or stellate. Theycontain modest amounts of eosinophiliccytoplasm. Nuclei are oval, round, orelongated and mitoses are very rare.Myxoma cells have a tendency to formprimitive or differentiated vessels, reflect-ed in expression of endothelial markers.Less myxoid stroma often forms a haloaround the vascular formations.The stroma contains variable amounts ofproteoglycans, collagen and elastin. Itshows strong reactivity with alcian blue,resistant to predigestion by hyaluro -nidase. The vessels within the tumour arethin-walled and lack pericytes. Occa -sionally, cavernous vascular spa ces con-taining blood or proteinaceous materialare encountered. Thick walled blood ves-sels with prominent muscular walls arepresent predominantly at the base oftumour and in the stalk. Extravasated redcells, foci of recent and organizinghaemorrhage and hemosiderin deposi-tion are frequent. Hemosiderin is seenfree within the stroma, within histiocytesand myxoma cells. Variable numbers oflymphocytes, plasma cells, macro -phages, dendritic cells, and mast cellsmay be present.Gamna-Gandy bodies as seen in chron-ic venous congestion of the spleen maybe encountered infrequently. Calci fi -cation and metaplastic bone formationmay also occur. The latter are more fre-quent in right atrial myxomas. The sur-face is usually composed of a singlelayer of flattened cells, but multilayeringand tufting may occur.

Fig. 4.11 Cardiac myxoma. A This incidental finding at autopsy is a sessile smooth surfaced mass attachedto the endocardium of the let atrium at the level of the oval fossa. Note the relationship to the mitral valve,which may often become partly obstructed in patients with left atrial myxoma, resulting in pulmonary hyper-tension. B Myxoma of the left atrium, with typical localization at the fossa ovalis. C Cut surface of a papil-lary myxoma of the left atrium. D Papillary myxoma with necrosis, left atrium. E Left atrial myxoma afterresection. F Left atrial myxoma with an old and recent haemorrhages.

FE

DC

A B



Heterologous componentsWell-defined columnar epithelium, occa-sionally forming glands occurs in about2% of myxomas. The epithelium mayshow moderate cytologic atypia, mitoticactivity and express cytokeratin. Ageand sex distribution of patients, signsand symptoms, frequency of syndromicassociation and sites of occurrence aresimilar for cardiac myxoma with or with-out glands. Recognition of the glands asa component of a myxoma is importantsince these structures may be confusedwith metastatic adenocarcinoma. Theglandular cells are positive for PAS-dia-stase, alcian blue and mucicarmine; theystain for cytokeratin (diffuse cytoplasmicstaining with antibodies to cytokeratin 7,AE1/AE3, 4betaE12 and Cam 5.2; andfocal staining for cytokeratin 20), EMA(diffuse cytoplasmic), and CEA (apicalcell border). Reactivity for CA19.9 hasalso been observed on the apical epithe-lial membrane of the glandular compo-nent of a myxoma from a patient with ele-vated serum CA19 {1190}. Foci ofextramedullary haematopoiesis may beseen in 7% of myxomas {245}. Thymicrests have also been observed {245}.

ImmunoprofileThe cells are cytokeratin negative, vari-ably S-100 positive, and variably positivefor smooth muscle and endothelial mark-ers e.g. CD 34 and CD31 {362,1269,1625,2013}. Calretinin is expressed inabout 75% of cardiac myxomas {16}.

Histogenesis

Some years ago myxomas were consid-ered nothing more than organised throm-bi. Their neoplastic nature is supportedby the presence of chromosomal abnor-malities {489}, abnormal DNA content{1226} and the presence of microsatelliteinstability {1853}. The presence of het-erologous elements, however, still sug-gest to some that they may be reactive orhamartomatous {1925}. The origin ofmyxoma cells is unclear. They arethought to arise from subendothelialvasoformative reserve cells or primitivecells which reside in the fossa ovalis andsurrounding endocardium. The minuteendocardial structures described byPrichard {1618} do not seem to corre-spond to the hypothetical subendothelialpluripotential vasoformative reserve cellsfrom which the myxomas would arise,because they do not share the immuno-

histochemical properties of myxomacells {15,16}. On the other hand, car-diomyocyte-specific transcription factormRNAs have been recently found in RNAextracted from myxoma lysates, suggest-ing cardiomyogenic differentiation inmyxoma cells and a possible origin incardiomyocite progenitor cells {1037}.


Although most myxomas are sporadic,some have been associated with themyxoma complex {295,483}. This auto-somal dominat syndrome has beenreported under the acronyms NAME(nevi, atrial myxoma, myxoid neurofibro-ma, ephelides), LAMB (lentigines, atrialmyxoma, mucocutaneous myxomas,blue nevi), and more recently as Carneysyndrome {295,299,530}. This syndromeincludes cardiac myxomas and extracar-

diac manifestations: abnormal skin pig-mentation (lentigines and blue nevi), cal-cifying Sertoli-Leydig testicular tumours,cutaneous myxomas, myxoid breastfibroadenomas, pigmented adrenal corti-cal hyperplasia, pituitary hyperactivity,psammomatous melanotic schwannomaand thyroid tumours {295}. Familial myx-omas are estimated to account for 7% ofatrial myxomas {299}, are more oftenmultiple, recurrent and right sided, ascompared to sporadic myxomas. Theaffected patients are also younger, mostpresenting at 20-30 years of age{530,1133,1544}.

Somatic genetics

The chromosomal patterns of sporadiccardiac myxoma are characterised byextensive intratumour heterogeneity. Inthe seventeen cases published to date,

Fig. 4.12 Cardiac myxoma. A Numerous rudimentary vessels. B Three stages of rudimentary vessels.C A primitive endothelial marker, CD34 is often present within the central areas of the vascular structuresformed by cardiac myxoma. D Cardiac myxoma glands with PAS-positive-diastase resistant material con-sistent with mucus. E Cardiac myxoma with complex glands whose cells show moderate cytologic atypia.F Cytokeratin 7 staining of a cardiac myxoma with heterologous components.

FE

DC

A B


263Papillary fibroelastoma

multiple unspecific chromosome aberra-tions have been reported, includingdicentric chromosomes and, in particu-lar, telomeric associations {489,497,498,502}. Intratumour heterogeneity, as foundin a variety of tumour types and grades{688}, is considered a sign of geneticinstability presumably resulting from dis-ruption of genes that control genomicintegrity. Studies of cardiac myxomassuggest that the chromosomal regions12p1 and 17p1 may play a specific rolein the development of these neoplasmssince they are frequently rearranged{497}.Cytogenetic analyses of three cases ofcardiac myxoma derived from patientswith the myxoma syndrome reveal chro-mosome patterns similar to thoseobserved in sporadic cases {489,1658,1882}. Whether there is a commongenetic mechanism underlying sporadicand familial cardiac myxomas is unclear.Based on linkage analysis, 2 loci havebeen proposed for genes causally relat-ed to the myxoma syndrome: 2p16{1882} and 17q2 {299}. Recently, a genelocated at 17q24 was cloned thatshowed mutations in myxoma patients{122,598,1018}. This gene, PRKAR1A,represents a putative tumour suppressorgene, coding for the type 1 alpha regula-tory subunit of protein kinase A (CNC1,OMIM #160980). No causal gene hasbeen identified at the 2p16 locus, andsome families that were initially thoughtto have disease related to this locusactually have chromosome 17q24PRKAR1A mutations {122}. At least onefurther locus remains to be identified. Asyet, neither mutations of PRKAR1A norloss of heterozygosity of markers at 17q2and 2p16 have been found in sporadiccardiac myxomas {598}.Flow cytometry shows abnormally hightetraploid DNA patterns in all cases ofsyndromic myxomas, whereas in spo-radic myxomas it is present only in about20%.


There is a remarkably different prognosisbetween patients with sporadic andfamilial myxomas. Patients with sporadictumours have a good prognosis, with 1-3% recurrence rate {1275,296,2227}.However, about 10% of patients withfamilial myxomas either have recurrenttumours or develop another tumour in adifferent location {1276,1598}. The recur-

rence interval in one series was 47.8months {296}. The probability of recur-rence has been related to DNA chromo-somal pattern {296,1276}. Patients with afamilial tumour need to followed longterm.Embolization is the major complication ofmyxoma and may result in ischemicsymptoms in a variety of arterial beds.Intracranial aneurysm due to emboliza-tion is also a rare, but potentially morbid,complication. The etiology of theseaneurysms is unclear but histologic veri-fication of myxoma cells in arterial wallshas been reported {1758}.

Treatment

Immediate surgical resection is advisedwhen the diagnosis of cardiac myxoma issuspected {1454}, because of the risk ofembolism {2001}. The tumour is removedunder cardiac arrest with cardiopul-monary bypass. Minimal manipulationand gentle management of the heart isrecommended so as not to precipitateembolism. After the tumour is resected,the cardiac chamber should be irrigatedwith saline solution to wash out residualtumour fragments.The approach to a left atrial myxoma isusually through a vertical incision. Whenthe tumour is not large, a transseptalapproach useful, whereas a transseptalbiatriotomy {516} is recommended for alarge tumour. As the majority of left atrialmyxomas arise from the interatrial sep-tum, the tumours can be removed enbloc with a 5 mm margin of normal tis-sue. The fossa ovalis, where the pre-tumour cells of myxomas are thoughtlikely to exist {2102}, should also beexcised if possible. For a right atrial myx-oma, direct caval cannulation avoidstumour fragmentation. When direct can-nulation to the inferior vena cava is

impractical, a cannula should be insert-ed from the femoral vein for the inferiorvena cava. Tumour resection with the fullthickness of the septum and patch repairis required for tumours with a broadbased attachment. However, when thetumour originates from the atrial wall,resection of the attachment, and 5 mm ofnormal tissue including endocardiumand underlying myocardium are recom-mended.

Papillary fibroelastoma

Definition

An endocardial based papilloma lined byendothelial cells with proteoglycan richavascualar stroma, usually rich in elastin.

Synonyms

Giant Lambl excrescence, fibroelasticpapilloma

Epidemiology

Papillary fibroelastoma is a rare andbenign tumour representing less than10% of primary cardiac tumours{121,247}. The true incidence is difficultto determine, as the tumour may be over-looked and there is morphologic overlapwith Lambl excresences, a reactive age-related valvular lesion {249,2080} Inrecent series of surgically excised car-diac tumours papillary fibroelastoma rep-resents the second most frequent benignlesion.Papillary fibroelastoma is the most com-mon primary tumour of cardiac valves. Intwo recent series of primary valvetumours, papillary fibroelastoma consti-tuted 73% and 89% of cases {531,1714}.Mean age of the patients is 60 years(range, newborn to 83 years) and there isan equal gender predilection {1714,1903}.

BAFig. 4.13 Papillary fibroelastoma. A Papillary fibroelastoma from aortic valve. Note multiple translucent pap-illary fronds. B Multiple papillary fibroelastomas (greater than 40) developing 17 years following open heartsurgery. From A.N. Kurup et al. {1105}.



Etiology

The histogenesis continues to be asource of controversy. Various gross,microscopic, and molecular characteris-tics of papillary fibroelastoma have led tothe lesions’ being described as neo-plasms, hamartomas, organized thrombi,and unusual endocardial responses totrauma. The histochemical presence offibrin, hyaluronic acid, and laminatedelastic fibers within the fronds supportsthe hypothesis that papillary fibroelas-tomas may be related to organizingthrombi. Evidence favouring the hamar-toma hypothesis includes a histologicappearance that suggests the prolifera-tion of miniature tendinous cords andapparent congenital papillary fibroelas-tomas associated with other congenitalcardiac anomalies. Due to the presenceof dendritic cells and cytomegalovirus inthe intermediate layers of some papillaryfibroelastomas, a recent study proposedthat papillary fibroelastomas may berelated to a chronic form of viral endo-carditis {734}.Repetitive hemodynamic trauma maycontribute to their development as theyhave been reported in association withdiseases resulting in abnormal flow ofblood in the heart including rheumaticheart disease, hypertrophic cardiomy-opathy, mitral valve prolapse and atrialseptal defect, among other diseases.However, the mechanisms by which suchhemodynamic abnormalities contribute topapillary fibroelastoma growth are unclear.There is increasing evidence that at leasta subset (18%) of these tumours developas a result of iatrogenic factors, includingthoracic irradiation and open-heart sur-gery (subaortic septal myectomy, valverepair, valve replacement and repair ofcongenital defects {1105}. In contrast tosporadic cases, which are most commonon cardiac valves, iatrogenic papillaryfibroelastomas tend to occur in a varietyof non-valvular endocardial surfaces,usually in close proximity to the predis-posing iatrogenic factor, e.g. in thechamber most closely associated withthe site of surgery.

Localization

Ninety percent of papillary fibroelas-tomas occur on heart valves, includingaortic, posterior and anterior mitralleaflets {531,597,842,1397,1819,2015},mitral chordae and papillary muscles{313,659}. Unusual locations include the

tricuspid and pulmonary valves, rightand left atrial and ventricular endocardialwalls, Chiari’s network, and coronaryostia {43,202,254,913,977,1179,1770,2249}. Autopsy series show an equalright and left heart distribution {205,531,1274}. However, surgical series havea high prevalence (81%) of left sidedpapillary fibroelastomas because left-sided lesions are much more frequentlysymptomatic.Tumours are found most commonly(69.5%) on diseased valves - 37.8%post-rheumatic valves and 62.2% valveswith fibrosis and calcification {1903}.Papillary fibroelastomas have beenlikened to Lambl excrescence, but unlikeLambl excrescences, which occur at theline of closure of semilunar valves, papil-lary fibroelastomas occur anywhere onthe valve surface.

Clinical features

The clinical diagnosis of papillary fibro-elastoma can be difficult becauseembolic complications can mimic a vari-ety of underlying diseases {1714}.Integrity of the superficial endotheliallayer of the fronds has been demonstrat-ed to be the main element leading tooccurrence of embolic events {734}.Embolism is related to the aggregation ofplatelets and fibrin {567,734,742}.Lesions adjacent to coronary ostia mayprolapse resulting in angina, syncope orsudden death {205,262}. The majority of

surgically excised cases occur inpatients with symptoms related to cere-bral ischemia. The diagnosis is made bymultiplanar transthoracic and trans-esophageal echocardiography {713,1151,1770,2015}. High-resolution echo-cardiography shows an echolucent centre.

Macroscopy

Papillary fibroelastomas range in sizefrom 2-50 mm in greatest dimension,although the majority are less than 10mm. They are generally opalescentwhite, but this colour may be obscuredby thrombus. They are usually attachedto the endocardial surface by a short sin-gle stalk, but those with more than oneattachment to the endocardium havebeen observed. Papillary fibroelastomashave multiple papillary fronds and, par-ticularly when immersed in water, theyresemble a pom-pom or sea anemone.Papillary fibroelastomas most oftenoccur singly (80-90%), but amongpatients with iatrogenic tumours, multipletumours (2 to greater than 40) occur withgreat frequency (67%). Such tumours areless likely to occur on the valves andhave been reported in a wide variety oflocations (on papillary muscles, tendi-nous cords, and atrial and ventricularseptal and free walls).

Histopathology

Papillary fibroelastomas have a superfi-cial endothelial layer, an intermediate

Table 4.02Immunohistochemical profile of cardiac papillary fibroelastomas. From D. Grandmougin et al. {734}

Marker Central fibrous Intermediate layer Endothelial border core

Vimentin (+) (+) (+)

S 100 Protein (-) (+) (-)

CD 31 (-) (-) (+)

CD 34 (-) (-) (+)

Factor VIII (-) (-) (+)*

CMV-LMP-1 (+)

EBV-LMP-1 (-)

*Staining intensity decreased in comparison to the adjacent normal endocardial endothelium with animmunoreactivity ratio of 0.4


265Papillary fibroelastoma

layer rich in proteoglycans and a centralavascular core. The inner layers containfibroblasts and occasional inflammatorycells including macrophages and den-dritic cells {742,1703}. Elastic fibres aremost prominent in the core but may besparse or absent in the distal parts of thepapillae. Acute and organizing thrombimay be seen on the surface and obscurethe papillary surfaces.

ImmunohistochemistryImmunohistologic studies demonstrate adisparity between surface and deeperlayers. Surface endothelial cells expressvimentin and CD34 with some loss ofintensity for CD31 and factor VIII relatedantigen in comparison to normal endo-cardial endothelium. It has been pro-posed that the decreased expression ofendothelial markers indicates endothelial

trauma or dysfunction {734,1200,1703}.Spindle cells in deeper layers may focal-ly express S100 protein. The S100 cellslikely represent competent antigen pre-senting dendritic cells. The presence of Tcells has not been investigated in theseregions.

DC

BA

Fig. 4.14 Papillary fibroelastoma. A Location at the aortic valve. B Movat pentachrome stain demonstrating an incidental papillary fibroelastoma on the surface ofthe valve. In this example, there is little elastic tissue within the papillae. C Papillary fibroelastoma showing multiple fronds with prominent elastic tissue cores(elastic van Gieson). D Fibroelastic papilloma with young vegetations.



Definition

Haemangiomas (angiomas) are benigntumours composed predominantly ofblood vessels. The histologic classifica-tion includes those composed of multipledilated thin-walled vessels (cavernoustype), smaller vessels resembling capillar-ies (capillary type), and dysplastic mal-formed arteries and veins (arterio-venoushaemangioma, cirsoid aneurysm). Car-diac haemangiomas often have com-bined features of cavernous, capillary andarteriovenous haemangiomas, and manycontain fibrous tissue and fat. These fea-tures are reminiscent of intramuscularhaemangiomas of skeletal muscle.

ICD-O code 9120/0

Clinical features

Most cardiac haemangiomas are discov-ered incidentally but patients may pres-ent with dyspnoea on exertion, arrhyth-mias, right-sided heart failure, pericardi-tis, pericardial effusion, and failure tothrive. Patients may have associatedvascular syndomes e.g. Kasabach-Merritt {675}.

Imaging

At echocardiography, haemangiomasare usually hyperechoic, circumscribed,and intracavitary solitary masss. At MRI,hemaniogmas may be intermediate tohigh on T1 weighted images, often arevery intense on T2 weighted images, and

also enhance brightly with contrastadministration {1003}. At CT the tumorsare usually circumscribed, low attenua-tion, heterogeneous and also enhancebrightly with contrast administration.{737}. The circumscribed, non-infiltrativeappearance of haemangioma, particular-ly on MRI which is most sensitive to tis-sue infiltration, can be used to suggestthat the neoplasm is benign, but a spe-cific diagnosis cannot be made withimaging.

Localization

The most frequent locations are the later-al wall of the left ventricle (21%), theanterior wall of the right ventricle (21%),the interventricular septum (17%) andoccasionally, the right ventricular outflowtract {226}.

Macroscopy

The tumours are often large and grossappearance depends on the size of thevascular spaces in the tumour. The cap-illary type is frequently slightly raisedfrom the endocardial sruface andappears red to purple. Intramusculartypes will appear infiltrative. Cavernoushaemangiomas are usually large and arealso poorly circumscribed.

Histopathology

Capillary haemangiomas are composedof nodules of small capillary-size vessels,each of which is subserved by a “feeder”

vessel. This lobular or grouped arrange-ment of vessels is helpful for distinguish-ing these benign from malignant vascu-lar proliferations. Mast cells and factorXIII-positive interstitial cells are a consis-tent feature.Intramuscular cardiac haemangioma hassuperficial resemblance to arteriovenousmalformation, with the presence of het-erogeneous vessel types, including mus-cularized arteries, veins, and capillaries.In contrast to capillary haemangioma,they are infiltrative lesions and occurwithin the myocardium. They are histo-logically identical to intramuscular hae-mangiomas within skeletal muscle, andmay possess, in addition to the vessels,fat and fibrous tissue. Because of the lat-ter features, some intramuscular cardiachaemangiomas are misclassified as lipo-mas or fibrolipomas.Cavernous haemangiomas are com-posed of large dilated vascular spaces.They tend to infiltrate the myocardium.The lining cells are bland and flattenedand mitotically inactive.


Genetic susceptibility to cardiac hae-mangiomas has not been identified.Extracardiac haemangiomas occur in avariety of contexts. They may be singlesporadic lesions or multiple lesions thatare components of complex genetic syn-dromes. Capillary haemangiomas occurin up to 10% of live births and are themost frequent tumour in newborns{1409}. When these tumours occur in theabsence of associated syndromes, theymay represent manifestations of an auto-somal dominant mendelian trait (OMIM#602089) {7}. Linkage analyses {224,2101} of multiplex kindreds affected byhereditary capillary haemangiomas haveidentified loci on chromosome 5 (q31-q33 and q13-q22) that appear to containas yet unidentified causal diseasegenes.A wide array of complex syndromes,such as von Hippel Lindau syndrome(OMIM #193300) and SC phocomelia/Roberts syndrome (OMIM #269000), that

Haemangioma H. TazelaarA.P. BurkeG. WatanabeC.T. Basson

BAFig. 4.15 Cardiac haemangioma. A MRI of right atrial haemangioma in a newborn who underwent partialsurgical resection of the tumor. ECG-triggered breath-hold T2-weighted fast spin echo sequence shows amarkedly hyperintense signal from the tumor (arrow). B Echocardiographic imaging of cardiac haeman-gioma involving the interventricular septum in a 7-year-old boy.


267Haemangioma

can be transmitted in a mendelian fash-ion include haemangiomas as compo-nents of their clinical presentations. TheKlippel-Trenaunay-Weber syndrome, inwhich cutaneous haemangiomas occurin the setting of osseous hypertrophy,shows familial clustering, but a clearmode of inheritance has not been estab-lished. Autosomal paradominant anddominant modes of inheritance havebeen proposed {306,775}. Translo -cations {2105 2130} have been identifiedin 2 Klippel-Trenaunay-Weber patients,t(5;11) (q13.3;p15.1) and t(8;14) (q22.3;q13), but specific gene defects remain tobe identified.

Somatic genetics

Specific genes have been associatedwith two disorders involving arteriove-nous malformations. Mutations in thegene on chromosome 9p21 encoding theendothelial cell-specific receptor tyrosinekinase TIE2 cause the autosomal domi-nant Bean or “Blue rubber-bleb nevus”syndrome (OMIM #112200) and familialmultiple cutaneous and mucosal venousmalformations (OMIM#600195) {2084}. Atleast some cases of hereditary cerebralcavernous malformations (OMIM#116860) are caused by mutations in thechromosome 7q21-q22 Krev interactiontrapped-1, KRIT-1, gene {1110}. KRIT1normal binds to RAP1A, a Ras GTPase,and the disease causing mutationsappear to disrupt these interactions.Other genetic loci for this disorder havebeen identified at chromosomes 17p15-p13 and 3q25.2-q27 and remain to bestudied. The genetic and clinical relation-ship of this disorder to hereditary neuro-cutaneous angioma (OMIM #106070) isunclear.

Syndromic associations

The majority of cardiac haemangiomasare sporadic, without evidence of extrac-ardiac vascular lesions. Rarely, theremay be extracardiac haemangiomas ofthe gastrointestinal tract and port-winestain of the face. Giant cardiac haeman-giomas can result in thrombosis andcoagulopathies (Kasabach-Merritt syn-drome) {239,675}.

Fig. 4.16 Haemangioma. This lesion has some features of arteriovenous malformation, with a non-uniformcollection of thick walled arteries, dilated veins and capillaries. In addition, there is fat and fibrous tissue,as ooccasionally seen in an intramuscular haemangioma.

Fig. 4.17 Haemangioma. This tumor shows a relatively uniform population of capillary type vessels with vari-able degrees of dilatation. The myxoid background may suggest myxoma, but other features of myxoma areabsent, and the vessels are mature.


268 Tumours of the heart - Benign tumours with myofibroblastic differentiation

Cardiac fibroma

Definition

Fibroma is a rare primary heart tumourcomposed of fibroblasts or myofibrob-lasts with a matrix containing collagen. Italmost exclusively occurs within themyocardium of the ventricles or ventricu-lar septum. It is not clear whether it is ahamartoma or a true neoplasm. Becausemost cases occur in infants and childrenit is likely congenital.

ICD-O code 8810/0

Synonyms

Fibroelastic hamartoma, fibrous hamar-toma.

Epidemiology

Most cardiac fibromas are discovered inchildren and often before one year of age{737,1944}. Prenatal diagnosis withsonography is possible {121,134,538}.However, cases are also reported inadults {307} and even as an incidentalfinding in the elderly {2093}. There is nosex predominance. The incidence is verylow with only about 200 cases reportedto date.

Localization

The most common site of cardiac fibro-ma is the ventricular septum, but the freewalls of the left and right ventricle are

other common locations. Atrial fibromasare quite rare.

Clinical features

One-third of cardiac fibromas causesymptoms because of their mass effect,either through obstruction of blood flowor interference with valvular function andpatients present with cardiac failure orcyanosis. In another third of the cases,cardiac fibromas, whatever their location,cause significant arrhythmias, syncopeor sudden death. The remaining patientsare asymptomatic and tumours are dis-covered because of heart murmur or aradiographic abnormality. Embolic phe-nomena are not a feature of cardiac fibro-mas {121,134,538,737,1944}.

Imaging

At echocardiography fibromas typicallyappear as a large, well-circumscribed,solitary mass in the septum or ventricularfree wall {1010,1242} and in some casesmay be confused with hypertrophic car-diomyopathy {66}. The tumors are fre-quently very large and may causeobstruction, which can be assessed bycolour Doppler. MRI likewise shows alarge, solitary, homogeneous myocardialmass centered in the ventricles {1003,1215,1660}. Because of the fibrousnature of the tumour, the signal intensityis often less than that of adjacent unin-volved myocardium, and contrast-

enhanced imaging usually demonstratesa hypoperfused tumour core. CT alsoshows a large, solitary, ventricular mass,which is usually low attenuation on CT.Unlike other imaging modalities CT maydetect calcification which is a helpful fea-ture in making a confident diagnosis.{66}. Overall, the imaging finding of a

Benign tumours with myofibroblastic

differentiation

E. DulmetA.P. BurkeT. GevaH. KamiyaH. Tazelaar

V. T. de MontprévilleC.T. Basson

G. WatanabeP.A. Araoz

Fig. 4.19 Cardiac fibroma. A The tumour fills the leftventricular cavity, which is obliterated. The rightventricle and tricuspid valve are on the left.B Cardiac fibroma with prominent whorled sur-face.

A

B

B CAFig. 4.18 Cardiac fibroma. A Left ventricular fibroma in a 6-month-old infant. A. ECG-triggered breath-hold proton-density fast spin echo MRI with double inversionrecovery sequence in the axial plane showing a large inhomogeneous mass involving the left ventricular free wall. B MRI of left ventricular fibroma in a 6-months-old infant. Post-gadolinium imaging shows enhancement of the uninvolved myocardium and the tumour’s periphery. Note the hypoperfused tumor core.C Echocardiogram of an infant with a large right ventricular fibroma causing right ventricular outflow tract obstruction.


269Cardiac fibroma

solitary, very large, hypovascular mass in achild is suggestive of a cardiac fibroma.

Macroscopy

They are typically rounded masses thatare fibrous, white and whorled, reminis-cent of uterine leimyomas. The marginmay be either circumscribed or infiltra-tive. In some cases, fibromas are mas-sive and can obliterate ventricular cavi-ties. They are nearly always mural,although polypoid endocardial basedlesions have been reported. Most occursingly. The mean diameter is 5 cm.

Histopathology

Fibromas are composed of bland-lookingspindle cells forming loose intersecting

bundles. They are not encapsulated andextend into the surrounding myocardium.Even in grossly circumscribed cases,entrapped myocytes can often be seendeep within the tumours, far from thegross margins {244,451}. The fibromacells have oval or tapered nuclei withoutnucleoli. Their cytoplasm is pale. Thesecells are associated with abundant col-lagenous stroma, which increases withthe age of the patient. Cellular lesions areobserved in infants during their firstmonths of life, while fibromas in olderpatients contain large amounts of colla-gen. Mitoses and foci of extramedullaryhaematopoiesis may be present in cellu-lar tumours {451}. Calcification isobserved in lesions from patients of all

ages, but is somewhat more common inolder individuals. Wavy elastic fibers arefrequent and may be prominent. Focalmyxoid change in the stroma and chron-ic inflammation may also be present{244}.

Immunoprofile

Tumour cells express vimentin andsmooth muscle actin, both in cellular andfibrous lesions. They do not expressdesmin, CD34 or S-100 protein.Reacitivity for markers of proliferation,are much more frequent in cellulartumours than in the fibrous ones {451}.

Somatic genetics

A clonal translocation has beendescribed in cell cultures of a subepicar-dial fibroma resected from an infant.Cytogenetic analysis in this tumorshowed a clonal reciprocal translocation,46,XY,t(1;9)(q32;q22),inv(9)(p11q12)c{572}.


Approximately 3% of patients with Gorlinsyndrome have cardiac fibromas {418,547,716}. Gorlin syndrome (or nevoidbasal cell carcinoma syndrome) is anautosomal dominant disorder character-ized by generalized body overgrowth,jaw keratocysts, developmental abnor-malities of the skeleton, and a predispo-sition to neoplasms, specifically cardiacfibroma. Gorlin syndrome results fromgermline mutations in the PTC gene,which maps to chromosome 9q22.3 andis homologous to the Drosophila patched(ptc) gene {756}. The ptc gene encodesa transmembrane protein in Drosophilathat represses the Hedgehog signalingpathway to control cell fate, growth, anddevelopment {756,893}. These data sug-gest that the PTC gene not only functionsas a tumour suppressor gene, but alsoplays a critical role in development.However, the precise role of the PTCgene in myocardial cell growth and dif-ferentiation and its role in the develop-ment of cardiac fibroma remains to bedefined {2077}.Associated hydrocephalus, cleft lip andpalate, and Sotos syndrome (megalen-cephaly with gigantism) have beenreported {446,1242}.


The cardiac fibroma is benign, but itsnature of slow but continuous growth

Fig. 4.20 Cardiac fibroma. A Fibroma infiltration into adjacent myocardium. B Calcifications in a fibrouslesion from a 19-year-old patient.

A

B


270 Tumours of the heart - Benign tumours with myofibroblastic differentiation

may cause conduction defects andarrhythmias. Extension into the ventricu-lar free walls may result in atrioventricularvalve inflow or arterial outflow obstruc-tion. Spontaneous regression as canoccur with congenital rhabdomyoma hasnot been observed.

Treatment

Operative intervention is usually required{451,615,2071}. When the tumour provesunresectable, heart transplantation is anoption {731,2071}. However, favourablelate results even after incomplete exci-sion have been reported {132,307,1880}.

Inflammatory myofibroblastictumour

Definition

Inflammatory myofibroblastic tumour iscomposed of myofibroblasts accompa-nied by a variable number of inflammato-ry cells including lymphocytes, macro-phages, plasma cells and eosinophils.

ICD-O code 8825/1

Synonyms

Plasma cell granuloma, inflammatorypseudotumour and possibly inflammato-ry fibrosarcoma

Epidemiology

These tumours are very rare in the heart,and only small series and case reportsappear in the literature.

Localization

Although there is a predilection for theventricles, especially the right ventricularoutflow tract, any site in the heart may beinvolved {1177}.

Clinical features

Signs and symptomsThere are no specific signs or symptomsrelated to cardiac inflammatory myofi-broblastic tumour, as these are related tolocation within the heart. One cardiac

inflammatory myofibroblastic tumour hasbeen reported in a patient with systemicvasculitis and another tumour regressedspontaneously.

Macroscopy

Inflammatory myofibroblastic tumours ofthe heart are large lesions, measuring upto 8 cm {451}. Grossly, they tend to haverelatively narrow attachments to theendocardium and project into the ven-tricular lumen.

Histopathology

Inflammatory myofibroblastic tumor iscomposed of spindled myofibroblasts,fibroblasts, chronic inflammatory cellsand sometimes eosinophils. Variouscombinations of these cell types makethese tumours quite variable from onecase to another Occasional mitoses andfoci of necrosis may be present.

Immunoprofile

The tumour cells strongly express actinand vimentin, but not desmin, CD34, S-

100 protein and p53. It is unknown ifALK-1 expression is diagnostically usefulin cardiac inflammatory myofibroblastictumours as is the case with extracardiactumours.


In contrast to fibromas, inflammatorymyofibroblastic tumours are endocardiallesions, and there is often organizing fib-rin thrombus on the surface. In additionthe tumours are more histologically vari-able, the spindle cells are larger than infibromas and the cells often have nucleoli.


The biologic behavior of inflammatorymyofibroblastic tumour is that of a low-grade lesion with the propensity for recur-rence, but overt malignancy is rare. Nocase of metastases arising from cardiacinflammatory myofibroblastic tumour hasbeen reported.

Fig. 4.21 Inflammatory myofibroblastic tumour of the left ventricle. Plump spindle cells are arranged in ahaphazard fashion and focally surround myocytes. A modest chronic inflammatory cell infiltrate includingplasma cells is also present.


271Cardiac lipoma

Definition

Benign tumour composed of mature,white adipocytes.

ICD-O code 8850/0

Epidemiology

Cardiac lipoma is rare and found in fewerthan 1 in 10,000 autopsies {1116}.Lipomas generally account for only 0.5-3% of excised heart tumours {121,573,952,1257,1672}. Higher estimates of upto 10% of heart tumours are likely be -cause lipomatous hypertrophy, a sepa-rate entity, has been included{1257,1628}. Lipomas occur in children,but account for less than 2% of hearttumours similar to the relative incidencein adults {134}.

Localization

Cardiac lipomas may occur anywhere inthe heart. There is a predilection for thepericardium and epicardial surfaces{540,1125,1628,2060}, where they mayattain enormous sizes. Other sitesinclude the ventricular septum {1869},and cardiac valves. When they involve

the latter site, the designation “fibrolipo-ma” has been used {149,280,1562}.

Clinical features

As is the case with other heart tumours,the presentation is varied, and dependson location. Many cardiac lipomas areincidental findings, or cause a variety ofarrhythmias, syncope and electrocardio-graphic abnormalities {342,638,1383,1562,1735}. Rarely, outflow tract obstruc-tion may occur {1869}. Computedtomography and magnetic resonanceimaging may establish the fatty nature ofthe tumour {1383}. Recurrences are rare{2146}.

Imaging

The echocardiographic appearance ofcardiac lipomas varies with their location.Lipomas in the pericardial space havevariable echogenecity but are oftenhypoechogenic, while intracavitary lipo-mas are typically echogenic {66}. Thereason for this difference is unknown. Atechocardiography, intracavitary lipomasare usually circumscribed but cannot bedifferentiated from other circumscribedcardiac masses. However, MRI and CTboth allow for very specific identificationof fat and therefore can be used to defin-itively diagnose lipomas {66}.

Histopathology

Similar to extracardiac lipomas, cardiaclipomas are circumscribed masses ofmature adipocytes. Unusual histologicvariants of lipoma have not beendescribed in the heart, with the excep-tion of pediatric cardiac lipoblastoma in achild, which possessed immature andmature adipocytes, with focal vascularmyxoid areas containing lipoblasts {500}.


The main differential is lipomatous hyper-trophy, a non-encapsulated lesion com-posed of mature fat and adipocytesresembling brown fat cells intermixedwith enlarged cardiac myocytes occur-ring solely in the interatrial septum.Lipomatous hypertrophy is most often anincidental finding at autopsy, but mayuncommonly be the cause of unex-plained atrial arrhythmias, congestiveheart failure, or superior vena cavaobstruction {242,365}.The differential diagnosis also includesthe intramuscular variant of haeman-gioma, which may contain variable num-bers of adipocytes.

Cardiac lipoma A.P. BurkeP.A. Araoz

Fig. 4.22 Lipomatous hypertophy of atrial septum.

Fig. 4.23 Lipomatous hypertrophy. Lipomatous hypertrophy of atrial septum. Note the multivacuolatedadipocytes which can mimic liposarcoma.


272 Tumours of the heart - Cystic tumour of atrioventricular node

Definition

Congenital multicystic tumour or restlocated at the base of the atrial septum inthe region of the atrioventricular node.Lining cells may be derived from primi-tive endoderm.

ICD-O code 8454/0

Synonyms

Mesothelioma of atrioventricular node,lymphangioma, endothelioma, inclusioncyst, Tawarian node, benign mesothe-lioma of Mahaim, endodermal rest, con-genital polycystic tumour of atrioventricu-lar node, intracardiac endodermal het-erotopia.

Epidemiology

The mean age at presentation is 38 years(range birth- 78 years) and women aremore frequently affected than men(approximately 3:1). One patient withlong standing heart block survived toage 95, at which time the diagnosis wasmade at autopsy {64}.

Etiology

Because most patients have a history ofcongenital heart block, they likely arecongenital rests. In 10% of patients thetumours occur in association with othermidline defects {240,1189,1617,1719,2021}. The precise intrauterine migrationdefect is unknown. The cell of origin isforegut endoderm, not mesothelium aspreviously believed. Because diagnosis

in advanced years occurs, the congeni-tal nature is not proved in all. Evidencethat limited cell proliferation occurs insome cases may explain presentationlater in life, and patients may live fordecades with complete heart block {64}.

Localization

By definition they occur adjacent to theatrioventricular node. Similar lesionshave not been described elsewhere inthe body.

Clinical features

Two-thirds of patients present with com-plete heart block, 15% with lesserdegress of atrioventricular block, and10% with sudden death without docu-mented history of heart block {240}. Theremainder are incidental findings in new-borns and infants with structural heartdefects. Only rarely are atrioventricularnodal tumours detected in patients withnormal sinus rhythm. Most tumours havefirst been diagnosed at autopsy but invivo diagnosis has been reported {102}.

Macroscopy

They range in size from 2-20 mm and aremulticystic, the cysts often barely per-ceptible.

Histopathology

They arise in the inferior interatrial sep-tum and generally respect the bound-aries of the central fibrous body, and donot involve ventricular myocardium or the

valves. Tumour cells occur in nests orline the variably sized cystic spaces.Cells can interdigitate with myocyteswithin the inferior septum, resulting indegenerative changes within themyocytes. Cells may be cuboidal, transi-tional, squamoid or show sebaceous dif-ferentiation. Multilayering may occuralong the cyst walls {240,1157,1189}.

Immunohistochemistry

The cells strongly express cytokeratin,epithelial membrane antigen, carcinoem-bryonic antigen and B72.3. Cells mayalso express calcitonin and serotonin.{465,523,1173,1345}.

Electron microscopy

Two cells types are characteristic. Withinthe solid nests, cells have well formedbasement membrane, cytoplasmictonofilaments and desmosomes. Cellslining the spaces are also connected bydesmosomes, have short microvilli andmay contain electron dense material{240}.

Prognosis

The tumours are benign neoplasms butmay result in significant arrythmias orsudden death. Surgical excision hasbeen reported in a few patients{951,1541}.

Cystic tumour of atrioventricular node A.P. BurkeP.A. Araoz


273Cardiac sarcomas

Angiosarcoma

Definition

Angiosarcoma is a malignant tumourwhose cells display endothelial differenti-ation.

ICD-O code 9120/3

Synonyms

Haemangioendothelioma, malignanthaemangioendothelioma, haeman-giosarcoma, haemangioendothelial sar-coma, malignant haemangioma andmalignant angioendothelioma {1179}.

Epidemiology

Angiosarcomas are the most commonmalignant differentiated cardiac neo-plasms {259,691}. They occur over awide age range (36 months to 80 years){259,1693} with a peak incidence in thefourth decade. It occurs with equal fre-quency in men and women.

Localization

It most often arises in the right atriumnear the atrioventricular groove (80%),but has been reported in the other threechambers as well as in the pericardium{921,1654}. Left atrial involvement isunusual though it has been reported{203,478,799}. In one series the right atri-um was involved in 55.6% and showed

co-involvement of the right ventricle(6.5%), pericardium (6.5%), and the leftatrium (0.9%) {1653}.

Clinical features

Signs and symptomsClinical features reflect location, size andthe extent of regional involvement, andthe presence or absence of metastases{259}. Most are initially silent. Because offrequent pericardial involvement {1653},dyspnoea is not an early symptom as isthe case with other cardiac sarcomas.The most common presenting symptomis chest pain (46%) {259}. Right-sidedheart failure, often associated with hemo-pericardium and supraventricular arrhyth mias are also frequent {1128A, 1398A}. Asignificant number of patients presentwith or have co-existent haemorrhagicepisodes, coagulopathy, anae mia, per-sistent haematomas or easy bruisability{25}. Sometimes, early pericardialinvolvement may lead to pericardialbiopsy during emergency surgical car-diac decompression for tamponade.Cardiac rupture may occur, but is rare.Presentation with lung metastases is notuncommon {23,186,2216}. In 10% ofcases, fever, weight loss, and fatigueremain unexplained for several months,resulting in delayed diagnosis, largetumour size, and advanced stage whensurgery is performed.

The predominant right-sided locationallows for diagnosis by endomyocardialbiopsy, generally out of reach of othersarcoma types (which have a predilec-tion for the left atrium). Sometimes theneoplasm remains undiagnosed in lifedue to the absence of specific symp-toms.

ImagingAt echocardiography angiosarcomastypically appear as an echogenic, nodu-lar or lobulated mass in the right atrium.Pericardial effusion or direct pericardialextension/invasion are frequently seen{66}. At MRI angiosarcoma also usuallyappears as a heterogeneous, nodularmass in the right atrium. MRI imagingsequences sensitive for hemorrhage (T1weighted images) may show areas ofhemorrhage which may be diffuse ornodular {65}. After administration of intra-venous contrast (gadolinium-DTPA)enhancement along vascular lakes maybe seen which has been described as a“sunray” appearance {527}. Like echo-cardiography, MRI may also show peri-cardial effusion or direct pericardial inva-sion, though MRI is more sensitive thanechocardiography for distinguishingbetween pericardial fluid and pericardialtumour. CT findings are similar to the MRIfindings. CT usually shows a heteroge-neous, nodular mass in the right atrium

Cardiac sarcomas A.P. BurkeH. TazelaarJ.W. ButanyD. El-DemellawyR. LoireT. GevaF. BonillaJ.R. Galvin

J.P. VeinotR. VirmaniH. Kamiya

G. WatanabeD. Grandmougin

M. HorimotoH. Hiraga

B CAFig. 4.24 Cardiac angiosarcoma. A CT section at the level of the aortic valve demonstrates a soft tissue mass completely filling the right atrium. B Cardiac angiosar-coma arising in right atrioventricular groove, forming a papillary right atrial mass. Note the extensive pericardial involvement. C Metastatic angiosarcoma to thelung, forming multiple haemorrhagic subpleural nodules (courtesy of Dr. William D. Edwards).


274 Tumours of the heart - Sarcomas

with possible pericardial effusion or inva-sion. At CT angiosarcomas are usuallylow attenuation due to necrosis but mayhave focal high areas of attenuation dueto hemorrhage. CT may show a similarpattern of contrast enhancement as MRI.With MRI or CT, the presence of a hem-orrhagic, irregular right atrial mass isvery suggestive of angiosarcoma, espe-cially if accompanied by a pericardialeffusion {66}.

Macroscopy

Angiosarcomas usually form lobulatedvariegated masses in the right atrial wall,protruding into the chamber. They rangefrom 2.0 cm to several centimeters. Themasses are classically dark, grey-brownto black in colour and may resemble amelanoma {249}, but tumours with lesswell-developed vascular spaces mayappear firm, yellow-white in colour, lack-ing the classic hemorrhagic appearance.The pericardium is frequently involved

and hence a hemorrhagic pericardialeffusion is a frequent accompaniment.While involvement of the tricuspid valveand extension or invasion of the venacavae is reported, involvement of the pul-monary artery and interatrial septum areunusual. In rare instances, the pericardi-um is the sole site of involvement.

Histopathology

Over two-thirds of cardiac angiosarco-mas are well to moderately differentiatedshowing well-formed vascular channelsand papillary structures. The vascularchannels are irregular, anastomosing,and sinusoidal. The lining cells are usual-ly pleomorphic and atypical. They mayform cord-like structures in which luminaare difficult to demonstrate. Mitoses areusually present {249,259,590}. Theremaining third are poorly differentiatedand composed predominantly ofanaplastic spindle cells. In angiosarco-ma with a focal or dominant spindle cellpattern, poorly formed vascular channelsand extravascular red blood cells canusually be identified focally. Generoussampling may be necessary in order toidentify diagnostic areas in such cases{249}. Often, metastatic as opposed toprimary lesions, show areas of better dif-ferentiation. Angiosarcoma with a solidpattern of growth and individual cellshaving epithelioid features have beenreported {2059}. In these cases the neo-plastic cells have eosinophilic cytoplasmwith occasional cytoplasmic vacuoles.The nuclei in this variety are usuallylarge, hyperchromatic and have promi-nent eosinophilic nucleoli. The stromacan be abundant and hyalinized.

ImmunoprofileImmunohistochemical staining is impor-tant for the definitive diagnosis of vascu-lar lesions, especially those with poorlydifferentiated patterns in which vascularchannels are difficult to identify. Mostangiosarcomas express, to variabledegrees, usual endothelial cell antigensincluding factor VIII (von Willebrand fac-tor), CD31 and CD34. Of these, CD31gives the most consistent results, hasgood specificity and excellent sensitivity(approximately 90%) {462,2119}.Vascular channels may be highlighted bythe use of laminin and type IV collagen.Cytokeratin and epithelial membraneantigen may be focally positive in con-ventional angiosarcoma and may be dif-fusely positive in epitheloid angiosarco-mas {2247}.

Electron microscopy

With the wide availability of immunohisto-chemistry, ultrastructural study is lesscritical for diagnosis. The classic ultra-structural feature of endothelial cells, theWeibel-Palade body, is not demonstrable

Fig. 4.25 Cardiac angiosarcoma. A Cardiac angiosarcoma with papillary features. Serpiginous and gapingvascular spaces lined by plump hyperchromatic endothelial cells. B Cardiac angiosarcoma with irregularvascular spaces lined by atypical hyperchromatic, somewhat epithelioid endothelial cells.

A

B

Fig. 4.26 Epithelioid angiosarcoma. Note the promi-nent eosinophilic cytoplasm (arrows).


275Epithelioid haemangioendothelioma

in most neoplastic cells. However,pinocytotic vesicles, abundant interme-diate filaments, and a moderate amountof rough endoplasmic reticulum andGolgi apparatus may be identified.Pericytes may be demonstrated adjacentto tumour cells {1291}.


In cases with a dominant spindle cell pat-tern distinction from an unclassified spin-dle cell sarcoma, fibrosarcoma or malig-nant fibrous histiocytoma may be diffi-cult. The detection of endothelial vac-uoles or papillary structures are helpful.Immunohistochemical stains for laminin,type IV collagen and even reticulin stainsmay help highlight the vascular lumina{545}. The increasing incidence ofKaposi sarcoma makes differentiationfrom the spindle cell areas of angiosar-coma essential, though cardiac Kaposisarcoma is usually metastatic. Pericardial angiosarcomas can be mis-taken for mesotheliomas {1277} andclumps of reactive mesothelial cells maybe trapped in areas of an angiosarcoma.Stains for cytokeratin, calretinin, cytoker-atin 5/6 and CD31 can help to differenti-ate the two populations of cells.

Genetics

Genetics studies involving cardiacangiosarcomas are rare and they onlyanalyze isolated patients with heart pri-mary tumours. Cytogenetic analyses ofcardiac angiosarcoma show no consis-tent chromosomal abnormality {590}. Acase of right atrial angiosarcoma demon-strated hyperdiploid clonal populationswith changes in chromosome number, asfollows: 55, XY, +der (1;17) (q10:q10),+2,+7, +8, +19, +20, +21, +22, as wellas polysomy of chromosome 8 {2247}.Other chromosomal changes reportedare gains of 5pter-p11, 8p12-qter, 20pter-q12 and losses of 4p, 7p15-pter-yand abnormalities involving 22q{310,590}. Molecular analyses on tumourtissues have focused on genetic alter-ations of TP53 and K-ras. The few reportsavailable show that TP53 is more fre-quently altered than K-ras. Mutations ofthe TP53 tumour suppressor gene havebeen revealed by PCR-SSCP andsequencing studies and by immunohis-tochemical staining in up to 50% oftumours studied {662,1428,2247}. A K-ras mutation has also been documentedin heart angiosarcoma {662}: a G-to-A

transition at the first base of codon 13,which resulted in one amino acid substi-tution (Gly-13-Ser), in 2 relatively youngpatients (31 and 36 years old).


Cardiac angiosarcomas have an espe-cially poor prognosis because they typi-cally present in the face of advanced disease {249}. In one study, 80% ofpatients had metastatic disease at thetime of diagnosis and 90% survived lessthan nine months {921}. A mean survivalof ten months after surgical excision, withor without adjuvant therapy, has beenreported in another study {823}. In soft tissue angiosarcomas, morphologic fea-tures that have statistically correlated with poor outcome include age, large size and high proliferative (Ki-67) index{478,590}. Metastases occur most fre-quently to the lung (70%), then liver. Nosignificant correlation has been reportedbetween DNA ploidy patterns and clinicaloutcome {590}.

Treatment

There are no randomized treatment trials,but patients are generally treated by acombination of surgery and radiation with or without sarcoma-type chemothera-py. Surgical resection is necessary, butcomplete excision cannot be achieved inmost cases, because lack of a dissectionplane and myocardial encroachment oftumoural tissue. However, even partialresection (with possible valve repair) may provide some months of symptom-free survival. However, local recurrence is the rule, even when resection wasthought to be complete. Heart transplan-tation has been used to treat cardiacangiosarcoma, but without long-term sur-vival {1654, 2043}.

Epithelioid haemangioendotheliomaDefinition

Epithelioid haemangioendothelioma is avascular tumour composed of epithelioidcells arranged in short strands or solidnests. The constituent endothelial cellsare round or oval, contain small intracel-lular lumina, and frequently infiltrate mus-cular walls of vessels.

ICD-O code 9133/3

Epidemiology

Fewer than five have been reported inthe heart {26,249,1241}. Epithelioid hae-mangioendothelioma has been reportedin association with myelodysplastic syn-drome {26}.

Histopathology

The intracellular lumens of epithelioidhaemangioendothelioma may mimic thevacuoles of adenocarcinoma, which maybe initially considered in the microscopicdifferential diagnosis. Immuno-histo-chemical stains for factor VIII-relatedantigen, CD31, or CD34 identify the cellsas endothelial. The differential diagnosisalso includes epithelioid haemangioma,a tumour even rarer as a cardiac primary{453}.

Prognosis

Approximately 10% of extracardiac hae-mangioendotheliomas develop metas-tases, and up to one third recur. The bio-logic behaviour of epithelioid haeman-gioendotheliomas of the heart isunknown. They should be consideredlow-grade malignant, based on availabledata on histologically similar extracar-diac tumours, and a case report of atumour that developed distant metas-tases {1241}.

Fig. 4.27 Epithelioid haemangioendothelioma.There are cords of tumor cells arranged circumfer-entially within a vessel wall. The cells show focalvacuolization, representing intracytoplasmic vas-cular lumina.



Pleomorphic malignant fibroushistiocytoma (MFH) /Undifferentiated pleomorphicsarcoma

Definition

Malignant fibrous histiocytoma or undif-ferentiated plemorphic sarcoma is high-grade malignancy showing fibroblasticor myobroblastic differentiation andareas of marked cellular pleomorphism.Malignant fibrous histiocytomas andfibrosarcomas represent a broad spec-trum of mesenchymal tumours and thedegree of cellular pleomorphism is themajor distinguishing feature.

ICD-O code

Malignant fibroushistiocytoma 8830/3

Synonym

Malignant fibrous histiocytoma is nowregarded as synonymous with undiffer-entiated pleomorphic sarcoma, as manytumours formerly classified as MFH havebeen found to have evidence of myo-genic or other more specific differentia-tion.

Epidemiology

Malignant fibrous histiocytoma, as histor-ically defined, is the second most com-mon malignant cardiac sarcoma in adultsand, if considered with all undifferentiat-ed sarcomas represents the most com-mon sarcoma. There is no genderpredilection and the mean age is around45 years (range, 20-80 years). Rarecases have been reported in infants.

Localization

Malignant fibrous histiocytoma tends tobe located in the left atrium of the heart,most commonly the posterior wall and /or interatrial septum {1056,1142,1526}.

In a recent review, 81% of 47 cases wereleft atrial {1508}. The other reported loca-tions included the pericardial space (3cases), right ventricle/ pulmonary valve(3 cases), right atrium (1 case), and leftventricle (1 case) {1508}. Although the

majority occur in the left atrium, wherethey most often present like cardiac myx-omas, they more commonly arise alongthe posterior wall in comparison to theseptum {1056,1142,1526}.

B CAFig. 4.28 Malignant fibrous histiocytoma. A Primary malignant fibrous histiocytoma with ossesous differentiation (osteosarcoma). B Malignant fibrous histiocytomawith osseous differentiation (osteosarcoma). C Large nodules in the right atrium.

Fig. 4.29 Malignant fibrous histiocytoma (pleomorphic undifferentiated sarcoma). A In this example, thereis a myxoid background and a prominent vascular pattern reminiscent of myxoid malignant fibrous histio-cytoma found in soft tissue. B Malignant fibrous histiocytoma arising in left atrium where it initially mim-icked a cardiac myxoma. Note mitotic activity. C Note pleomorphic growth pattern. D Malignant fibroushistiocytoma with osseous differentiation (osteosarcoma). Note formation of the mature bone trabeculae. E Osteoid formation. F Cartilagenous differentiation.

FE

DC

A B


277Fibrosarcoma / myxosarcoma

Clinical features

Most occur on the left side of the heartand cause signs and symptoms relatedto pulmonary congestion, mitral stenosisand pulmonary vein obstruction.Tumours may also present with metas-tases and the lungs, lymph nodes, kid-ney and skin are common sites.Constitutional signs and symptoms mayprecede symptoms referable to theheart. Diagnosis of cardiac sarcomarests on echocardiography; MRI is help-ful preoperatively to determine precisetumour size, location, and adjacent tis-sues invasion, and post-operatively forassessment of excision and recurrence.

Macroscopy

Malignant fibrous histiocytoma typicallypresents as a soft or firm polypoid endo-cardial based tumour. It may be sessileor pedunculated, simulating myxoma,but unlike myxoma, may form multiplemasses not obviously part of the sametumour {1142}. The mass may distendthe atrium and impinge upon the mitralvalve. Extension into the pulmonary veinsand lung parenchyma may be present{1056} They may be uniform tan-white orvariegated due to haemorrhage andnecrosis. Calcification is uncommon.

Histopathology

Malignant fibrous histiocytoma or undif-ferentiated pleomorphic sarcoma is adiagnosis of exclusion, and immunohis-tochemical studies are important in rulingout metastatic myogenic, melanocyticand neurogenic tumours as well as sar-comatoid carcinomas. Of the subtypes ofmalignant fibrous histiocytomadescribed in the soft tissue, the pleomor-phic (greater than 90%) and giant cellsubtypes have been recognized in theheart. The tumours are heterogeneous inappearance and are variably cellular.The constituent cells may be spindled orepithelioid and sometimes have abun-dant eosinophilic cytoplasm. Intermixedgiant cells are common. A storiformarrangement of tumour cells is commonand they usually have marked pleomor-phism. Mitotic activity is easy to find.

OsteosarcomaUndifferentiated pleomorphic sarcomasdemonstrate areas of osseous differenti-ation in 15% of cases. There is debate asto whether these tumours should be clas-sified as extra skeletal osteosarcomas or

undifferentiated pleomorphic sarcomaswith osteosarcomatous differentiation.Virtually all osteosarcomas of the heartreported thus far have occurred in the leftatrium. Like skeletal osteosarcoma,areas of malignant giant cell tumour(giant cell malignant fibrous histiocy-toma), chondroid differentiation, andosseous differentiation have been foundto coexist in variable amounts in a singlelesion.

GeneticsGenetic studies of cardiac sarcomas arelimited. In studies of extra cardiac malig-nant fibrous histiocytoma, the commonsignature of genetic alterations includesrecurring low-level copy number increas-es at new sites on chromosome 7, andlosses of chromosome 2 sequences{1546}. Genomic imbalance at chromo-some 13 has also been observed, withhigh gains for Xp and bands 1q21-22,1p31, 3q27 and 9q3. The losses at chro-mosome 13 were observed in a largeproportion at regions 13q12-14 and13q21-22 {1131,1224}. Specific losses inregions that harbour tumour suppressorgenes like INK4a (9p21) and RB1(13q14) have been revealed by Southernblot and comparative genomic hybridiza-tion {1828}. RB1 gene is probably impli-cated in tumourigenesis of malignantfibrous histiocytoma due to the high cor-relation between absence of RB1 proteinexpression and chromosome 13 lossesand mutations found in this gene {353}.Mutations localized to the core domain ofTP53 have been found by immunohisto-chemical and sequencing procedures{1982}, as have other abnormalities likeprotein accumulation {1647}. TP53 muta-tions and accumulation of p53 proteinhave been detected in tumours withMDM2 gene amplification {1647}.

Treatment

Complete resection of malignant primarycardiac tumours can rarely be achieved,but palliative surgery is usually undertak-en because many patients present withmechanical obstruction {731}. Adjunctivechemotherapy, radiation therapy or bothare sometimes used {731}, however, theoptimal protocol and efficacy are unclear{731,1508,1962,2043}. Patients withunresectable primary malignant cardiactumours who are free of metastases maybe considered for heart transplantation{731,1962,2043}.


For malignant fibrous histiocytoma andfibrosarcoma there is some evidence thatgrading is useful in predicting survival,but the majority of patients with thesetumours die of either local or metastaticdisease {731,952,1508}. The mean post-operative survival is 5-18 months. Thecause of death may be related tometastatic disease, bulky intracardiacrecurrences, or general debilitation.

Fibrosarcoma and myxosarcoma

Definition

Fibrosarcoma is a malignant tumourcomposed of fibroblasts with variableamounts of intercellular collagen and aclassic herringbone architecture. Somefibrosarcomas with abundant myxoidstroma have been called myxosarcomasbut are not considered malignant vari-ants of cardiac myxoma. Tumours withmarked pleomorphism, or a prominentvascular or storiform pattern are betterclassified as malignant fibrous histiocy-toma.

ICD-O code

Fibrosarcoma 8810/3

Fig. 4.30 A Myxosarcoma from the left atrium. Cutsurface showing variable solid, soft and haemor-rhagic regions. B Fibromyxosarcoma. A portion ofthe tumor near the endocardial surface shows anundifferentiated spindle cell sarcoma withoutprominent vascularity or pleomorphism and anabundant proteoglycan matrix.

A

B



Epidemiology

Fibrosarcoma represents 5-10% of allcardiac sarcomas depending on the cri-teria used for diagnosis. Fibrosarcomasare less frequent, and occur over abroader age range than malignantfibrous histiocytoma, some having beenreported in children.

Localization

Fibrosarcomas are most common in theleft atrium, but have been reported toarise in all chambers. Fibrosarcomasmay also infiltrate the pericardial space,thus mimicking mesothelioma {1034}.

Clinical features

The clinical features of fibrosarcomashave not been well-delineated from relat-ed cardiac sarcomas such as malignantfibrous histiocytoma (undifferentiatedpleomorphic sarcoma) as the classifica-tion of these lesions has not been stan-dardized in large series. As with othersarcomas, signs and symptoms varydepending on the location of the tumour.Because most occur on the left side ofthe heart, signs and symptoms related topulmonary congestion, mitral stenosisand pulmonary vein obstruction are mostfrequent. Rarely, cardiac fibrosarcomamay present with metastases in thelungs, lymph nodes, skin, and kidney.

Macroscopy

Fibrosarcoma typically presents as a softpolypoid tumour projecting into thechamber from whose walls they arise.They have a gross appearance similar toMFH {329}, but haemorrhage, necrosis,and variegation are less common.

Histopathology

Fibrosarcoma of adult type is composedof spindle shaped cells arranged insweeping fascicles that are oftenarranged at angles to one another result-ing in a “herringbone” pattern. The nucleiare usually elongate with tapered endsand darkly staining. Mitotic activity isvariable. In the myxoid variant tumourcells spindling is less pronounced andcells may take on a stellate or ovoid con-figuration. However in all types pleomor-phism is minimal and prominent vascu-larity is absent.


The differential diagnosis for the typicalvariant of fibrosarcoma includes mono -

phasic synovial sarcoma, inflammatorymyofibroblastic tumours and localizedfibrous tumours, and for the myxoid vari-ant, other myxoid sarcomas (MFH,leiomyosarcoma, etc.) and cardiac myx-oma. The latter is generally distinguishedby the presence of myxoma cells, abun-dant organizing hemorrhage, andabsence of mitotic figures and high cel-lularity. Fibromas are easily distinguishedfrom typical fibrosarcoma by lack of cel-lularity and abundant collagen.


See discussion on treatment of maligantfibrous histiocytoma. There is no provendifference in prognosis between cardiacfibrosarcoma and malignant fibrous histi-ocytoma as demonstrated in a meta-analysis using actuarial methods {249}.

Rhabdomyosarcoma

Definition

Rhabdomyosarcoma is a malignanttumour with striated muscle differentiation.

ICD-O code 8900/3

Epidemiology

Rhabdomyosarcoma is a very rare sub-type of cardiac sarcoma. In the past,before immunohistochemical documen-tation of tumour histogenesis was routine,it was stated that a large proportion ofcardiac sarcomas were rhabdomyosar-comas. However, in more recent series,the proportion is less than 5% {250}, andin one recent series of cardiac sarcomaswith rigorous immunohistochemical doc-umentation, none of 24 was classified asrhabdomyosarcoma {509}.

Localization

Rhabdomyosarcomas occur anywhere inthe heart. Approximately 50% occur inthe atria, and 50% in the ventricles. Thefrequency of ventricular involvement isgreater than other cardiac sarcomas.Contrary to sarcomas with fibro- or myofi-broblastic differentiation, they are notusually intracavitary tumours, but aremore often mural.

Clinical features

Cardiac rhabdomyosarcomas are usual-ly of the embryonal variant and, there-

Fig. 4.31 Embryonal rhabdomyosarcoma predenting as small cell undifferentiated tumor with cellular areasconcentrated towards the surface.

Fig. 4.32 Embryonal rhabdomyosarcoma with rhab-domyoblasts containing abundant eosinophiliccytoplasm.


279Rhabdomyosarcoma

fore, occur most frequently in childrenand young adults; it is the most commonprimary cardiac malignancy in children.The mean age at presentation is approx-imately 20 years, compared to 40-50years of age for other subtypes of car-diac sarcoma. Rhabdomyosarcoma ismore likely than other primary cardiacsarcomas to involve the valves. The clin-ical presentation, as with other cardiactumours, depends on the cardiac loca-tion.

Macroscopy

Cardiac rhabdomyosarcomas are bulky,invasive tumours that may be grosslymucoid or gelatinous, similar to cardiacmyxoma, or soft and necrotic, with varie-gation and heterogeneity. They usuallyarise within the myocardium and are lesslikely than sarcomas with myofibroblasticor fibroblastic differentiation to be endo-cardial based, luminal tumours.

Tumour spread and staging

Sites of metastatic spread are, in order ofdescending frequency: lungs, regionallymph nodes, central nervous system,gastrointestinal tract, kidney, adrenals,thyroid, ovary, bone and pancreas.

Histopathology

Cardiac rhabdomyosarcomas are almostexclusively embryonal. Embryonal rhab-domyosarcoma is small cell neoplasmwith variable numbers of PAS-positiverhabdomyoblasts (tadpole or strapcells). Well-differentiated embryonalrhabdomyosarcoma has numerous tad-pole-shaped rhabdomyoblasts. Nuclearstaining with antibodies against myo-

genin greatly facilitates the diagnosis{1630}. Desmin is also useful in docu-menting muscular differentiation.Alveolar rhabdomyosarcoma, character-ized by a collagenous stroma and apaucity of rhabdomyoblasts, has beendescribed in the heart generally as ametastatic lesion.Sarcoma botryoides,with characteristic grape-like structuresand a so-called cambium layer, a form ofembryonal rhabdomyosarcoma, has alsobeen described in the heart {760}.


The differential diagnosis includes othercardiac sarcomas, especially undifferen-tiated lesions and metastatic small roundcell tumours in children and youngadults. Immunohistochemical stains arevital in identifying rhabdomyoblasts.Adult cellular rhabdomyomas, in contrastto rhabdomyosarcoma, lack significantmitotic activity, necrosis, and do notexpress myogenin.

Electron microscopy

The diagnostic features are thick and thinfilaments reminiscent of normal striatedmuscle. Internal A and I banding may ormay not be present, but Z-bands are fre-quently well formed. Plentiful glycogengranules and abundant mitochondria arealso present. Tumour nuclei are lobulat-ed, containing variable amounts of con-densed chromatin. Occasionally, severalgrids must be examined before rhab-domyoblasts are identified.

Somatic genetics

At exon 1 of K-ras, a mutation at the firstbase of codon 13 (G to A transition) has

been detected in cardiac rhabdomyosar-coma {662}.

Treatment

SurgerySurgical resection of the tumour is usual-ly indicated even if it is considered aspalliative to relieve obstruction to cardiacblood flow and to clarify the diagnosis{301,470,952}. Total orthotopic hearttransplantation may offer relatively long-term survival {67,701,733} if there are nodistant metastases.

ChemotherapyAlthough the outcome of chemotherapyon cardiac rhabdomyosarcoma has notbeen fully studied, due to the rarity of thetumour, there have been advances in thetreatment of soft tissue rhabdomyosarco-ma {423,529, 1194,1749} with a three-year progression-free survival of approx-imately 65%. Neoadjuvant chemotherapymay optimize a surgical approach{1749}.

RadiotherapyAdjuvant radiotherapy is commonlymandatory to preclude local relapse or tooptimize the results of a surgicalapproach. However radiotherapy may beused preoperatively to decrease tumorsize and allow surgical resection.


Specific prognostic microscopic featureshave not been devised for cardiac rhab-domyosarcomas. However, grading issimilar for other subtypes of cardiac sar-comas, and includes an assessment ofmitotic activity and necrosis {509}. The

Fig. 4.33 Leiomyosarcoma. A The tumour is cellular, composed of fascicles of relatively uniform cells. B Note tumour cellularity and focal necrosis.

BA



prognosis is poor, with recurrence andeventual metastasis with death of thepatient within months the rule {1944}. Themean survival rarely exceeds 12 months.

Leiomyosarcoma

Definition

A malignant tumour composed of cellswith distinct smooth muscle features.

ICD-O code 8890/3

Epidemiology

Cardiac leiomyosarcoma is uncommon,representing less 10% of cardiac sarco-mas. There is no sex predilection, andmost occur in patients between 40 and50 years of age.

Clinical features

Dyspnoea is the main clinical feature.Sometimes patients present with chestpain, cough, atrial arrythmias, or haemo-ptysis.

Macroscopy

Most of them are located in the left atrium(posterior wall) and invade pulmonaryveins or mitral valve. But, tumours canarise elsewhere, including the right atri-um and ventricle, or pulmonary valve ortrunk. The tumours tend to be firm, fleshy,grey and sessile. They may present asmultiple intra-cavitary nodules.

Histopathology

Leiomyosarcoma is composed of com-pact bundles of spindle cells that pos-sess blunt-ended nuclei and are often

oriented at sharp angle or 90° to oneanother. Inconstant characteristic fea-tures include the presence of cytoplas-mic glycogen and perinuclear vacuoles.Pleomorphic and giant cells may bepresent. Zones of necrosis and mitoticfigures are generally plentiful. Usualimmunohistochemical markers of neo-plastic cells are smooth muscle alphaactin and desmin. Alpha actin alsoshows numerous normal little vessels inthe tumour tissue. There may occasional-ly be aberrant expression of cytokeratinand epithelial membrane antigen.Demonstration of smooth muscle cellderivation virtually confirms malignancy,as leiomyomas remain undescribed inthis location.

Treatment and prognosis

Treatment consists of surgical excision,almost always incomplete. This mayallow some patients several months ofsymptom free survival, typically less thanone year. Chemotherapy and radiationtherapy may provide palliation.

Synovial sarcoma

Definition

Synovial sarcoma is a biphasic tumourcomposed of spindled and epithelioidareas, characterized by X;18 chromoso-mal translocations.

ICD-O code 9040/3

Epidemiology

Synovial sarcomas account for approxi-mately 5% of cardiac sarcomas {173,

300,400,1466}. The true incidence hasprobably been underestimated, asmolecular studies can now confirm thediagnosis in the monophasic variant,which is the most common form in theheart. An association between cardiacsynovial sarcoma and asbestos expo-sure has been reported {1144}.

Localization

There is a predilection for the atria andpericardial surfaces.

Clinical features

Clinical symptoms may arise fromobstruction, embolism, and tamponade.

Macroscopy

Synovial sarcomas are bulky, infiltrativetumours that are typically firm and white.Necrosis or hemorrhage may be present.

Histopathology

The classic lesion is biphasic, but themonomorphic variant is especially com-mon in the heart. The spindle componentresembles a fibrosarcoma, but alternatingcellular and oedematous areas are typi-cal. The spindle cells are small, compact,and often infiltrated by sparse mononu-clear lymphoid cells. The epithelioid cellsform clusters and nests, and occasional-ly larger gland–like spaces which mayshow branching. Immunohistochemically,cytokeratin and epithelial membrane anti-gen are strongly expressed in the epithe-lioid cells. Staining for these markers inthe spindle cells may be very focal.Spindle cells express vimentin and occa-sionally smooth muscle actin. The cellsdo not express CD34.

Fig. 4.34 Synovial sarcoma. A The tumour is highly cellular and composed predominantly of spindled cells. The epithelial areas may be difficult to discern on rou-tine stains. B Immunohistochemical stain demonstrating expression of pancytokeratin in islands of epithelial cells.

BA


281Synovial sarcoma


Distinction of synovial sarcoma frommesothelioma, another biphasic tumour,can usually be made on the basis oftumour location (mesotheliomas do notoccur within the atria) and growth pattern(synovial sarcoma is usually a circum-scribed solitary lesion while mesothe-lioma tends to grow diffusely over thepericardium. Additionally, the spindle cellareas of synovial sarcoma tend to be rel-atively monomophic. The X;18 transloca-tion may be confirmed on formalin fixed,paraffin embedded tissues and has ahigh degree of sensitivity and specificity{1506}. Reactivity for calretinin has beendescribed in both mesothelioma and syn-ovial sarcoma, and is not helpful in the

differential diagnosis. Unlike mesothe-lioma, solitary fibrous tumour is generallylower-grade, usually expresses CD34antigen, is less cellular and tends to havealternating hyper- and hypocellular areas.

Somatic genetics

Cytogenetically the reciprocal transloca-tion t(X;18)(p11.2;q11.2) is seen in morethan 90% of soft tissue synovial sarco-mas {1330}. This is considered to be theprimary cytogenetic abnormality andspecific for synovial sarcomas.The breakpoints of the t(X;18) have beencloned, and it has been shown that thistranslocation results in fusion of SS18gene (previously described as SYT orSSXT) at the chromosome 18q11.2 to

either of two genes, SSX1 or SSX2, atXp11.2. This rearrangement of genesproduces a chimeric SS18 /SSX tran-script, which could be implicated intumourigenesis {375}. The SS18/SSXtranscripts can be specific markers ofsynovial sarcoma that can be detectedby the reverse transcriptase-polymerasechain reaction (RT-PCR). The transcriptscan be identified in almost all synovialsarcomas when there is adequatetumour RNA {837}. This molecular diag-nostic method also can be applied toparaffin-embedded tissue {747}.

B CAFig. 4.35 Synovial sarcoma. A An example of detection of fusion SS18/SSX transcripts by RT-PCR. M; 1kb ladder, lane 1; a biphasic synovial sarcoma of soft tissue,lane 2; a synovial sarcoma of peritoneum, lane 3; a malignant mesothelioma, lane 4; an adenocarcinoma of the lung. B Schematic diagram of domain structure ofthe SS18, SSX, and SS18/SSX proteins. SNH (SS18 amino terminal domain) might act as a inhibitor of the QPGY domain, which is a C-Terminal domain rich in glut-amine, proline, glycine and tyrosine and might function as a transcription activation domain. KRAB (kruppel-associated box) is a transcription repression domain.However, the KRAB-like domain of SSX appears to be an inefficient or even inactive repressor domain. SSX-RD is a novel repressor domain, which is highly con-served in the SSX family. C Schematic representation of the translocation t(X;18)(p11.2;q11.2).


282 Tumours of the heart - Lymphomas

Definition

Primary cardiac lymphoma (PCL) is anextra-nodal lymphoma involving only theheart and/or the pericardium. A lessrestrictive definition includes small sec-ondary lesions elsewhere, with the vastbulk of the tumour arising in the heart. Itis clinically defined as a lymphoma pre-senting as cardiac disease with the bulkof the tumour being intra-pericardial.Cardiac involvement by disseminatednon-Hodgkin lymphoma should beexcluded.

Epidemiology

PCL is an uncommon malignancy,accounting for 1.3% of primary cardiactumours and 0.5% of extranodal lym-phomas {249,273,1679}. The publishedseries account for about 80 cases, whilecardiac involvement in disseminatedlymphoma has been documented innearly 20% of autopsy cases {1280}. Theappearance of PCL in patients with AIDS{1736} and in a kidney recipient {1667}suggests that immunodeficiency may be

a predisposing factor. However, the heartis an uncommon site for immunodeficien-cy-related lymphoma. Most PCL arise inimmunocompetent patients. The medianage of the reported cases is 62 years(range, 5-90 years) with a male-to-femaleratio of 3:1. The clinical course is generally short,with a mean survival of 7 months (range,0-48 months).

Clinical features

Signs and symptomsThe clinical course is generally acute inonset. There is no pathognomonic clini-cal presentation and patients are gener-ally investigated because of chest pain,pericardial effusion, refractory heart fail-ure, arrhythmia, or lightheadness andsyncope due to a myxoma-like intracav-itary mass {308}. Superior vena cavaobstruction {363}, multiple pulmonaryemboli and infarction {1832} and hyper-trophic cardiomyopathy {266} have alsobeen reported as initial diagnosis inpatients with PCL. Complete atrio-ven-tricular block may be the major clinicalpresentation {1416}.

ImagingBecause the gross pathologic features ofprimary cardiac lymphoma are variable,the imaging findings are variable.Cardiac lymphomas most commonlymanifest as circumscribed, nodularmasses in the myocardium, often with anassociated pericardial effusion. Thesefindings are usually well seen at echocar-diography, MRI, and CT. Lymphoma mayalso manifest as an ill-defined, infiltrativemass, in which case, they are typicallybest depicted with MRI because of itssuperior soft tissue contrast {66}. Internalimaging features and contrast enhance-ment patterns are very variable with car-diac lymphomas. Lymphomas may havehigh or low signal on MRI, may have sim-ilar attenuation as muscle or lower atten-uation than muscle on CT, and may showincreased, or decreased contrastenhancement. In some cases, pericar-dial effusion or pericardial thickening

may be the only findings. In additon toechocardiography, MRI, and CT, nuclearmedicine techniques may be useful pro-cedures for the non-invasive assessmentof cardiac lymphomas. Gallium-67uptake is non-specific, though a markedaccumulation in the heart without extrac-ardiac uptake can suggest the diagnosisof PCL {1680}.

Diagnostic approachWhen pericardial effusion is present itsdrainage may have both palliative anddiagnostic purposes. Lymphoma cellsmay be detected in serous fluid in up to88% of cases {308}.When cytology is not available, the diag-nosis of PCL is usually assessed byexplorative thoracotomy with cardiacmass biopsy. Recently, less invasive pro-cedures have been performed, such astransoesophageal echocardiography(TEE) guided percutaneous intracardiacbiopsy {46,947}.

Macroscopy

PCL may arise in either atrium or ventri-cle. Usually the tumour is large, infiltrat-ing myocardium and extending into theright atrium and ventricle in the form ofmultiple intracavitary polypoid nodules,which may eventually obliterate the cavi-ties. The right atrium is involved in morethan 2/3 of patients. The pericardium isusually thickened by white-greyishtumour infiltration. Pericardial effusion,which is generally massive, may be iso-lated (12.5% of cases) or associated witha heart mass (near half of cases) {737}.

Cytology

A diagnostic cytologic sample sample isobtained in less than 20% of primary car-diac lymphomas (PCL) {1680}. It may bedifficult to differentiate PCL from benignreactive lymphocytosis by cytologyalone. Immunocytochemical staining{1724}, cytogenetic studies {1} and poly-merase chain reaction {964} have beenperformed successfully to confirm thelymphoid lineage and detect the pres-ence of a monoclonal population.

Cardiac lymphomas G. RollaF. Calligaris-CappioA.P. Burke

Fig. 4.36 Cardiac lymphoma. Mulitofocal massesinvolving both atria and ventricular walls.


283Cardiac lymphomas

Histopathology

Diffuse large B-cell lymphoma is the sub-type most frequently observed (80% ofpublished cases). Non-cleaved smallcell lymphoma has been reported in afew cases; the histopathology wasunspecified in the other cases. Recentlytwo cases of diffuse large B-cell lym-phoma with CD5 expression have beenreported {317}. This is a recently identi-fied subgroup of diffuse large B-cell lym-phomas, which differs for clinical charac-teristics (elderly, female and extranodalinvolvement) and aggressive clinicalcourse {2181}. One case of Burkitt lym-phoma in an immunocompetent patienthas been described {317}.

Somatic genetics

A complex abnormal karyotype contain-ing t(8;14) (q24;q32) has been reportedin a case of diffuse large B-cell lym-phoma mainly involving the heart withcells which were CD5+ and CD20+ witha c-myc rearrangement {1948}. In situhybridization for EBER-1 was negative.


Late diagnosis appears to be a majorfactor in the poor outcome in PCLpatients. Irrespective of the treatmentapplied, 60% of the patients died of theirtumour 1.8 months after diagnosis {317}.Prompt anthracycline-based chemother-apy results in near 60% of complete

response (mean follow-up 17 months;range 3-40 months). PCL should betreated like other aggressive lymphomasarising in other primary sites.

B CAFig. 4.37 Cardiac lymphomas. A Mass limited to the myocardium in a 40-year old man. Tumour cells are moderately sized with high mitotic rate; immunophenotypewas consistent with diffuse large B-cell lymphoma. B In this example of a localized left ventricular tumour, the lymphoma cells are large and irregular.Immunophenotypically, the tumour typed as a diffuse large B-cell lymphoma. C Occasionally, cardiac lymphomas are of the high-grade small cell type (lym-phoblastic lymphoma). In this lesion, the immunophenotype confirmed B-cell Burkitt subtype.


284 Tumours of the heart - Secondary tumours

Definition

Malignant cardiac neoplasm with a non-pericardial or myocardial primary site.Metastatic tumors that infiltrate myocardi-um are frequently accompanied by peri-cardial metastases, especially in thecases of carcinomas, which additionallyinvolve mediastinal lymph nodes.

Epidemiology

In a series of 133 surgically resected car-diac tumors, 14% were metastatic{1411}. In a recent review, cardiacmetastases were present in 12% ofautopsies performed for widespreadmalignancy {12}. Primary tumors indecreasing order of frequency includecarcinomas of the lung, lymphomas, car-cinomas of the breast, leukemia, carcino-mas of the stomach, malignantmelanoma, hepatocellular carcinomaand carcinomas of the colon. The follow-ing tumors have an especially high rateof cardiac metastasis if the incidence ofthe primary tumor is considered:leukemia, melanoma, thyroid carcinoma,extracardiac sarcomas, lymphomas,renal cell carcinomas, carcinomas of thelung and carcinomas of the breast.These tumors all had a greater than 15%rate of cardiac metastasis in a largeautopsy study {1398}.The rate of cardiac involvement bymetastatic disease has not appeared tochange over a 14-year period, indicatingthat current treatment modalities may nothave a significant effect on the rate ofmetastatic malignancy to the heart.

Clinical features

The cardiac location of the tumor greatlyaffects the signs and symptoms. Thesecan include symptoms related pericar-dial effusions, arrhythmias, or congestiveheart failure. Obstruction of the mitral oraortic valve may cause syncope. Involve -ment of the right heart and tricuspidvalves may give rise to right-sided failure.

Localization

Malignancies spread to the heart bydirect extension, usually from mediastinal

tumor; haematogenously; via lymphatics;and rarely by intracavitary extension fromthe inferior vena cava or pulmonaryveins. Lymphatic spread is generallyaccompanied by involvement andenlargement of pulmonary hilar or medi-astinal lymph nodes. Haematogenousspread is characterized by myocardialinvolvement.Epithelial malignancies typically spreadto the heart by lymphatics. Melanoma,sarcomas, leukemia and renal cell carci-noma metastasize to the heart by ahaematogenous route. Melanomas, renaltumours, including Wilms’ tumour andrenal cell carcinoma, adrenal tumours,liver tumours, and uterine tumours arethe most frequent intracavitary tumours.Metastatic cardiac tumours affect theright side of the heart in 20-30% ofcases, the left side in 10-33% of cases,and show bilateral or diffuse involvementin approximately 30-35% of cases. Theendocardium or chamber cavities areinvolved in 5% of cases {1398}. The mostcommon epithelial malignancies tometastasize to the heart are carcinomasof the breast and lung. In most casesthere is pericardial involvement withsuperficial myocardial infiltration. Thevalves and endocardium are usuallyspared. Generally, the heart is not theonly organ involved, and metastaticdeposits are usually present in extracar-diac sites.The myocardium is involved in virtually100% of cases of metastatic melanoma,

and there is less frequent infiltration ofepi- and endocardium.Leukemic and lymphomatous infiltratesare typically widespread, involving theepicardium (61%), and myocardium dif-fusely. The left ventricle is involved in55%, and right atrium in 54% of cases.Sarcomatous deposits are found withinthe myocardium (50%), pericardium(33%), or both myocardium and peri-cardium (17% of cases). Valvular metas-tases are uncommon {764}.Osteosarcoma, liposarcoma, leiomyosar-coma, unclassifiable sarcomas, rhab-domyosarcoma, neurofibrosarcoma, syn-ovial sarcoma, and maligant fibrous histi-ocytoma have been reported to involvethe heart secondarily.

Pathologic findings

Metastatic deposits may be diffuse,multinodular, or consist of a single domi-nant mass. Especially with carcinomas,there may be diffuse studding and thick-ening of the pericardial surfaces. Thispattern can grossly be confused withmesothelioma, or benign fibrosing peri-carditis. The tumour burden in the heartis the highest with melanoma, as com-pared to any other malignancy.Carcinomatous spread in the myocardi-um is frequently most prominent insubepicardial lymphatics, whereasmelanomas, sarcomas, renal cell carci-nomas and lymphoid neoplasms formintramyocardial interstitial tumours. Thehistopathologic distinction between pri-mary and metastatic sarcoma may beimpossible upon surgical resection of acardiac tumour. Most sarcomas metasta-tic to the heart cause symptoms at theirprimary site before cardiac symptomsare evident, however {764}. Although pri-mary sarcomas of the heart are uncom-mon, extracardiac sarcomas presentingas cardiac metastases are even rarer.

Metastatic tumours to the heart G. RollaF. Calligaris-Cappio

Fig. 4.38 Metastases of a large cell carcinoma ofthe lung in the heart.


285Solitary fibrous tumour

Solitary fibrous tumour

Definition

An uncommon, spindle-cell, fibroblastictumour which often shows a prominenthaemangiopericytoma-like vascular pat-tern.

ICD-O code

Solitary fibrous tumour 8815/1

Synonyms

Benign mesothelioma, fibrous mesothe-lioma, submesothelial fibroma

Localization

The most common locations, outside thepleura, include the head and neck, espe-cially orbit, soft tissue, especiallyabdomen, extremities, and meninges{233,1384,1473}. As with any lesion com-mon to the pleura, there have beenexamples of solitary fibrous tumourreported in the pericardium and rarelywithin the heart.

Clinical features

Clinical features are related to pericardialmass effect.

Macroscopy

Solitary fibrous tumours tend to be well-circumscribed, firm, fleshy or white

although diffuse mesothelial surfaceinvolvement has been described.

Histopathology

Histologic variability is the rule and multi-ple growth patterns have been described.Most tumours will have a predominantmonomorphic spindle cell pattern resem-bling low-grade fibrosarcoma althoughbroad tumour cell fascicles are rare.Areas of hypercellularity typically alternatewith those that are less cellular. The lesscellular areas can by myxoid or containabundant collagen {459}. Typically thenuclei of tumour cells are closely apposedto collagen bundles. A haemangiopericy-toma-like vascular pattern may be con-spicuous, present in a small portion of thelesion, or absent. The differential diagno-sis includes other monomorphic spindlecell tumours, including neurogenictumours, spindle cell mesotheliomas,monophasic synovial sarcoma, andfibrosarcoma {1311}. Recently, desmoidtumour of the pleura has been added inthe list of differential diagnostic consider-ations {2151}. See pleural section foradditional information.

ImmunoprofileSolitary fibrous tumours are CD34 andbcl-2 positive. They are consistently neg-ative for epithelial markers, muscle spe-

cific actin, desmin, CD31, CD117 (c-kit),S-100 protein calretinin, and inhibin{596,772,1473,2127}.

Differential diagnosisSarcomatous mesotheliomas of the peri-cardium are distinguished from solitaryfibrous tumours by their diffuse growthpattern, and keratin and calretinin reac-tivity. On the other hand, solitary fibroustumour may closely mimic monophasicsynovial sarcoma and low- gradefibrosarcoma. Fibrosarcoma tends to bemore architecturally monomorphic andnegative for CD34. Monophasic synovialsarcoma has higher grade cytology,plumper nuclei and shows focal keratinreactivity. Endometrial stromal sarcoma,and metastatic granulosa cell tumourmay be excluded by negative reactivityfor cytokeratin, estrogen and proges-terone receptors, and inhibin.

Pericardial tumours A. BurkeR. LoireR. Virmani

Fig. 4.39 Mesothelioma of pericardium. A Note theextensive tumour encasing the pericardium. B Inmany cases, the pericardial mass is in continuitywith pleural mesothelioma.

A

B

Fig. 4.40 Localized fibrous tumor of the mesothelium is identical in appearance to those of the pleura. Notethe spindle cell growth with prominent vascularity and variable cellularity.


286 Pericardial tumours


The prognosis is generally good,although recurrences and local spreadhave been reported. Criteria for malig-nancy of pleural tumours include necro-sis and a mitotic count of greater than 4per 10 high powered fields, but the appli-cability of these criteria to tumours in theheart and pericardium is unknown.

Malignant mesothelioma

Definition

Malignant mesothelioma arises frommesothelial cells or demonstratesmesothelial differentiation. The definitionof primary pericardial mesothelioma stip-ulates that there is no tumour presentoutside the pericardium, with the excep-tion of lymph node metastases.

ICD-O code 9050/3

Epidemiology

Mesothelioma of the pericardium repre-sents approximately 0.7% of malignantmesotheliomas {831}. As with mesothe-liomas in other sites, the incidence maybe increasing, due to the latencybetween asbestos exposure and tumourdevelopment {1074}.

Etiology

Like pleural mesotheliomas, a large pro-portion of mesotheliomas of the peri-cardium are induced by asbestos {1074}.Iatrogenically induced pericardialmesotheliomas have been reporteddecades after exposure to pericardialdusting with asbestos and fibreglass asa treatment for angina pectoris.Therapeutic radiation for breast cancerand mediastinal lymphoma has alsobeen implicated in rare patients.However, there remains a subset of

patients with mesothelioma who have noknown exposure history.

Clinical features

Signs and symptomsThe mean age of patients with pericardialmesothelioma is about 45 years, with awide age range, including elderly, olderchildren and young adults. The initialcourse is usually related to pericardialeffusions. Tamponade may eventuallyoccur {1202}.

ImagingEchocardiography usually shows peri-cardial effusions and may show pericar-dial thickening. However, because peri-cardium is at the periphery of the field ofview obtainable with echocardiography,MRI or CT are usually necessary. MRIand CT usually demonstrate pericardialfluid as well as pericardial thickeningand/or pericardial masses {737}.

Macroscopy

Malignant mesotheliomas of the peri-cardium can form bulky nodules that fillthe pericardial cavity. The tumour canalso spread diffusely over the pericardialsurface and completely encase theheart. They can further encircle the greatvessels and may obstruct the venaecavae.

Histopathology

Malignant mesotheliomas of the peri-cardium resemble pleural mesothe-liomas. Although the majority are of theepithelioid type, forming tubules, papil-lary structures, and cords of infiltratingcells that can incite a desmoplasticresponse, the sarcomatous variant isalso common. Variants similar to thosedescribed in the pleura may also be seenin the pericardium e.g. microcystic, ade-nomatoid, deciduoid {1649,1802}.

ImmunoprofileThe immunohistochemical profile of peri-cardial mesothelioma is similar to that ofpleural mesothelioma. Expression ofmesothelial antigens, such as calretinin,and cytokeratins 5/6 are helpful in thediagnosis, as are negative reactions foradenocarcinoma markers, such as carci-noembryonic antigen.

Electron microscopy

Ultrastructurally, mesothelioma cells fromepithelioid areas contain branched,bushy microvilli. Cytoplasmic tonofibrilsare present in approximately 50% oftumours. Asbestos bodies may be identi-fied within pericardial mesothelioma, butare of no diagnostic utility.


The distinction between mesotheliomaand pleural-based lung adenocarcinomacan be quite difficult, and is generallybased on immunohistochemical findings.Distinction from reactive mesothelial cellproliferations may also be difficult; incomparison to reactive pleural mesothe-lial proliferations, reactive pericardialmesothelial cells may be more deeply“invasive”. Reactive stromal cells mayalso often attain bizarre and pleomorphicshapes, confusing the histopathologicpicture. Other malignancies that may beconfused with mesothelioma includepericardial-based angiosarcoma, whichmay elicit a prominent mesothelialresponse, malignant solitary fibroustumour and synovial sarcoma.Immunohistochemistry is invaluable insuch circumstances. Mesothelioma lacksthe X;18 translocation of synovial sarco-ma.


The prognosis of pericardial mesothe-lioma is poor. Fifty per cent of patients

B CAFig. 4.41 Pericardial mesothelioma. A The majority of pericardial mesotheliomas are epithelioid. B Strong expression of calretinin. C Strong expression of cyto-keratin 7.


287Germ cell tumours

survive 6 months, and an exceptionalpatient may live as long as 48 months{248}.

Germ cell tumours

Definition

A neoplasm of germ cell origin classifiedby histologic type into seminoma (dys-germinoma), embryonal carcinoma, yolksac tumour (endodermal sinus tumour),choriocarcinoma, and teratoma.

Epidemiology

Approximately 100 cases of intrapericar-dial germ cell tumours have been report-

ed, over 90% within the pericardium, andthe remainder in the myocardium. Themajority are pericardial teratomas {248},and the remainder are yolk sac tumours{411,1178}. Reports of intrapericardialteratoma describing the presence of onlyone or two germ cell layers may repre-sent misclassified bronchogenic cysts.

Clinical features

Patient age ranges from intrauterine lifeto 66 years {411}. Teratomas generallyoccur in infants while adults tend to havemalignant germ cell tumours. Over 75%of cardiac teratomas occur in childrenunder age 15. There is a slight femalepredominance. Symptoms include respi-ratory distress, pericardial tamponade,and cyanosis. Occasionally mediastinalteratomas in adults may secondarilyinvolve the pericardium.Due to the routine use of fetal echocar-diography, an increasing number of peri-cardial teratomas are being diagnosed insecond and third trimester fetuses {1615,1786,2005}. Neonates may die at birthfrom cardiac tamponade and cardiaccompression. Prenatal resection andintrauterine pericardiocentesis havebeen successfully accomplished {1615,1935}.Intramyocardial teratomas haveoccurred in the newborn period or in thefirst 6 years of life {1615}. Most patientsare symptomatic and present with con-gestive heart failure; rarely, a patient maybe asymptomatic, or sudden death may

be the first symptom, due to acutearrhythmia caused from the tumour’sinterventricular location.

Macroscopy

Cardiac teratomas may be massive,measuring up to 15 cm. They have asmooth surface and are lobulated. Thetumours are multicystic with interveningsolid areas. The tumours usually dis-place the heart and rotate it along its lon-gitudinal axis. Intrapericardial teratomasare usually located on the right side ofthe heart, displacing the organs to theleft and posteriorly; those located on theleft side will produce the opposite effect.Teratomas are usually attached by apedicle to one of the great vessels witharterial supply directly from the aorta.

Histopathology

Teratomas of the heart are similar toextracardiac teratomas. A minority ofgerm cell tumours of the pericardium areyolk sac tumours {248,411,1792}.

Histogenesis

The cell of origin of extragonadal ter-atoma, including pericardial teratoma, isthe primordial germ cell. Although nor-mal germ cells migrate from the yolk sacto the gonad, they may lodge early inembryogenesis in midline structuressuch as the mediastinum.

Treatment

Surgical excision is the only effectivetreatment for cardiac teratoma. Since theblood supply is usually from the root ofthe ascending aorta, the surgeon mustperform a careful dissection and ligationof these vessels to prevent massive hem-orrhage. Intracardiac teratomas,because of their location in the interven-tricular septum, are more difficult toremove than pericardial teratomas.Malignant germ cell tumours requirestandard chemotherapy.

Metastatic pericardial tumours

A high percentage of pericardial biop-sies occur in patients in whom the diag-nosis of malignancy has not yet beenmade, either for life-threatening tampon-ade or to establish the cause of peri-carditis {1201,1499}. In about two-thirdsof patients with positive pericardial biop-sy, the clinical diagnosis is pericarditis,

Fig. 4.42 Pericardial teratoma. T1-weighted spinecho MR image in the coronal plane showing largepericardial teratoma (T). The right atrium (RA) iscompressed by the tumour.

Fig. 4.43 Yolk sac tumour. The patient was a young woman with a pericardial mass, detected incidentally.



and in the remainder, tamponade. Falsenegative biopsies may occur due to sam-pling, and it is not uncommon to have apositive cytology and a negative biopsy.Most adenocarcinomas presenting aspericardial metastases originate either in

the lung or an undetermined primary site.Breast carcinoma, unlike lung carcinoma,usually manifests as pericardial diseaseonly after the primary site is known. Othertumours found in pericardial biopsiesinclude lymphoma, melanoma, multiplemyeloma, thymoma, metastatic semino-ma {121,249,1398}. The sites of origin oftumours discovered initially at pericardialbiopsy are shown in Table 4.03.The distinction between reactivemesothelial hyperplasia and metastaticcarcinoma can be difficult, and is assist-ed by immunohistochemistry. The pres-ence of carcinoembryonic antigen,berEP4, B72.3 antigen, and Leu M1favour carcinoma over mesothelialhyperplasia. Calretinin and cytokeratin5/6 reactivity favour the diagnosis of amesothelial process.The treatment of malignant pericardialdisease includes establishing a pericar-dial window, sclerosis with tetracycline orother agents, and radiation therapy{1069}. Malignant pericardial effusionsare generally a sign of rapidly progres-sive disease, necessitating emergencytreatment. Patients with metastatic peri-cardial disease have a mean survival of4.3 months {1201}. In contrast, patients

with pericardial malignant lymphoma orwith involvement by thymoma often faresignificantly better.

Table 4.03 Malignant tumours diagnosed at pericardial biopsy{1201}.

Tumour type Number Fraction

Carcinoma 54 68%Adenocarcinoma 32 40%Squamous cell 14 18%Large cell 7 9%Small cell 1 1%Lymphoma 12 15%Sarcoma 7 9%MFH 3 3%Angiosarcoma 2 2%Leiomyosarcoma 1 1%NeurofibrosarcomaThymoma 5 6%Melanoma 2 2%

Total 80 100%

Fig. 4.44 Metastatic pericardial tumors. Gross largemetastatic nodules in cardiac chambers andmyocardium (renal cell carcinoma).


Documents

Tumours of the Heart - IARC · Tumours of the Heart ... Left atrial tumours, especially those that ... Rarely, tumours such as myxoma, cause systemic symptoms,including anorexia,