Tumours of the Heart

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					                      CHAPTER 4

         Tumours of the Heart

Although tumours of the heart do not contribute significantly to
the overall tumour burden, they may cause a variety of cardiac
and systemic symptoms. Clinical features depend not only on
the 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 considerably
improved the prognosis. However, cardiac sarcomas are still
life-threatening diseases.

Due to the low frequency, there is no specific garding scheme
for malignant heart tumours. This volume largely follows the
principles of classification and grading detailed in the WHO
Classification of Tumours of Soft Tissue and Bone.
WHO histological classification of tumours of the heart
  Benign tumours and tumour-like lesions                                            Malignant tumours
  Rhabdomyoma                                                       8900/0          Angiosarcoma                                                       9120/3
  Histiocytoid cardiomyopathy                                                       Epithelioid haemangioendothelioma                                  9133/3
  Hamartoma of mature cardiac myocytes                                              Malignant pleomorphic fibrous histiocytoma
  Adult Cellular Rhabdomyoma                                        8904/0          (MFH)/Undifferenciated pleomorphic sarcoma                         8830/3
  Cardiac myxoma                                                    8840/0          Fibrosarcoma and myxoid fibrosarcoma                               8840/3
  Papillary fibroelastoma                                                           Rhabdomyosarcoma                                                   8900/3
  Haemangioma                                                       9120/0          Leiomyosarcoma                                                     8890/3
  Cardiac fibroma                                                   8810/0          Synovial sarcoma                                                   9040/3
  Inflammatory myofibroblastic tumor                                8825/1          Liposarcoma                                                        8854/3
  Lipoma                                                            8850/0          Cardiac lymphomas
  Cystic tumour of the atrioventricular node                                        Metastatic tumours

                                                                                    Pericardial tumours
                                                                                    Solitary fibrous tumour                                            8815/1
                                                                                    Malignant mesothelioma                                             9050/3
                                                                                    Germ cell tumours
                                                                                    Metastatic pericardial tumours

  __________
  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.




250 Tumours of the heart
Tumours of the heart: Introduction                                                            A.P. Burke
                                                                                              J.P. Veinot
                                                                                                                           H. Tazelaar
                                                                                                                             H. Kamiya
                                                                                              R. Loire                       P.A. Araoz
                                                                                              R. Virmani                  G. Watanabe




Epidemiology                                   that determine clinical features {737}.        carditis may also result from tumour infil-
The estimated frequency of cardiac             Large tumours may be relatively silent,        tration.
tumours ranges from 0.0017-0.33%               whereas small tumours in a critical loca-      Rarely, tumours such as myxoma, cause
{2165}. In a review of 22 autopsy-based        tion may give rise to devastating clinic       systemic symptoms, including anorexia,
series of primary cardiac tumours a fre-       consequences.                                  weight loss, fatigue and malaise which
quency of 0.021% was identified among          Left atrial tumours, especially those that     may mimic a variety of systemic disor-
731,309 patients {1656}. In one 20-year        are mobile or pedunculated, may lead to        ders {356,737,1774,2077}. Interestingly,
(1972-1991) review of 12,485 autopsy           systemic embolism involving the coro-          they may also cause haematologic
cases, there was a 0.056% incidence of         nary, cerebral and peripheral circulations     abnormalities, including anemia, poly-
primary tumours and a 1.23% incidence          {737,1568,2077}, resulting in myocardial       cythemia, leukocytosis, thrombocytosis
of secondary tumours {1116}. However,          infarction, stroke or ischemic viscera or      and elevated sedimentation rate {1225}.
these data may have a high referral bias       limbs. Left atrial tumours may also inter-     Tumour production of mediators, includ-
and may not reflect population-based           fere with mitral valve function resulting in   ing interleukins, has been reported
incidence rates {2079}. At the Mayo            mitral stenosis or regurgitation. Cardiac      {1774}.
Clinic, the autopsy incidence of primary       murmurs and a characteristic tumour
cardiac tumours from 1915 to 1931 was          “plop” may be auscultated. Valve dys-          Imaging
0.05%, but more than tripled to 0.17%          function manifests as left-sided heart fail-   Primary tumours of the heart and peri-
between 1954 and 1970 {2165}; again,           ure with shortness of breath, orthopnea,       cardium may be detected as an abnor-
referral bias may have played a role in        paroxysmal nocturnal dyspnoea, pul-            mal finding on a chest radiogram or
this change.                                   monary edema, fatigue, cough, and              another imaging test obtained for an
When most cardiac tumours were diag-           chest pain {356}.                              unrelated reason. Once detected car-
nosed at autopsy, myxomas and sarco-           Intramural left ventricular tumours may        diac imaging is needed to define (1)
mas were reported at a similar frequency.      be asymptomatic or present with a mass         tumour location, extent and boundaries;
With the utilization of cardiopulmonary        effect. With protrusion into the cavity,       (2) relationships with adjacent key car-
bypass and surgical excision, the report-      hemodynamic compromise may result              diac structures such as valves and coro-
ed frequency of myxomas as opposed to          {1225}. Local extension of the tumour          nary arteries; (3) tumour type; and (4)
cardiac sarcomas has increased sub-            may cause conduction or coronary artery        presence and degree of functional
stantially {249,1568}. In a review of surgi-   compromise with chest pain, myocardial         impairment. The main non-invasive imag-
cal series, cardiac myxomas constitute         infarction, arrhythmia, heart block or sud-    ing modalities for evaluating primary car-
77% of surgically excised tumours, and         den death {356,737,1225,1791}.                 diac tumours each have advantages and
cardiac sarcomas, 10% {249}.                   Right atrial or right ventricular tumours      disadvantages. They are often used
In children, cardiac tumours are not com-      may result in right heart failure from atri-   together in a complementary manner for
mon and most are benign {249}. The             oventricular or pulmonary outflow              diagnosis and surgical planning.
most common pediatric tumours include          obstruction, resulting in peripheral
rhabdomyomas, fibromas, myxomas,               edema, hepatomegaly, ascites, short-           Echocardiography
and teratomas {249,356}.                       ness of breath, syncope and sometimes,         The primary advantage of echocardiog-
Secondary cardiac tumours, either              sudden death {737}. If the tumours inter-      raphy is that it has the best spatial and
metastatic or by direct invasion, outnum-      fere with valve function they may result in    temporal resolution and provides excel-
ber primary cardiac neoplasms {1116}. A        regurgitation or stenosis {1791}.              lent anatomic and functional information
review of 3,314 autopsies found a 2.9%         Right-sided cardiac tumours may                {492,705,1070,1162,2104,2215}. It is the
frequency of metastatic tumours involv-        embolize to the lungs and present as pul-      optimal imaging modality for small mass-
ing the heart {12}. The most common pri-       monary emboli with chest pain, pul-            es (<1 cm) or masses arising from
mary sites are lung, breast, and cuta-         monary infarction and haemoptysis              valves. A second major advantage of
neous melanoma.                                {1634,1791}. Chronic embolization may          echocardiography is the ability to image
                                               also mimic chronic thromboembolic dis-         velocities with Doppler, which allows for
Clinical features                              ease with signs and symptoms of pul-           assessment of presence, degree, and
Cardiac neoplasms may cause a variety          monary hypertension.                           location of obstructions to blood flow or
of signs and symptoms {1225,1791,              Pericardial tumours may cause chest            valve regurgitation. Echocardiography is
2079}. The clinical presentation depends       pain typical of pericarditis {1225,1568}.      typically the modality used for the initial
on the size of the tumour and its anatom-      The tumours may be haemorrhagic and            evaluation of cardiac tumours and may
ic location. Growth rate, friability, and      cause pericardial effusion and tampon-         be the only diagnostic test required in
invasiveness are also important factors        ade {1634}. However, constrictive peri-        some patients. Disadvantages include

                                                                                                                      Introduction 251
suboptimal image quality in patients with       Fig. 4.01                                          Classification of Tumours of Soft Tissue
poor acoustic windows, inability to image       Parameters of the grading system for sarcomas of   and Bone {590}. The concept of grading
extent of disease outside of the medi-          the Féderation Nationale des Centres de Lutte      sarcomas was first introduced in 1977
                                                Contre le Cancer (FNCLCC).
astinum, and relatively low soft tissue                                                            {1712}. Several grading systems have
contrast, which limits detection of tumour       Tumour differentiation                            since been proposed which have shown
infiltration and characterization of tumour      Score 1: Sarcomas closely resembling              to correlate with prognosis {412,1247,
tissue. Also, intravenous contrast agents                   normal adult mesenchymal tissue        1418,2031,2070}. The two most impor-
are not routinely used with echocardiog-                    (e.g., low-grade leiomyosarcoma).      tant parameters in non-cardiac soft tis-
raphy, which limits the ability to charac-       Score 2: Sarcomas for which histological          sue seem to be the mitotic index and
terize tumour vascularity.                                  typing is certain (e.g., Myxoid        extent of tumour necrosis {1793,2031,
                                                            Fibrosarcoma)                          2070}. Most pathologists recognize three
                                                 Score 3: Undifferentiated, angiosarcoma
Magnetic Resonance Imaging (MRI)                                                                   grades of malignancy: G1, low grade;
The primary advantage of MRI is its                                                                G2, intermediate grade; and G3, high
                                                 Mitotic count
excellent soft tissue contrast which             Score 1: 0-9 mitoses per 10 HPF*                  grade. Some use a 4-tiered system.
makes it the most sensitive modality for         Score 2: 10-19 mitoses per 10 HPF                 The two most widely used systems are
detection of tumour infiltration. MRI has        Score 3: ≥20 mitoses per 10 HPF                   those of the NCI (U.S. National Cancer
more manipulable imaging parameters                                                                Institute) {412,413} and the FNCLCC
than other imaging modalities. Because           Tumour necrosis                                   (Fédération Nationale des Centres de
of this, MRI is the best modality for char-      Score 0: No necrosis                              Lutte Contre le Cancer) {387-389,748,
acterizing tumour tissue {1003,1768,             Score 1: <50% tumour necrosis                     2031}.
1831,2156}. For example, a T2-weighted           Score 2: ≥50% tumour necrosis                     According to the methodology defined in
standard or fast spin echo sequence dis-                                                           1984 {412} and refined in 1999 {413}, the
                                                 Histologic grade
tinguishes tumours with high water con-                                                            NCI system uses a combination of histo-
                                                 Grade 1: Total score 2,3
tent, such as haemangioma, from                  Grade 2: Total score 4,5
                                                                                                   logic type, cellularity, pleomorphism and
tumours with low water content, such as          Grade 3: Total score 6, 7, 8                      mitotic rate for attributing grade 1 or 3.
fibroma. A third advantage of MRI is the                                                           All the other types of sarcomas are clas-
ability to characterize tumour vascularity       Modified from Trojani et al {2031}.               sified as either grade 2 or grade 3
with intravenous contrast. Though not as         *A high-power field (hpf) measures 0.1734mm2      depending on the amount of tumour
flexible as echocardiography, MRI does                                                             necrosis, with 15% necrosis as the
allow assessment of wall motion and                                                                threshold for separation of grade 2 and
assessment of velocities through large          tissue contrast and ability to characterize        grade 3 lesions.
vessels. This allows for characterization       tumour infiltration and tumour type is less        The FNCLCC system is based on a score
of ventricular function, inflow or outflow      than that of MRI. Intravenous contrast             obtained by evaluating three features:
obstruction and valve regurgitation. The        can provide information about tumour               tumour differentiation, mitotic rate and
primary disadvantage of MRI is long             vascularity, an advantage CT shares with           amount of tumour necrosis {2031}. A
examination times, which translates into        MRI. CT may be used as an adjunct to               score is attributed independently to each
the need for sedation in children, and the      both echocardiography and MRI.                     parameter and the grade is obtained by
need for reliable ECG gating. MRI should                                                           adding the three attributed scores.
be considered when the tissue type,             Cardiac Catheterization                            Tumour differentiation is highly depend-
exact location, or the relationships of the     This is seldom required for diagnosis of           ent on histologic type and subtype. The
tumour with neighbouring structures are         cardiac tumours, but may be performed              reproducibility of this system has been
not completely defined by echocardiog-          in adults to exclude coronary artery dis-          tested by 15 pathologists: the crude pro-
raphy or when surgical resection of the         ease. Angiography provides indirect and            portion of agreement was 75% for tumour
tumour is considered.                           nonspecific imaging based on filling               grade, but only 61% for histologic type
                                                defects within the cardiac chambers and            {748}.
Computed Tomography (CT)                        displacement of the coronary arteries              Because of the limitations and pitfalls of
ECG gated CT scans with the latest gen-         {347,1840}. Two exceptions are worth               grading, the following guidelines have
eration of multidetector scanners or with       noting. First, endomyocardial biopsy for           been suggested to improve reliablility:
electron beam scanners are also very            tissue typing may be considered in                 > Grading should be used only for
useful for cardiac imaging {65,275}. In         selected patients. Second, selective               untreated primary soft tissue sarcomas.
many ways, the advantages and disad-            coronary angiography is helpful when               > Grading should be performed on rep-
vantages of CT are intermediate between         planning surgical resection of an                  resentative and well-processed material.
those of echocardiography and MRI.              intramyocardial tumour.                            > Grading is not a substitute for a histo-
Modern CT scanners have excellent spa-                                                             logic diagnosis and does not differentiate
tial resolution, which is better than that of   Tumour grading and staging                         benign and malignant lesions. Before
MRI, but not as high echocardiograpy.           Given the low frequency of malignant               grading a soft tissue lesion, one must be
CT has better soft tissue contrast than         cardiac tumours, there is no grading               sure that one is dealing with a true sar-
echocardiography, and can be used to            scheme specifically referring to malig-            coma and not a pseudosarcoma.
definitively characterize fatty content and     nant heart tumours. This volume uses the           > Parameters of grading must be carefully
calcifications; however, the overall soft       criteria published in the recent WHO               evaluated, particularly the mitotic rate.

252 Tumours of the heart
The WHO Classification of Tumuors of         Surgical strategy varies by tumour type.       and reconstruction would be expected to
Soft Tissue and Bone {590} offers addi-      Cardiac myxomas arise mainly from the          cause irreparable damage to essential
tional information on the grading of soft    left atrial septum, and the surgical strate-   cardiac structures {731}.
tissue sarcomas.There is no TNM classi-      gy usually includes complete tumour            For malignant cardiac tumours, complete
fication for cardiac malignancies.           resection       with  underlying      stalk.   resection is often impossible because of
                                             Sometimes reconstruction using a pros-         local spread {2071}. The prognosis of
Treatment and prognosis                      thetic patch is necessary {952}. The           patients with primary malignant cardiac
In general, surgical resection, when pos-    prognosis of patients with cardiac myxo-       tumours is very poor even if complete re-
sible, is the treatment of choice for pri-   mas is excellent. They may occasionally        section is attempted {952,2071}. Adjuvant
mary cardiac tumours in symptomatic          recur, especially in patients with Carney      chemotherapy and irradiation are usually
patients. It is also highly desirable for    complex, an autosomal dominant syn-            also given, but these are not effective in
patients whose tumours are identified        drome characterized by associated skin         most cases {2071}. Favourable results of
incidentally because of the ever-present     lesions, endocrine abnormalities and           heart transplantation for primary malig-
risk of sudden death, embolism, obstruc-     other unusual tumours {1018}. It is diffi-     nant cardiac tumours have been reported
tion, or arrhythmia {307,952}. In patients   cult to suggest a regular surgical strate-     despite immunosuppression {731,733,
with rhabdomyomas and so called histio-      gy for other cardiac tumours as they           1962, 2071}.
cytoid cardiomyopathy, predominantly         arise in various locations. The prognosis
children, there are some who suggest         for other benign tumours is generally
that surgical intervention is only neces-    favourable with low recurrence, and it is
sary in the face of life-threatening symp-   quite good even if incompletely excised
toms, as these tumours are benign and        {307,952,1880}. Orthotopic heart trans-
known to regress with age {1880}.            plantation is an option if tumour resection




                                                                                                                    Introduction 253
Benign tumours with myocyte                                                                             B.M. Shehata
                                                                                                        A.P. Burke
                                                                                                                                       R. Virmani
                                                                                                                                          T. Geva
differentiation                                                                                         H. Tazelaar
                                                                                                        C.R. Patel
                                                                                                                                  G. Tornambene
                                                                                                                                     D.J. Radford




Rhabdomyoma                                         in any location in the heart, but are more          be identified as early as 21 weeks by
                                                    common in the ventricles. In patients with          ultrasound {863}. The tumours may
Definition                                          tuberous sclerosis, tumours are usually             cause infant respiratory distress, con-
A benign tumour of the cardiac myocyte,             multiple (> 90%) and can consist of                 gestive heart failure, or low cardiac out-
which can be solitary or multiple. The              numerous miliary nodules measuring less             put. Right-sided tumours that cause
cells typically contain large glycogen              than 1 mm; in this instance, the term               obstruction may cause cyanosis, or fea-
filled vacuoles.                                    “rhabdomyomatosis” has been used. The               tures suggestive of tetralogy of Fallot or
                                                    most common locations are the left ven-             pulmonary stenosis {41,583}. Left-sided
ICD-O code                     8900/0               tricle and ventricular septum, although             tumours may present as subaortic
                                                    30% will have atrial wall or right ventricu-        obstruction, or hypoplastic left heart syn-
Epidemiology                                        lar involvement {1602}. In contrast to              drome {2068}. Rarely they can be asso-
Cardiac rhabdomyoma is commonly                     patients with tuberous sclerosis, approxi-          ciated with structural cardiac defects
associated with tuberous sclerosis, an              mately 50% of sporadic rhabdomyomas                 {2113}. Patients with “rhabdomyomato-
autosomal dominant disorder with a high             occur singley.                                      sis” or diffuse microscopic involvement
mutation rate. It involves multiple organs                                                              of the myocardium may present as
including brain, kidney, pancreas, retina           Clinical features                                   though they have a cardiomyopathy.
and skin. In autopsy series, patients with          Signs and symptoms                                  Spontaneous regression is a common
tuberous sclerosis have a 30% incidence             Rhabdomyomas are the most common                    feature {1254,1840}.
of    cardiac     rhabdomyoma        {571}.         tumours in the pediatric age group. They            Electrocardiographic abnormalities will
However, the actual incidence is likely             are also the tumours most commonly                  vary depending on location, but evi-
higher since series that have evaluated             diagnosed during the prenatal period by             dence of ventricular hypertrophy and ST-
patients with echocardiography have                 foetal echocardiography. Intrauterine as            T wave abnormalities consistent with
found an incidence between 40% and                  well as sudden death after birth has                ischemia and/or strain are common. The
86% {119,492,777}. The presence of                  been attributed to these tumours.                   conduction abnormalities consist of bun-
multiple cardiac rhabdomyomas prena-                Clinical and hemodynamic findings are               dle branch block, preexcitation, and first
tally may be the earliest manifestation of          related to the number, position, and size           to third degree atrioventricular block.
tuberous sclerosis.                                 of the tumours. For instance large intra-
                                                    mural or intracavitary tumours may                  Imaging
Localization                                        obstruct valvular orifices, or occlude              At echocardiography rhabdomyomas
Rhabdomyomas are firm, white, well-cir-             intracavitory spaces {1254}. Foetal dys-            appear as homogeneous, well-circum-
cumscribed lobulated nodules that occur             rhythmias or non-immune hydrops may                 scribed echogenic masses in the ventric-
                                                                                                        ular myocardium, possibly protruding
                                                                                                        into the ventricular cavity. Although
                                                                                                        uncommon, extensive rhabdomyomas
                                                                                                        can be associated with ventricular dys-
                                                                                                        function. Given that the finding of multi-
                                                                                                        ple cardiac masses is diagnostic of rhab-
                                                                                                        domyoma, especially in patients with
                                                                                                        tuberous sclerosis, and that the tumours
                                                                                                        are not infiltrative, echocardiography
                                                                                                        usually provides adequate information
                                                                                                        for diagnosis and clinical management. If
                                                                                                        there is question of tumour type or of
                                                                                                        tumour invasion, MRI or CT may be used
                                                                                                        to further define the tumours. At MRI,
                                                                                                        rhabdomyomas appear as well-circum-
                                                                                                        scribed masses with signal characteris-
A                                                  B                                                    tics similar to that of normal myocardium
Fig. 4.01 Rhabdomyoma. A Echocardiogram of an infant who presented with supraventricular tachycardia.   {155,737,1003}. Compared with the sig-
There are multiple rhabdomyomas. These eventually regressed and the arrhythmias resolved.               nal from uninvolved myocardium, the
B Echocardiographic imaging from the apical chamber view, showing multiple cardiac rhabdomyomas         masses are hypointense on post-
involving the left (LV) and right (RV) ventricles.                                                      gadolinium imaging. At CT, rhabdomy-

254 Tumours of the heart - Benign tumours with myocyte differentiation
                                                                                                             with sparse myofilaments. There is a
                                                                                                             strong reaction with periodic acid-Schiff
                                                                                                             reagent, reflecting the presence of abun-
                                                                                                             dant intracellular glycogen.

                                                                                                             Immunoprofile
                                                                                                             Immunohistochemical studies document
                                                                                                             the striated muscle characteristics of
                                                                                                             rhabdomyoma cells, which express myo-
A                                                     B                                                      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 likely
                                                                                                             hamartomas as opposed to neoplasms
                                                                                                             {248}.

                                                                                                             Electron microscopy
                                                                                                             By electron microscopy, the cells resem-
                                                                                                             ble altered myocytes. They possess
                                                                                                             abundant glycogen, small and sparse
C                                                     D                                                      mitochondria, and cellular junctions
Fig. 4.02 Cardiac rhabdomyoma. A Multiple rhabdomyomas in an infant with tuberous sclerosis complex          resembling intercalated disks surround
(courtesy of William D. Edwards, M.D.). B Intraoperative photograph. The tumour nearly fills the ventricu-   the cell periphery. In contrast, the inter-
lar cavity, and is glistening and polypoid. C Stillborn child with a ventricular rhabdomyoma. D Subaortic    calated disks of differentiated myocytes
rhabdomyoma in an 5 months old child.                                                                        are located exclusively at the poles of the
                                                                                                             cell. Intercalated discs and myofibrils or
                                                                                                             collections of Z band material are pres-
omas also appear as multiple nodules,                  cially in sporadic cases. In one series of            ent. Rarely one may observe there primi-
which may be hyper or hypoattenuating                  14 cases, the range was 0.3-9.0 cm, with              tive T-tubules. Leptomeric fibers close to
compared to normal myocardium. With                    a mean of 3.4 cm {248}. They most often               the sarcolemma may also be identified.
MRI or CT, the rest of the body can be                 occur in the ventricle, but can be found
imaged for signs of tuberous sclerosis.                in the atria, at the cavoatrial junction and          Differential diagnosis
However, because rhabdomyoma has                       on the epicardial surface. Large tumours              The diagnosis of cardiac rhabdomyoma
many imaging features similar to normal                may obliterate and distort a ventricular              in infants and young children is straight-
myocardium, echocardiography, MRI,                     cavity.                                               forward. In patients with multiple non-cal-
and CT may be complementary as rhab-                                                                         cifying masses, especially with other
domyomas that are not visible by one                   Histopathology                                        manifestations of tuberous sclerosis
modality may be visible on another {737}.              Cardiac rhabdomyomas are well-demar-                  complex, a tissue diagnosis is unneces-
                                                       cated nodules of enlarged cardiac                     sary. However, because the tumours
Macroscopy                                             myocytes with cleared cytoplasm. In                   have been shown to regress with age
Single or multiple, they are well-circum-              some cells, strands of eosinophilic cyto-             and multiple biopsies do not allow for
scribed, non-capsulated white or grey                  plasm stretch from a central nucleus to               evaluation of the morphologic changes
white nodules which may vary in size                   the cell membrane giving rise to cells                that characterize this process, the rela-
from millimeters to several centimeters.               that resemble a spider (“spider cells”).              tionship between persistent rhabdomy-
Tumours can become quite large, espe-                  The majority of cells show vacuolization              omas and so-called adult rhabdomy-




A                                                     B
Fig. 4.03 Rhabdomyoma. A The subendocardium shows a poorly demarcated area of cellular vacuolization.        Fig. 4.04 Cardiac rhabdomyoma with classic spider
B A higher magnification note "spider" cells, several vacuolated tumor cells, and cells with abundant        cell.
eosinophilic cytoplasm , which is more typical for rhabdomyomas in older children.


                                                                                                                                     Rhabdomyoma 255
omas and hamartomas is not clear. In the               be continued until the arrhythmias or                   The female preponderance is 3:1. In
rare examples of rhabdomyomas in older                 tumours regress. If drugs fail to control               approximately 5% of cases there seems
children, there is often a paucity of spider           arrhythmias, surgical resection is indicat-             to be a familial tendency.
cells, resulting in a tumour with some                 ed. When a tumour is causing intracar-
characteristics of adult rhabdomyomas,                 diac obstruction, surgery is necessary                  Clinical features
but without the proliferative activity.                {180,525,538,1289}.                                     Histiocytoid cardiomyopathy is an
Hamartoma of mature cardiac myocytes,                                                                          arrhythmogenic disorder; 70% of pub-
which, like rhabdomyoma, is a non-prolif-                                                                      lished cases the patients present with a
erative hamartomatous lesion, occurs in                Histiocytoid cardiomyopathy                             spectrum of arrhythmias and electrical
adults. These tumours lack circumscrip-                                                                        disturbances including: paroxysmal atrial
tion and spider cells.                                 Definition                                              tachycardia, atrial fibrillation, ventricular
                                                       Histiocytoid cardiomyopathy is a rare,                  fibrillation, ventricular tachycardia, pre-
Genetic alterations                                    but distinctive arrhythmogenic disorder                 mature atrial contractions, premature
The familial form of tuberous sclerosis,               caused by a neoplastic or hamartoma-                    ventricular contractions, Wolff-Parkinson-
which is present in up to 50% of patients              tous proliferation of cardiac cells with                White syndrome, and right or left bundle
with cardiac rhabdomyoma, exhibits                     some Purkinje cell characteristics.                     branch block.
autosomal dominant inheritance. Two                                                                            Approximately 20% of patients present
disease genes have been identified:                    Synonyms                                                as sudden death and often such cases
TSC-1 at chromosome 9q34, and TSC-2                    Purkinje cell hamartoma, arachnocytosis                 have been misclassified as Sudden
at chromosome 16p13 {1613}. The TSC-                   of the myocardium, infantile cardiomy-                  Infant Death Syndrome (SIDS). Other
1 gene encodes hamartin, and TSC-2                     opathy, infantile xanthomatous cardio-                  infants experience flu-like symptoms pre-
tuberin, proteins involved in tumour sup-              myopathy, oncocytic cardiomyopathy,                     ceding or accompanying the cardiac
pression. Loss of heterozygosity is often              focal lipid cardiomyopathy, isolated car-               manifestations. The majority of patients
found at these loci in tumours from                    diac lipidosis, infantile cardiomyopathy                (95%) display cardiomegaly, but may
patients with tuberous sclerosis. The pre-             with histiocytoid changes, myocardial or                also have a number of associated anom-
cise roles of TSC-1 and TSC-2 in the                   conduction system hamartoma, foamy                      alies, including cardiac malformation
development of cardiac tumours and                     myocardial transformation, and congeni-                 (16%): ventricular and atrial septal
regulation of embryonic and neonatal                   tal cardiomyopathy.                                     defects, hypoplastic left heart syndrome;
cardiomyocyte growth remain to be elu-                                                                         and endocardial fibroelastosis. Extra-
cidated.                                               Epidemiology                                            cardiac anomalies occur in 17% of
                                                       Histiocytoid cardiomyopathy occurs pre-                 patients including corneal opacities,
Treatment and Prognosis                                dominantly in the first two years of life;              microcephaly, cataract, aphakia, hydro-
Rhabdomyomas have a natural history of                 20% of cases are diagnosed in the first                 cephalus, agenesis of the corpus callo-
spontaneous regression {204,556,1840}.                 month, 60% in the first year, and less                  sum, cleft palate, laryngeal web, and lin-
However, serious symptoms may precip-                  than 3% after two years of life. The preva-             ear skin defect. Combined cardiac and
itate the need for surgical resection.                 lence of this disease may be higher than                extracardiac anomalies occur in 4%, and
When arrhythmias are the presenting                    the reported cases would suggest, since                 7% show extracardiac histiocytoid cells
symptom, treatment with anti-arrhythmic                some cases are undoubtedly diagnosed                    in exocrine and endocrine glands {1794}.
drugs is commenced. If control is                      as Sudden Infant Death Syndrome
achieved by that means, then drugs can                 (SIDS).




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


256 Tumours of the heart - Benign tumours with myocyte differentiation
A                                                                            B
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.


Etiology                                           may show a mottled appearance with                   able size, scattered desmosomes, inter-
Many theories of the etiopathogenesis              irregular ill-defined yellowish-tan areas.           calated discs, and leptometric fibers.
have been proposed, including viral
infection, myocardial ischemia, toxic              Histopathology                                       Differential diagnosis
exposure, and metabolic disorders such             Histiocytoid cardiomyopathy lesions                  The disease has been confused with mito-
as glycogen storage disease, cardiac               appear as multifocal, ill-defined islands            chondrial cardiomyopathy. However, there
lipidosis, and various mitochondrial               of large polygonal cells with granular               are major gross, light microscopic, and
myopathies. However, the clinical, gross,          eosinophilic cytoplasm, small round to               ultrastructural differences between the two
microscopic, and ultrastructural findings          oval shaped nuclei containing occasion-              diseases. Mitochondrial cardiomyopathy
show clear differences between the                 al nucleoli. The cytoplasmic appearance              shows no discrete nodules as present in
above-mentioned disorders and histiocy-            is due to extensive accumulation of mito-            histiocytoid cardiomyopathy. Additionally,
toid cardiomyopathy. The clinical presen-          chondria. The cells are distributed along            in mitochondrial cardiomyopathy, all
tation (arrhythmia), the distribution of his-      the bundle branches of the conduction                myocytes are affected, but to a variable
tiocytoid cells, and their ultrastructural         system. The sinoatrial and atrioventricu-            degree, whereas in histiocytoid cardiomy-
and immunohistochemical characteris-               lar nodes are involved in 28% of cases;              opathy, only focal areas of the heart are
tics, all point to the cardiac conduction          however, these areas are not sampled                 involved, but the affected cells are affect-
system as playing a key role. The primi-           routinely {1794}.                                    ed totally. The ultrastructural changes in
tive Purkinje cells of the developing heart                                                             histiocytoid cardiomyopathy cells consist
show a striking resemblance to histiocy-           Immunoprofile                                        of increased numbers of mitochondria with
toid cells. Both types of cells show strong        Histiocytoid cardiomyopathy cells react              and without structural changes and
positivity for cholinesterase by frozen            with anribodies to desmin, myoglobin,                reduced myofibrils. In mitochondrial car-
section histochemistry and for neutral             myosin, and muscle specific actin. There             diomyopathy, the mitochondria are consis-
lipids with the Sudan Black stain.                 is no expression of macrophage or histi-             tently abnormal in a varitey of ways. They
Cholinesterase is present only in the con-         ocyte antigens (CD68, CD69, MAC 387,                 are enlarged, show variation in size and
duction tissue of the heart; it is not pres-       LN3, HAM-56). The cells also fail to react           shape, contain occasional glycogen parti-
ent in contractile myocytes {1794}.                with antibodies to vimentin and cytoker-             cles, and have cristae which are
                                                   atin (CAM-5.2), whereas S-100 protein                increased in number and on cross section,
Macroscopy                                         reactivity is variable. Cell proliferation           are arranged in a concentric circular fash-
Single or multiple subendocardial yellow-          markers (Ki-67 and MIB-1) are usually                ion (like growth rings of a tree) surrounding
tan nodules or plaques ranging from 1-             negative {682,1713}.                                 occasional dense bodies.
15 mm may be seen in both ventricles,
the septum, and on all four cardiac                Electron microscopy                                  Genetic susceptibility
valves. Although these nodules are main-           Ultrastructurally, the cells of histiocytoid         Familial recurrence of histiocytoid car-
ly seen beneath the endocardium follow-            cardiomyopathy show poorly developed                 diomyopathy in 5% of cases has led to
ing the distribution of the bundle branch-         intercellular junctions. Their cytoplasm             several proposals of a genetic mecha-
es of the conduction system, they can              contains a superabundance of swollen                 nism. The female preponderance of
also be seen in the inner myocardium               mitochondria with disorganized cristae               cases suggests an X-linked mutation
and subepicardial areas. Lesions may be            and dense membrane bounded gran-                     causing prenatal lethality in the homozy-
grossly inapparent as nodules, but multi-          ules, which push the diminished myofib-              gous male {168,234,1898}. A female
ple cross sections of the myocardium               rils to the periphery of the cell. The cyto-         infant with “oncocytic cardiomyopathy”
                                                   plasm also contains lipid droplets of vari-          and microphthalmia with linear skin

                                                                                                                Histiocytoid cardiomyopathy 257
defects showed monosomy for Xp22
{1543}. Biochemical {1543} and molecu-
lar (mitochondrial DNA) {57} evidence
suggest a defect of complex III (reduced
coenzyme Q-cytochrome c reductase) of
the respiratory chain in cardiac mito-
chondria. Such a mechanism could be
responsible for the mitochondrial
changes observed by light and electron
microscopy, and the systemic involve-          A                                                      B
ment in some patients. It has been sug-
                                               Fig. 4.07 Histiocytoid cardiomyopathy. A Electron microscopic illustration showing histiocytoid cells packed
gested that the disease is due to a muta-      with mitochondria. The diminished myofibrils are displaced to the periphery of the cell (arrows). B Higher
tion in Sox6 gene (p100H), which is asso-      magnification showing abundant swollen mitochondria with disorganized cristae and dense membrane
ciated with widespread myopathies              bounded granules.
{385}. From reported cases with known
ethnic background, histiocytoid car-
diomyopathy appears to be more com-            Etiology                                                demonstrates      increased   collagen.
mon in Caucasian (80%) followed by             The etiology of cardiac hamartoma is                    Interspersed fat cells may be present in
African-American (15%), and Latin-             unknown. Some have suggested that                       small numbers.
American infants (3%); it is rare in Asian     these tumours may represent maturing
infants {1794}.                                congenital rhabdomyomas. However,                       Immunoprofile
                                               there has been no association of hamar-                 The tumours are similar to normal car-
Prognosis and predictive factors               toma of mature cardiac myocytes with                    diac myocytes, and express actin and
Histiocytoid cardiomyopahty causes             other syndromes including the tuberous                  myosin. Abnormal accumulations of
incessant ventricular tachycardia in small     sclerosis complex, making this unlikely.                these intermediate filaments may be
children and can result in sudden death.                                                               appreciated, particularly of actin. There
Surgical excision or direct-vision cryo-       Localization                                            is no evidence of proliferation by
ablation of the multiple small nodular         Hamartomas of mature cardiac myocytes                   immunohistochemical stains for Ki-67 or
tumours is required for long-term cure         may occur in the ventricles or atria, and               PCNA.
{665}. Surgical intervention, electrophys-     may be single or multiple {243}. Unusual
iologic mapping, and ablation of the           examples of diffuse multiple tumourlets                 Electron microscopy
arrhythmogenic foci result in a survival       similar to so-called rhabdomyomatosis,                  The cells show features of myocytes, but
rate of approximately 80%. Some authors        have also been described.                               abnormal accumulations of actin and
have found that aggressive anti-arrhyth-                                                               myosin may be identified.
mic treatment may allow the tumours to         Clinical features
regress without subjectiing patients to        As is the case with most cardiac                        Differential diagnosis
surgery. A few patients with extensive         tumours, the clinical features depend on                The disorganized hypertrophied muscle
disease have undergone cardiac trans-          the location. Tumours in the atria may                  fibers of a hamartoma are also reminis-
plant {664,678,984,1286}.                      result in supraventricular arrhythmias                  cent of the disarray characteristic of
                                               and Wolf Parkinson White syndrome, and                  hypertrophic cardiomyopathy, but with
                                               those in the ventricles sudden death, or                rare exception (apical variant), hyper-
Hamartoma of mature cardiac                    no symptoms at all.                                     trophic cardiomyopathy is not associated
myocytes                                                                                               with a focal mass lesion.
                                               Macroscopy
Definition                                     They are usually poorly demarcated firm                 Prognosis and predictive factors
The term “hamartoma” has been loosely          white masses and range in size from 2                   These tumours are benign neoplasms
applied to several cardiac tumours, most       mm to 5 cm in greatest dimension. They                  and can be excised, resulting in cure.
commonly histiocytoid cardiomyopathy           resemble normal myocardium, but the                     However, arrhythmias and sudden death
(“Purkinje cell hamartoma”). The term          bundles of muscle may appear disorgan-                  may be the initial presentation.
has also been applied to lesions or mal-       ized and associated with bands of con-
formations composed of a variety of car-       nective tissue.
diac elements, and other tumours com-
posed primarily of a single cell type (e.g.,   Histopathology
rhabdomyoma). The term hamartoma of            They are composed of enlarged
mature cardiac myocytes is used for a          myocytes with obvious cross striations,
distinct tumour in adults, composed of         and contain enlarged, irregular nuclei.
cardiac myocytes. This lesion may be           They are poorly demarcated and may
single or multiple.                            interdigitate with normal myocytes at the
                                               edges of the tumour. The interstitium



258 Tumours of the heart - Benign tumours with myocyte differentiation
A                                                    B
Fig. 4.08 Hamartoma of mature cardiac myocytes. A The tumour was circumscribed, with the appearance        Fig. 4.09 Adult cellular rhabdomyoma. Note the
of muscle. B The tumour cells are hypertrophic, forming disorganized bundles with interstitial fibrosis.   monomorphic, bland spindled cells; their myogenic
                                                                                                           nature is not clearly evident on routine stains.


Adult cellular rhabdomyoma                            tures distinguish these tumours from                 tumours, the absence of tumour necro-
                                                      other cardiac tumours with muscle differ-            sis, mitotic figures, myogenin expression,
Definition                                            entiation.                                           and the presence of a well-defined
Adult cellular rhabdomyoma is a benign                                                                     pseudocapsule help to distinguish it from
neoplasm of striated myocytes. A similar              Histopathology                                       rhabdomyosarcoma.
tumour frequently occurs in the head and              These tumours are histologically distinct
neck region (extracardiac rhabdomy-                   from cardiac rhabdomyomas, and are                   Histogenesis
oma).                                                 composed of tightly packed, round to                 The lesion is believed to be a true neo-
                                                      polygonal cells with eosinophilic, finely            plasm of striated muscle origin.
ICD-O code                      8904/0                granular cytoplasm, occasional vacuoles
                                                      and occasional spider cells. Conversely,             Somatic genetics
Epidemiology                                          cardiac rhabdomyomas are composed                    Due to the rarity of these lesions, molec-
The adult form of extracardiac rhab-                  of large cells with clear cytoplasm con-             ular and genetic characterization has not
domyoma occurs primarily in the head                  taining abundant glycogen and many                   been undertaken. In extracardiac rhab-
and neck region of men and women over                 spider cells.                                        domyoma, a reciprocal translocation
40 years. Four cases of “extracardiac”                                                                     between chromosomes 15 and 17 and
rhabdomyomas have been described in                   Differential diagnosis                               abnormalities of the long arm of chromo-
the heart {241,2226}.                                 In contrast to congenital rhabdomyomas,              some 10 have been described {680}.
                                                      adult cellular rhabdomyomas occur in
Clinical features and localization                    adults, demonstrate evidence of cellular             Prognosis and predictive factors
Three of the four reported cases of adult             proliferation e.g. by expression of Ki-67            The prognosis of adult cellular rhab-
cellular rhabdomyoma have occurred in                 antigen, and contain relatively few vac-             domyoma is unknown, but presumed to
the atria, and all have occurred in adults            uolated or spider cells. Unlike hamar-               be benign, based on the biologic behav-
from 35-55 years of age. Common to any                toma of mature cardiac myocytes, the                 iour of extracardiac rhabdomyomas in
heart tumour, the mode of presentation is             tumours are well circumscribed, and                  adults. Late recurrences have been
often electrical disturbance such as                  although not as frequent as in congential            described in extracardiac rhabdomyoma
supraventricular tachycardia or nonsus-               rhabdomyoma, some vacuolated cells                   {680}.
tained ventricular tachycardia. The                   are usually present. Furthermore, the dis-
masses may be identified incidentally.                organized masses of myofilaments char-
                                                      acteristic of hamartoma of mature car-
Macroscopy                                            diac myocytes are not seen. Rhabdo-
They range in size from 2–5 cm. The                   myosarcoma shares some features with
tumours are soft, bulging, tan to brown               adult cellular rhabdomyoma. Despite the
and have a pseudocapsule. These fea-                  evidence of cell proliferation in the latter




                                                                                                                   Adult cellular rhabdomyoma 259
Benign tumours of pluripotent                                                                                  A.P. Burke
                                                                                                               H. Tazelaar
                                                                                                                                             C.T. Basson
                                                                                                                                           R. Rami-Porta
mesenchyme                                                                                                     J.J. Gomez-
                                                                                                               Roman
                                                                                                                                                E. Maiers
                                                                                                                                           A.E. Edwards
                                                                                                               R. Loire                          P. Walter
                                                                                                               P. Chopra                      J.R. Galvin
                                                                                                               M. Tomsova                  S. Tsukamoto
                                                                                                               J.P. Veinot              D. Grandmougin
                                                                                                               T. Dijkhuizen                   P.A. Araoz

Cardiac myxoma                                          Clinical features                                      Embolism
                                                        Clinical presentation is diverse and                   Embolic phenomena are the second
Definition                                              dependent upon tumour location and to                  most common manifestation (30-40% of
Myxoma is a neoplasm composed of                        a lesser extent morphology {175,643,                   patients). Frequent sites of embolization
stellate to plump cytologically bland                   1598,1616}. About 20% of cardiac myxo-                 inclulde the central nervous system, kid-
mesenchymal cells set in a myxoid stro-                 mas are asymptomatic; they are usually                 ney, spleen and extremities. Coronary
ma.                                                     smaller than 40 mm {722,736}.                          embolism may result in myocardial
                                                                                                               infarction {524,1542}. There is some evi-
ICD-O code                       8840/0                 Cardiac symptoms                                       dence that fibrous lesions are more likely
                                                        In over 50% of patients left atrial myxo-              to produce valvular obstruction while
Epidemiology                                            mas cause symptoms of mitral valve                     polypoid and myxoid ones are more like-
Cardiac myxoma represents one of the                    stenosis or obstruction (dyspnoea and                  ly to embolize {722,736}.
most common benign cardiac tumours                      orthopnoea from pulmonary oedema or
{2013,2165}. In most surgical series, they              heart failure). Right atrial myxomas may               Systemic symptoms
account for almost 80% of cases                         obstruct the tricuspid valve and cause                 These are possibly related to IL-6 pro-
{249,1986}. In large registries and repos-              symptoms of right-sided heart failure.                 duction by tumour cells. They are seen in
itories with significant referral bias myxo-            The majority of patients have an abnor-                approximately 20% of patients and
mas represent between 20 and 40% of                     mal physical examination, most charac-                 include myalgia, muscle weakness,
primary cardiac tumours {249,1338}.                     teristically a diastolic or systolic murmur.           arthralgia, fever, fatigue and weight loss.
Patient age ranges from 2-97 years.                     A “tumour plop” may be occasionally                    Although infection of a myxoma is rare,
Mean age at presentation is 50 years                    heard in early diastole {722,1598,1616}.               when present the initial manifestations
{1133}. About 90% of individuals are                    Abnormal, but nonspecific electrocardio-               mimic those of infective endocarditis,
between the ages of 30 and 60 years                     graphic changes may be identified in 20-               and can include fever, chills, petechiae,
{2165}. A recent analysis of 1,195 indi-                40% of patients and include atrial fibrila-            subconjunctival haemorrhages, Osler
viduals with myxomas revealed that 67%                  tion or flutter and left and right bundle              nodes and positive blood culture.
were female and 33% were male {2212}.                   branch block {643,1616}. Chest                         Anaemia, leukocytosis and elevated ery-
Patients with the myxoma (Carney) com-                  roentgenograms also show only nonspe-                  throcyte sedimentation rate are the most
plex are generally younger and more                     cific findings, including cardiomegaly,                common laboratory findings {175,1616}.
often male than patients with sporadic                  chamber enlargement, and pulmonary                     Most myxomas are sporadic, although
myxomas.                                                oedema {1616}.                                         syndromic and familial cases (Carney or
                                                                                                               myxoma complex) are well recognised.
                                                                                                               In familial cases, the patients present at
                                                                                                               a younger age, they occur in unusual
                                                                                                               locations and have a higher recurrence
                                                                                                               rate than in non-familial cases
                                                                                                               {296,2114}.

                                                                                                               Imaging
                                                                                                               At echocardiography carciac myxomas
                                                                                                               typically appear as a mobile mass
                                                                                                               attached to the endocardial surface by a
                                                                                                               stalk, usually arising from the fossa
                                                                                                               ovalis. Myxomas with this appearance
                                                                                                               can be confidently diaganosed by
A                                                      B                                                       echocardiography and further imaging is
                                                                                                               not necessary {1298}. In fact, because
Fig. 4.10 Cardiac myxoma. A Long axis MRI view of the left ventricle demonstrating a well-circumscribed
myxoma (T) centered in the left atrium. The inferior portion of the mass abuts the tricuspid valve. B The      the tumours are usually small and
mass seen in the previous figure (T) originates from the atrial septum and is best demonstrated on the axial   mobile, myxomas are typically better
view. The right-sided effusion and consolidation (E) are unrelated to the myxoma (the patient had metasta-     defined by echocardiography than by
tic malignant melanoma, with an incidental cardiac myxoma).                                                    either MRI or CT, because echocardiog-

260 Tumours of the heart - Benign tumours of pluripotent mesenchyme
                                                                                                                  Myxomas are ovoid, globular, lobulated
                                                                                                                  or polypoid. They may be smooth and
                                                                                                                  glistening or have multiple papillary, vil-
                                                                                                                  lous, finger-like projections. They may be
                                                                                                                  grey white and fibrous, gelatinous and
                                                                                                                  myxoid, or a combination of both. The
                                                                                                                  papillary structures may be quite friable
                                                                                                                  increasing the risk of embolisation.
                                                                                                                  Superficial thrombi also embolize.
A                                                       B                                                         Marked variation in colour is characteris-
                                                                                                                  tic. Pale grey, pearly white or yellow
                                                                                                                  brown areas are frequently admixed with
                                                                                                                  haemorrhagic dark brown or red areas.
                                                                                                                  Tumour consistency depends on the
                                                                                                                  quantity and distribution of fibrous tissue,
                                                                                                                  and calcification. Rarely, the bulk of the
                                                                                                                  tumour becomes calcified {120,1180}.

                                                                                                                  Histopathology
                                                                                                                  The myxoma cells may be arranged
C                                                       D                                                         singly, in cords, or in vasoformative ring
                                                                                                                  structures {245,361,1625}. The cells can
                                                                                                                  be elongated, fusiform or stellate. They
                                                                                                                  contain modest amounts of eosinophilic
                                                                                                                  cytoplasm. Nuclei are oval, round, or
                                                                                                                  elongated and mitoses are very rare.
                                                                                                                  Myxoma cells have a tendency to form
                                                                                                                  primitive or differentiated vessels, reflect-
                                                                                                                  ed in expression of endothelial markers.
                                                                                                                  Less myxoid stroma often forms a halo
                                                                                                                  around the vascular formations.
E                                                       F
                                                                                                                  The stroma contains variable amounts of
Fig. 4.11 Cardiac myxoma. A This incidental finding at autopsy is a sessile smooth surfaced mass attached
                                                                                                                  proteoglycans, collagen and elastin. It
to 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-
                                                                                                                  shows strong reactivity with alcian blue,
tension. B Myxoma of the left atrium, with typical localization at the fossa ovalis. C Cut surface of a papil-    resistant to predigestion by hyaluro-
lary myxoma of the left atrium. D Papillary myxoma with necrosis, left atrium. E Left atrial myxoma after         nidase. The vessels within the tumour are
resection. F Left atrial myxoma with an old and recent haemorrhages.                                              thin-walled and lack pericytes. Occa-
                                                                                                                  sionally, cavernous vascular spaces con-
                                                                                                                  taining blood or proteinaceous material
raphy has the best spatial and temporal                  Multiple tumours occurring at sites other                are encountered. Thick walled blood ves-
resolution. If the narrow stalk is not visi-             than fossa ovalis and ventricles are gen-                sels with prominent muscular walls are
ble, the diagnosis cannot be made by                     erally found in the inherited form of car-               present predominantly at the base of
echocardiography and further imaging,                    diac myxoma. Very rarely, cardiac myxo-                  tumour and in the stalk. Extravasated red
usually MRI, is necessary to show the                    mas have also been documented to                         cells, foci of recent and organizing
tumour’s margins and to exclude tumour                   occur on valves and chordae tendineae.                   haemorrhage and hemosiderin deposi-
infiltration. At MRI and CT myxoma                                                                                tion are frequent. Hemosiderin is seen
appears as an intracavitary heteroge-                    The external appearance, consistency,                    free within the stroma, within histiocytes
neous, lobular mass. As with echocardio-                 size and weight are extremely variable.                  and myxoma cells. Variable numbers of
graphy, if the narrow stalk is visible, myx-             They may be as small as a few millime-                   lymphocytes, plasma cells, macro-
oma can be diagnosed by MRI or CT                        ters and as large as 14 cm in diameter.                  phages, dendritic cells, and mast cells
{66}.                                                    The weight ranges from 2-250 gm. Tiny                    may be present.
                                                         cardiac myxomas may be totally asymp-                    Gamna-Gandy bodies as seen in chron-
Macroscopy                                               tomatic and discovered incidentally at                   ic venous congestion of the spleen may
Cardiac myxomas are intracavitary                        surgery for another purpose or autopsy.                  be encountered infrequently. Calcifi-
masses that occur most often in the left                 Larger ones are either sessile or pedun-                 cation and metaplastic bone formation
atrium {361}. They arise from the endo-                  culated, but the site of attachment is                   may also occur. The latter are more fre-
cardium of the atrial septum near the                    always discrete and usually in the region                quent in right atrial myxomas. The sur-
fossa ovalis in 85-90% of cases. Most of                 of the fossa ovalis. Occasionally, the                   face is usually composed of a single
the remainder are located in the right atri-             stalk may be long, resulting in free mobil-              layer of flattened cells, but multilayering
um. Rarely, they arise in the ventricles.                ity of the tumour within the atrial cavity.              and tufting may occur.

                                                                                                                                      Cardiac myxoma 261
Heterologous components
Well-defined columnar epithelium, occa-
sionally forming glands occurs in about
2% of myxomas. The epithelium may
show moderate cytologic atypia, mitotic
activity and express cytokeratin. Age
and sex distribution of patients, signs
and symptoms, frequency of syndromic
association and sites of occurrence are
similar for cardiac myxoma with or with-     A                                                     B
out glands. Recognition of the glands as
a component of a myxoma is important
since these structures may be confused
with metastatic adenocarcinoma. The
glandular cells are positive for PAS-dia-
stase, alcian blue and mucicarmine; they
stain for cytokeratin (diffuse cytoplasmic
staining with antibodies to cytokeratin 7,
AE1/AE3, 4betaE12 and Cam 5.2; and
focal staining for cytokeratin 20), EMA
(diffuse cytoplasmic), and CEA (apical       C                                                     D
cell border). Reactivity for CA19.9 has
also 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 of
extramedullary haematopoiesis may be
seen in 7% of myxomas {245}. Thymic
rests have also been observed {245}.

Immunoprofile
                                             E                                                     F
The cells are cytokeratin negative, vari-
                                             Fig. 4.12 Cardiac myxoma. A Numerous rudimentary vessels. B Three stages of rudimentary vessels.
ably S-100 positive, and variably positive
                                             C A primitive endothelial marker, CD34 is often present within the central areas of the vascular structures
for smooth muscle and endothelial mark-      formed by cardiac myxoma. D Cardiac myxoma glands with PAS-positive-diastase resistant material con-
ers e.g. CD 34 and CD31 {362,1269,           sistent with mucus. E Cardiac myxoma with complex glands whose cells show moderate cytologic atypia.
1625,2013}. Calretinin is expressed in       F Cytokeratin 7 staining of a cardiac myxoma with heterologous components.
about 75% of cardiac myxomas {16}.

Histogenesis
Some years ago myxomas were consid-          histochemical properties of myxoma                     diac manifestations: abnormal skin pig-
ered nothing more than organised throm-      cells {15,16}. On the other hand, car-                 mentation (lentigines and blue nevi), cal-
bi. Their neoplastic nature is supported     diomyocyte-specific transcription factor               cifying Sertoli-Leydig testicular tumours,
by the presence of chromosomal abnor-        mRNAs have been recently found in RNA                  cutaneous myxomas, myxoid breast
malities {489}, abnormal DNA content         extracted from myxoma lysates, suggest-                fibroadenomas, pigmented adrenal corti-
{1226} and the presence of microsatellite    ing cardiomyogenic differentiation in                  cal hyperplasia, pituitary hyperactivity,
instability {1853}. The presence of het-     myxoma cells and a possible origin in                  psammomatous melanotic schwannoma
erologous elements, however, still sug-      cardiomyocite progenitor cells {1037}.                 and thyroid tumours {295}. Familial myx-
gest to some that they may be reactive or                                                           omas are estimated to account for 7% of
hamartomatous {1925}. The origin of          Genetic susceptibility                                 atrial myxomas {299}, are more often
myxoma cells is unclear. They are            Although most myxomas are sporadic,                    multiple, recurrent and right sided, as
thought to arise from subendothelial         some have been associated with the                     compared to sporadic myxomas. The
vasoformative reserve cells or primitive     myxoma complex {295,483}. This auto-                   affected patients are also younger, most
cells which reside in the fossa ovalis and   somal dominat syndrome has been                        presenting at 20-30 years of age
surrounding endocardium. The minute          reported under the acronyms NAME                       {530,1133,1544}.
endocardial structures described by          (nevi, atrial myxoma, myxoid neurofibro-
Prichard {1618} do not seem to corre-        ma, ephelides), LAMB (lentigines, atrial               Somatic genetics
spond to the hypothetical subendothelial     myxoma, mucocutaneous myxomas,                         The chromosomal patterns of sporadic
pluripotential vasoformative reserve cells   blue nevi), and more recently as Carney                cardiac myxoma are characterised by
from which the myxomas would arise,          syndrome {295,299,530}. This syndrome                  extensive intratumour heterogeneity. In
because they do not share the immuno-        includes cardiac myxomas and extracar-                 the seventeen cases published to date,

262 Tumours of the heart - Benign tumours of pluripotent mesenchyme
multiple unspecific chromosome aberra-
tions have been reported, including
dicentric chromosomes and, in particu-
lar, telomeric associations {489,497,498,
502}. Intratumour heterogeneity, as found
in a variety of tumour types and grades
{688}, is considered a sign of genetic
instability presumably resulting from dis-
ruption of genes that control genomic
integrity. Studies of cardiac myxomas        A                                                       B
suggest that the chromosomal regions
                                             Fig. 4.13 Papillary fibroelastoma. A Papillary fibroelastoma from aortic valve. Note multiple translucent pap-
12p1 and 17p1 may play a specific role       illary fronds. B Multiple papillary fibroelastomas (greater than 40) developing 17 years following open heart
in the development of these neoplasms        surgery. From A.N. Kurup et al. {1105}.
since they are frequently rearranged
{497}.
Cytogenetic analyses of three cases of       rence interval in one series was 47.8                    impractical, a cannula should be insert-
cardiac myxoma derived from patients         months {296}. The probability of recur-                  ed from the femoral vein for the inferior
with the myxoma syndrome reveal chro-        rence has been related to DNA chromo-                    vena cava. Tumour resection with the full
mosome patterns similar to those             somal pattern {296,1276}. Patients with a                thickness of the septum and patch repair
observed in sporadic cases {489,1658,        familial tumour need to followed long                    is required for tumours with a broad
1882}. Whether there is a common             term.                                                    based attachment. However, when the
genetic mechanism underlying sporadic        Embolization is the major complication of                tumour originates from the atrial wall,
and familial cardiac myxomas is unclear.     myxoma and may result in ischemic                        resection of the attachment, and 5 mm of
Based on linkage analysis, 2 loci have       symptoms in a variety of arterial beds.                  normal tissue including endocardium
been proposed for genes causally relat-      Intracranial aneurysm due to emboliza-                   and underlying myocardium are recom-
ed to the myxoma syndrome: 2p16              tion is also a rare, but potentially morbid,             mended.
{1882} and 17q2 {299}. Recently, a gene      complication. The etiology of these
located at 17q24 was cloned that             aneurysms is unclear but histologic veri-                Papillary fibroelastoma
showed mutations in myxoma patients          fication of myxoma cells in arterial walls
{122,598,1018}. This gene, PRKAR1A,          has been reported {1758}.                                Definition
represents a putative tumour suppressor                                                               An endocardial based papilloma lined by
gene, coding for the type 1 alpha regula-    Treatment                                                endothelial cells with proteoglycan rich
tory subunit of protein kinase A (CNC1,      Immediate surgical resection is advised                  avascualar stroma, usually rich in elastin.
OMIM #160980). No causal gene has            when the diagnosis of cardiac myxoma is
been identified at the 2p16 locus, and       suspected {1454}, because of the risk of                 Synonyms
some families that were initially thought    embolism {2001}. The tumour is removed                   Giant Lambl excrescence, fibroelastic
to have disease related to this locus        under cardiac arrest with cardiopul-                     papilloma
actually have chromosome 17q24               monary bypass. Minimal manipulation
PRKAR1A mutations {122}. At least one        and gentle management of the heart is                    Epidemiology
further locus remains to be identified. As   recommended so as not to precipitate                     Papillary fibroelastoma is a rare and
yet, neither mutations of PRKAR1A nor        embolism. After the tumour is resected,                  benign tumour representing less than
loss of heterozygosity of markers at 17q2    the cardiac chamber should be irrigated                  10% of primary cardiac tumours
and 2p16 have been found in sporadic         with saline solution to wash out residual                {121,247}. The true incidence is difficult
cardiac myxomas {598}.                       tumour fragments.                                        to determine, as the tumour may be over-
Flow cytometry shows abnormally high         The approach to a left atrial myxoma is                  looked and there is morphologic overlap
tetraploid DNA patterns in all cases of      usually through a vertical incision. When                with Lambl excresences, a reactive age-
syndromic myxomas, whereas in spo-           the tumour is not large, a transseptal                   related valvular lesion {249,2080} In
radic myxomas it is present only in about    approach useful, whereas a transseptal                   recent series of surgically excised car-
20%.                                         biatriotomy {516} is recommended for a                   diac tumours papillary fibroelastoma rep-
                                             large tumour. As the majority of left atrial             resents the second most frequent benign
Prognosis and predictive factors             myxomas arise from the interatrial sep-                  lesion.
There is a remarkably different prognosis    tum, the tumours can be removed en                       Papillary fibroelastoma is the most com-
between patients with sporadic and           bloc with a 5 mm margin of normal tis-                   mon primary tumour of cardiac valves. In
familial myxomas. Patients with sporadic     sue. The fossa ovalis, where the pre-                    two recent series of primary valve
tumours have a good prognosis, with 1-       tumour cells of myxomas are thought                      tumours, papillary fibroelastoma consti-
3% recurrence rate {1275,296,2227}.          likely to exist {2102}, should also be                   tuted 73% and 89% of cases {531,1714}.
However, about 10% of patients with          excised if possible. For a right atrial myx-             Mean age of the patients is 60 years
familial myxomas either have recurrent       oma, direct caval cannulation avoids                     (range, newborn to 83 years) and there is
tumours or develop another tumour in a       tumour fragmentation. When direct can-                   an equal gender predilection {1714,
different location {1276,1598}. The recur-   nulation to the inferior vena cava is                    1903}.

                                                                                                                      Papillary fibroelastoma 263
Etiology                                       Table 4.02
The histogenesis continues to be a             Immunohistochemical profile of cardiac papillary fibroelastomas.
source of controversy. Various gross,          From D. Grandmougin et al. {734}
microscopic, and molecular characteris-         Marker                       Central fibrous       Intermediate layer   Endothelial border
tics of papillary fibroelastoma have led to                                       core
the lesions’ being described as neo-
plasms, hamartomas, organized thrombi,          Vimentin                          (+)                   (+)                (+)
and unusual endocardial responses to
trauma. The histochemical presence of           S 100 Protein                     (-)                   (+)                (-)
fibrin, hyaluronic acid, and laminated
                                                CD 31                             (-)                   (-)                (+)
elastic fibers within the fronds supports
the hypothesis that papillary fibroelas-        CD 34                             (-)                   (-)                (+)
tomas may be related to organizing
thrombi. Evidence favouring the hamar-          Factor VIII                       (-)                   (-)                (+)*
toma hypothesis includes a histologic
appearance that suggests the prolifera-         CMV-LMP-1                                               (+)
tion of miniature tendinous cords and
apparent congenital papillary fibroelas-        EBV-LMP-1                                               (-)
tomas associated with other congenital
cardiac anomalies. Due to the presence          *Staining intensity decreased in comparison to the adjacent normal endocardial endothelium with an
of dendritic cells and cytomegalovirus in       immunoreactivity ratio of 0.4
the intermediate layers of some papillary
fibroelastomas, a recent study proposed
that papillary fibroelastomas may be
related to a chronic form of viral endo-       tricuspid and pulmonary valves, right                 surgically excised cases occur in
carditis {734}.                                and left atrial and ventricular endocardial           patients with symptoms related to cere-
Repetitive hemodynamic trauma may              walls, Chiari’s network, and coronary                 bral ischemia. The diagnosis is made by
contribute to their development as they        ostia {43,202,254,913,977,1179,1770,                  multiplanar transthoracic and trans-
have been reported in association with         2249}. Autopsy series show an equal                   esophageal echocardiography {713,
diseases resulting in abnormal flow of         right and left heart distribution {205,               1151,1770,2015}. High-resolution echo-
blood in the heart including rheumatic         531,1274}. However, surgical series have              cardiography shows an echolucent centre.
heart disease, hypertrophic cardiomy-          a high prevalence (81%) of left sided
opathy, mitral valve prolapse and atrial       papillary fibroelastomas because left-                Macroscopy
septal defect, among other diseases.           sided lesions are much more frequently                Papillary fibroelastomas range in size
However, the mechanisms by which such          symptomatic.                                          from 2-50 mm in greatest dimension,
hemodynamic abnormalities contribute to        Tumours are found most commonly                       although the majority are less than 10
papillary fibroelastoma growth are unclear.    (69.5%) on diseased valves - 37.8%                    mm. They are generally opalescent
There is increasing evidence that at least     post-rheumatic valves and 62.2% valves                white, but this colour may be obscured
a subset (18%) of these tumours develop        with fibrosis and calcification {1903}.               by thrombus. They are usually attached
as a result of iatrogenic factors, including   Papillary fibroelastomas have been                    to the endocardial surface by a short sin-
thoracic irradiation and open-heart sur-       likened to Lambl excrescence, but unlike              gle stalk, but those with more than one
gery (subaortic septal myectomy, valve         Lambl excrescences, which occur at the                attachment to the endocardium have
repair, valve replacement and repair of        line of closure of semilunar valves, papil-           been observed. Papillary fibroelastomas
congenital defects {1105}. In contrast to      lary fibroelastomas occur anywhere on                 have multiple papillary fronds and, par-
sporadic cases, which are most common          the valve surface.                                    ticularly when immersed in water, they
on cardiac valves, iatrogenic papillary                                                              resemble a pom-pom or sea anemone.
fibroelastomas tend to occur in a variety      Clinical features                                     Papillary fibroelastomas most often
of non-valvular endocardial surfaces,          The clinical diagnosis of papillary fibro-            occur singly (80-90%), but among
usually in close proximity to the predis-      elastoma can be difficult because                     patients with iatrogenic tumours, multiple
posing iatrogenic factor, e.g. in the          embolic complications can mimic a vari-               tumours (2 to greater than 40) occur with
chamber most closely associated with           ety of underlying diseases {1714}.                    great frequency (67%). Such tumours are
the site of surgery.                           Integrity of the superficial endothelial              less likely to occur on the valves and
                                               layer of the fronds has been demonstrat-              have been reported in a wide variety of
Localization                                   ed to be the main element leading to                  locations (on papillary muscles, tendi-
Ninety percent of papillary fibroelas-         occurrence of embolic events {734}.                   nous cords, and atrial and ventricular
tomas occur on heart valves, including         Embolism is related to the aggregation of             septal and free walls).
aortic, posterior and anterior mitral          platelets and fibrin {567,734,742}.
leaflets {531,597,842,1397,1819,2015},         Lesions adjacent to coronary ostia may                Histopathology
mitral chordae and papillary muscles           prolapse resulting in angina, syncope or              Papillary fibroelastomas have a superfi-
{313,659}. Unusual locations include the       sudden death {205,262}. The majority of               cial endothelial layer, an intermediate

264 Tumours of the heart - Benign tumours of pluripotent mesenchyme
A                                                                                  B




C                                                                                  D
Fig. 4.14 Papillary fibroelastoma. A Location at the aortic valve. B Movat pentachrome stain demonstrating an incidental papillary fibroelastoma on the surface of
the 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.


layer rich in proteoglycans and a central               Immunohistochemistry                                     trauma or dysfunction {734,1200,1703}.
avascular core. The inner layers contain                Immunohistologic studies demonstrate a                   Spindle cells in deeper layers may focal-
fibroblasts and occasional inflammatory                 disparity between surface and deeper                     ly express S100 protein. The S100 cells
cells including macrophages and den-                    layers. Surface endothelial cells express                likely represent competent antigen pre-
dritic cells {742,1703}. Elastic fibres are             vimentin and CD34 with some loss of                      senting dendritic cells. The presence of T
most prominent in the core but may be                   intensity for CD31 and factor VIII related               cells has not been investigated in these
sparse or absent in the distal parts of the             antigen in comparison to normal endo-                    regions.
papillae. Acute and organizing thrombi                  cardial endothelium. It has been pro-
may be seen on the surface and obscure                  posed that the decreased expression of
the papillary surfaces.                                 endothelial markers indicates endothelial




                                                                                                                                 Papillary fibroelastoma 265
Haemangioma                                                                                              H. Tazelaar
                                                                                                         A.P. Burke
                                                                                                         G. Watanabe
                                                                                                         C.T. Basson




Definition                                           also enhance brightly with contrast                 vessel. This lobular or grouped arrange-
Haemangiomas (angiomas) are benign                   administration {1003}. At CT the tumors             ment of vessels is helpful for distinguish-
tumours composed predominantly of                    are usually circumscribed, low attenua-             ing these benign from malignant vascu-
blood vessels. The histologic classifica-            tion, heterogeneous and also enhance                lar proliferations. Mast cells and factor
tion includes those composed of multiple             brightly with contrast administration.              XIII-positive interstitial cells are a consis-
dilated thin-walled vessels (cavernous               {737}. The circumscribed, non-infiltrative          tent feature.
type), smaller vessels resembling capillar-          appearance of haemangioma, particular-              Intramuscular cardiac haemangioma has
ies (capillary type), and dysplastic mal-            ly on MRI which is most sensitive to tis-           superficial resemblance to arteriovenous
formed arteries and veins (arterio-venous            sue infiltration, can be used to suggest            malformation, with the presence of het-
haemangioma, cirsoid aneurysm). Car-                 that the neoplasm is benign, but a spe-             erogeneous vessel types, including mus-
diac haemangiomas often have com-                    cific diagnosis cannot be made with                 cularized arteries, veins, and capillaries.
bined features of cavernous, capillary and           imaging.                                            In contrast to capillary haemangioma,
arteriovenous haemangiomas, and many                                                                     they are infiltrative lesions and occur
contain fibrous tissue and fat. These fea-           Localization                                        within the myocardium. They are histo-
tures are reminiscent of intramuscular               The most frequent locations are the later-          logically identical to intramuscular hae-
haemangiomas of skeletal muscle.                     al wall of the left ventricle (21%), the            mangiomas within skeletal muscle, and
                                                     anterior wall of the right ventricle (21%),         may possess, in addition to the vessels,
ICD-O code                      9120/0               the interventricular septum (17%) and               fat and fibrous tissue. Because of the lat-
                                                     occasionally, the right ventricular outflow         ter features, some intramuscular cardiac
Clinical features                                    tract {226}.                                        haemangiomas are misclassified as lipo-
Most cardiac haemangiomas are discov-                                                                    mas or fibrolipomas.
ered incidentally but patients may pres-             Macroscopy                                          Cavernous haemangiomas are com-
ent with dyspnoea on exertion, arrhyth-              The tumours are often large and gross               posed of large dilated vascular spaces.
mias, right-sided heart failure, pericardi-          appearance depends on the size of the               They tend to infiltrate the myocardium.
tis, pericardial effusion, and failure to            vascular spaces in the tumour. The cap-             The lining cells are bland and flattened
thrive. Patients may have associated                 illary type is frequently slightly raised           and mitotically inactive.
vascular syndomes e.g. Kasabach-                     from the endocardial sruface and
Merritt {675}.                                       appears red to purple. Intramuscular                Genetic susceptibility
                                                     types will appear infiltrative. Cavernous           Genetic susceptibility to cardiac hae-
Imaging                                              haemangiomas are usually large and are              mangiomas has not been identified.
At echocardiography, haemangiomas                    also poorly circumscribed.                          Extracardiac haemangiomas occur in a
are usually hyperechoic, circumscribed,                                                                  variety of contexts. They may be single
and intracavitary solitary masss. At MRI,            Histopathology                                      sporadic lesions or multiple lesions that
hemaniogmas may be intermediate to                   Capillary haemangiomas are composed                 are components of complex genetic syn-
high on T1 weighted images, often are                of nodules of small capillary-size vessels,         dromes. Capillary haemangiomas occur
very intense on T2 weighted images, and              each of which is subserved by a “feeder”            in up to 10% of live births and are the
                                                                                                         most frequent tumour in newborns
                                                                                                         {1409}. When these tumours occur in the
                                                                                                         absence of associated syndromes, they
                                                                                                         may represent manifestations of an auto-
                                                                                                         somal dominant mendelian trait (OMIM
                                                                                                         #602089) {7}. Linkage analyses {224,
                                                                                                         2101} of multiplex kindreds affected by
                                                                                                         hereditary capillary haemangiomas have
                                                                                                         identified loci on chromosome 5 (q31-
                                                                                                         q33 and q13-q22) that appear to contain
                                                                                                         as yet unidentified causal disease
A                                                   B                                                    genes.
Fig. 4.15 Cardiac haemangioma. A MRI of right atrial haemangioma in a newborn who underwent partial      A wide array of complex syndromes,
surgical resection of the tumor. ECG-triggered breath-hold T2-weighted fast spin echo sequence shows a   such as von Hippel Lindau syndrome
markedly hyperintense signal from the tumor (arrow). B Echocardiographic imaging of cardiac haeman-      (OMIM #193300) and SC phocomelia/
gioma involving the interventricular septum in a 7-year-old boy.                                         Roberts syndrome (OMIM #269000), that

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

Somatic genetics
Specific genes have been associated
with two disorders involving arteriove-
nous malformations. Mutations in the          Fig. 4.16 Haemangioma. This lesion has some features of arteriovenous malformation, with a non-uniform
gene on chromosome 9p21 encoding the          collection of thick walled arteries, dilated veins and capillaries. In addition, there is fat and fibrous tissue,
endothelial cell-specific receptor tyrosine   as ooccasionally seen in an intramuscular haemangioma.
kinase TIE2 cause the autosomal domi-
nant Bean or “Blue rubber-bleb nevus”
syndrome (OMIM #112200) and familial
multiple cutaneous and mucosal venous
malformations (OMIM#600195) {2084}. At
least some cases of hereditary cerebral
cavernous       malformations       (OMIM
#116860) are caused by mutations in the
chromosome 7q21-q22 Krev interaction
trapped-1, KRIT-1, gene {1110}. KRIT1
normal binds to RAP1A, a Ras GTPase,
and the disease causing mutations
appear to disrupt these interactions.
Other genetic loci for this disorder have
been identified at chromosomes 17p15-
p13 and 3q25.2-q27 and remain to be
studied. The genetic and clinical relation-
ship of this disorder to hereditary neuro-
cutaneous angioma (OMIM #106070) is
unclear.

Syndromic associations
                                              Fig. 4.17 Haemangioma. This tumor shows a relatively uniform population of capillary type vessels with vari-
The majority of cardiac haemangiomas
                                              able degrees of dilatation. The myxoid background may suggest myxoma, but other features of myxoma are
are sporadic, without evidence of extrac-
                                              absent, and the vessels are mature.
ardiac vascular lesions. Rarely, there
may be extracardiac haemangiomas of
the gastrointestinal tract and port-wine
stain of the face. Giant cardiac haeman-
giomas can result in thrombosis and
coagulopathies (Kasabach-Merritt syn-
drome) {239,675}.




                                                                                                                                    Haemangioma 267
Benign tumours with myofibroblastic                                                                             E. Dulmet
                                                                                                                A.P. Burke
                                                                                                                                           V. T. de Montpréville
                                                                                                                                                    C.T. Basson
differentiation                                                                                                 T. Geva
                                                                                                                H. Kamiya
                                                                                                                                                   G. Watanabe
                                                                                                                                                      P.A. Araoz
                                                                                                                H. Tazelaar



Cardiac fibroma                                        other common locations. Atrial fibromas
                                                       are quite rare.
Definition
Fibroma is a rare primary heart tumour                 Clinical features
composed of fibroblasts or myofibrob-                  One-third of cardiac fibromas cause
lasts with a matrix containing collagen. It            symptoms because of their mass effect,
almost exclusively occurs within the                   either through obstruction of blood flow
myocardium of the ventricles or ventricu-              or interference with valvular function and
lar septum. It is not clear whether it is a            patients present with cardiac failure or
hamartoma or a true neoplasm. Because                  cyanosis. In another third of the cases,                   A
most cases occur in infants and children               cardiac fibromas, whatever their location,
it is likely congenital.                               cause significant arrhythmias, syncope
                                                       or sudden death. The remaining patients
ICD-O code                       8810/0                are asymptomatic and tumours are dis-
                                                       covered because of heart murmur or a
Synonyms                                               radiographic abnormality. Embolic phe-
Fibroelastic hamartoma, fibrous hamar-                 nomena are not a feature of cardiac fibro-
toma.                                                  mas {121,134,538,737,1944}.

Epidemiology                                           Imaging
Most cardiac fibromas are discovered in                At echocardiography fibromas typically
                                                                                                                  B
children and often before one year of age              appear as a large, well-circumscribed,                   Fig. 4.19 Cardiac fibroma. A The tumour fills the left
{737,1944}. Prenatal diagnosis with                    solitary mass in the septum or ventricular               ventricular cavity, which is obliterated. The right
                                                                                                                ventricle and tricuspid valve are on the left.
sonography is possible {121,134,538}.                  free wall {1010,1242} and in some cases
                                                                                                                B Cardiac fibroma with prominent whorled sur-
However, cases are also reported in                    may be confused with hypertrophic car-                   face.
adults {307} and even as an incidental                 diomyopathy {66}. The tumors are fre-
finding in the elderly {2093}. There is no             quently very large and may cause
sex predominance. The incidence is very                obstruction, which can be assessed by                   enhanced imaging usually demonstrates
low with only about 200 cases reported                 colour Doppler. MRI likewise shows a                    a hypoperfused tumour core. CT also
to date.                                               large, solitary, homogeneous myocardial                 shows a large, solitary, ventricular mass,
                                                       mass centered in the ventricles {1003,                  which is usually low attenuation on CT.
Localization                                           1215,1660}. Because of the fibrous                      Unlike other imaging modalities CT may
The most common site of cardiac fibro-                 nature of the tumour, the signal intensity              detect calcification which is a helpful fea-
ma is the ventricular septum, but the free             is often less than that of adjacent unin-               ture in making a confident diagnosis.
walls of the left and right ventricle are              volved myocardium, and contrast-                        {66}. Overall, the imaging finding of a




A                                                      B                                                      C
Fig. 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 inversion
recovery 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.


268 Tumours of the heart - Benign tumours with myofibroblastic differentiation
                                                                                                            ages, but is somewhat more common in
                                                                                                            older individuals. Wavy elastic fibers are
                                                                                                            frequent and may be prominent. Focal
                                                                                                            myxoid change in the stroma and chron-
                                                                                                            ic inflammation may also be present
                                                                                                            {244}.

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

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

                                                                                                            Genetic susceptibility
                                                                                                            Approximately 3% of patients with Gorlin
                                                                                                            syndrome have cardiac fibromas {418,
                                                                                                            547,716}. Gorlin syndrome (or nevoid
                                                                                                            basal cell carcinoma syndrome) is an
                                                                                                            autosomal dominant disorder character-
                                                                                                            ized by generalized body overgrowth,
                                                                                                            jaw keratocysts, developmental abnor-
                                                                                                            malities of the skeleton, and a predispo-
                                                                                                            sition to neoplasms, specifically cardiac
                                                                                                            fibroma. Gorlin syndrome results from
                                                                                                            germline mutations in the PTC gene,
                                                                                                            which maps to chromosome 9q22.3 and
B                                                                                                           is homologous to the Drosophila patched
Fig. 4.20 Cardiac fibroma. A Fibroma infiltration into adjacent myocardium. B Calcifications in a fibrous
                                                                                                            (ptc) gene {756}. The ptc gene encodes
lesion from a 19-year-old patient.
                                                                                                            a transmembrane protein in Drosophila
                                                                                                            that represses the Hedgehog signaling
solitary, very large, hypovascular mass in a          bundles. They are not encapsulated and                pathway to control cell fate, growth, and
child is suggestive of a cardiac fibroma.             extend into the surrounding myocardium.               development {756,893}. These data sug-
                                                      Even in grossly circumscribed cases,                  gest that the PTC gene not only functions
Macroscopy                                            entrapped myocytes can often be seen                  as a tumour suppressor gene, but also
They are typically rounded masses that                deep within the tumours, far from the                 plays a critical role in development.
are fibrous, white and whorled, reminis-              gross margins {244,451}. The fibroma                  However, the precise role of the PTC
cent of uterine leimyomas. The margin                 cells have oval or tapered nuclei without             gene in myocardial cell growth and dif-
may be either circumscribed or infiltra-              nucleoli. Their cytoplasm is pale. These              ferentiation and its role in the develop-
tive. In some cases, fibromas are mas-                cells are associated with abundant col-               ment of cardiac fibroma remains to be
sive and can obliterate ventricular cavi-             lagenous stroma, which increases with                 defined {2077}.
ties. They are nearly always mural,                   the age of the patient. Cellular lesions are          Associated hydrocephalus, cleft lip and
although polypoid endocardial based                   observed in infants during their first                palate, and Sotos syndrome (megalen-
lesions have been reported. Most occur                months of life, while fibromas in older               cephaly with gigantism) have been
singly. The mean diameter is 5 cm.                    patients contain large amounts of colla-              reported {446,1242}.
                                                      gen. Mitoses and foci of extramedullary
Histopathology                                        haematopoiesis may be present in cellu-               Prognosis and predictive factors
Fibromas are composed of bland-looking                lar tumours {451}. Calcification is                   The cardiac fibroma is benign, but its
spindle cells forming loose intersecting              observed in lesions from patients of all              nature of slow but continuous growth

                                                                                                                                Cardiac fibroma 269
may cause conduction defects and
arrhythmias. Extension into the ventricu-
lar free walls may result in atrioventricular
valve inflow or arterial outflow obstruc-
tion. Spontaneous regression as can
occur with congenital rhabdomyoma has
not been observed.

Treatment
Operative intervention is usually required
{451,615,2071}. When the tumour proves
unresectable, heart transplantation is an
option {731,2071}. However, favourable
late results even after incomplete exci-
sion have been reported {132,307,1880}.


Inflammatory myofibroblastic
tumour

Definition                                      Fig. 4.21 Inflammatory myofibroblastic tumour of the left ventricle. Plump spindle cells are arranged in a
Inflammatory myofibroblastic tumour is          haphazard fashion and focally surround myocytes. A modest chronic inflammatory cell infiltrate including
composed of myofibroblasts accompa-             plasma cells is also present.
nied by a variable number of inflammato-
ry cells including lymphocytes, macro-
phages, plasma cells and eosinophils.           inflammatory myofibroblastic tumour has                100 protein and p53. It is unknown if
                                                been reported in a patient with systemic               ALK-1 expression is diagnostically useful
ICD-O code                   8825/1             vasculitis and another tumour regressed                in cardiac inflammatory myofibroblastic
                                                spontaneously.                                         tumours as is the case with extracardiac
Synonyms                                                                                               tumours.
Plasma cell granuloma, inflammatory             Macroscopy
pseudotumour and possibly inflammato-           Inflammatory myofibroblastic tumours of                Differential diagnosis
ry fibrosarcoma                                 the heart are large lesions, measuring up              In contrast to fibromas, inflammatory
                                                to 8 cm {451}. Grossly, they tend to have              myofibroblastic tumours are endocardial
Epidemiology                                    relatively narrow attachments to the                   lesions, and there is often organizing fib-
These tumours are very rare in the heart,       endocardium and project into the ven-                  rin thrombus on the surface. In addition
and only small series and case reports          tricular lumen.                                        the tumours are more histologically vari-
appear in the literature.                                                                              able, the spindle cells are larger than in
                                                Histopathology                                         fibromas and the cells often have nucleoli.
Localization                                    Inflammatory myofibroblastic tumor is
Although there is a predilection for the        composed of spindled myofibroblasts,                   Prognosis and predictive factors
ventricles, especially the right ventricular    fibroblasts, chronic inflammatory cells                The biologic behavior of inflammatory
outflow tract, any site in the heart may be     and sometimes eosinophils. Various                     myofibroblastic tumour is that of a low-
involved {1177}.                                combinations of these cell types make                  grade lesion with the propensity for recur-
                                                these tumours quite variable from one                  rence, but overt malignancy is rare. No
Clinical features                               case to another Occasional mitoses and                 case of metastases arising from cardiac
Signs and symptoms                              foci of necrosis may be present.                       inflammatory myofibroblastic tumour has
There are no specific signs or symptoms                                                                been reported.
related to cardiac inflammatory myofi-          Immunoprofile
broblastic tumour, as these are related to      The tumour cells strongly express actin
location within the heart. One cardiac          and vimentin, but not desmin, CD34, S-




270 Tumours of the heart - Benign tumours with myofibroblastic differentiation
Cardiac lipoma                                                                                         A.P. Burke
                                                                                                       P.A. Araoz




Definition
Benign tumour composed of mature,
white adipocytes.

ICD-O code                       8850/0

Epidemiology
Cardiac lipoma is rare and found in fewer
than 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 up
to 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 heart
                                                    Fig. 4.23 Lipomatous hypertrophy. Lipomatous hypertrophy of atrial septum. Note the multivacuolated
tumours similar to the relative incidence
                                                    adipocytes which can mimic liposarcoma.
in adults {134}.

Localization                                        the latter site, the designation “fibrolipo-       Histopathology
Cardiac lipomas may occur anywhere in               ma” has been used {149,280,1562}.                  Similar to extracardiac lipomas, cardiac
the heart. There is a predilection for the                                                             lipomas are circumscribed masses of
pericardium and epicardial surfaces                 Clinical features                                  mature adipocytes. Unusual histologic
{540,1125,1628,2060}, where they may                As is the case with other heart tumours,           variants of lipoma have not been
attain enormous sizes. Other sites                  the presentation is varied, and depends            described in the heart, with the excep-
include the ventricular septum {1869},              on location. Many cardiac lipomas are              tion of pediatric cardiac lipoblastoma in a
and cardiac valves. When they involve               incidental findings, or cause a variety of         child, which possessed immature and
                                                    arrhythmias, syncope and electrocardio-            mature adipocytes, with focal vascular
                                                    graphic abnormalities {342,638,1383,               myxoid areas containing lipoblasts {500}.
                                                    1562,1735}. Rarely, outflow tract obstruc-
                                                    tion may occur {1869}. Computed                    Differential diagnosis
                                                    tomography and magnetic resonance                  The main differential is lipomatous hyper-
                                                    imaging may establish the fatty nature of          trophy, a non-encapsulated lesion com-
                                                    the tumour {1383}. Recurrences are rare            posed of mature fat and adipocytes
                                                    {2146}.                                            resembling brown fat cells intermixed
                                                                                                       with enlarged cardiac myocytes occur-
                                                    Imaging                                            ring solely in the interatrial septum.
                                                    The echocardiographic appearance of                Lipomatous hypertrophy is most often an
                                                    cardiac lipomas varies with their location.        incidental finding at autopsy, but may
                                                    Lipomas in the pericardial space have              uncommonly be the cause of unex-
                                                    variable echogenecity but are often                plained atrial arrhythmias, congestive
                                                    hypoechogenic, while intracavitary lipo-           heart failure, or superior vena cava
                                                    mas are typically echogenic {66}. The              obstruction {242,365}.
                                                    reason for this difference is unknown. At          The differential diagnosis also includes
                                                    echocardiography, intracavitary lipomas            the intramuscular variant of haeman-
                                                    are usually circumscribed but cannot be            gioma, which may contain variable num-
                                                    differentiated from other circumscribed            bers of adipocytes.
                                                    cardiac masses. However, MRI and CT
                                                    both allow for very specific identification
                                                    of fat and therefore can be used to defin-
Fig. 4.22 Lipomatous hypertophy of atrial septum.   itively diagnose lipomas {66}.

                                                                                                                               Cardiac lipoma 271
Cystic tumour of atrioventricular node                                                      A.P. Burke
                                                                                            P.A. Araoz




Definition                                    in advanced years occurs, the congeni-        valves. Tumour cells occur in nests or
Congenital multicystic tumour or rest         tal nature is not proved in all. Evidence     line the variably sized cystic spaces.
located at the base of the atrial septum in   that limited cell proliferation occurs in     Cells can interdigitate with myocytes
the region of the atrioventricular node.      some cases may explain presentation           within the inferior septum, resulting in
Lining cells may be derived from primi-       later in life, and patients may live for      degenerative changes within the
tive endoderm.                                decades with complete heart block {64}.       myocytes. Cells may be cuboidal, transi-
                                                                                            tional, squamoid or show sebaceous dif-
ICD-O code                  8454/0            Localization                                  ferentiation. Multilayering may occur
                                              By definition they occur adjacent to the      along the cyst walls {240,1157,1189}.
Synonyms                                      atrioventricular node. Similar lesions
Mesothelioma of atrioventricular node,        have not been described elsewhere in          Immunohistochemistry
lymphangioma, endothelioma, inclusion         the body.                                     The cells strongly express cytokeratin,
cyst, Tawarian node, benign mesothe-                                                        epithelial membrane antigen, carcinoem-
lioma of Mahaim, endodermal rest, con-        Clinical features                             bryonic antigen and B72.3. Cells may
genital polycystic tumour of atrioventricu-   Two-thirds of patients present with com-      also express calcitonin and serotonin.
lar node, intracardiac endodermal het-        plete heart block, 15% with lesser            {465,523,1173,1345}.
erotopia.                                     degress of atrioventricular block, and
                                              10% with sudden death without docu-           Electron microscopy
Epidemiology                                  mented history of heart block {240}. The      Two cells types are characteristic. Within
The mean age at presentation is 38 years      remainder are incidental findings in new-     the solid nests, cells have well formed
(range birth- 78 years) and women are         borns and infants with structural heart       basement membrane, cytoplasmic
more frequently affected than men             defects. Only rarely are atrioventricular     tonofilaments and desmosomes. Cells
(approximately 3:1). One patient with         nodal tumours detected in patients with       lining the spaces are also connected by
long standing heart block survived to         normal sinus rhythm. Most tumours have        desmosomes, have short microvilli and
age 95, at which time the diagnosis was       first been diagnosed at autopsy but in        may contain electron dense material
made at autopsy {64}.                         vivo diagnosis has been reported {102}.       {240}.

Etiology                                      Macroscopy                                    Prognosis
Because most patients have a history of       They range in size from 2-20 mm and are       The tumours are benign neoplasms but
congenital heart block, they likely are       multicystic, the cysts often barely per-      may result in significant arrythmias or
congenital rests. In 10% of patients the      ceptible.                                     sudden death. Surgical excision has
tumours occur in association with other                                                     been reported in a few patients
midline defects {240,1189,1617,1719,          Histopathology                                {951,1541}.
2021}. The precise intrauterine migration     They arise in the inferior interatrial sep-
defect is unknown. The cell of origin is      tum and generally respect the bound-
foregut endoderm, not mesothelium as          aries of the central fibrous body, and do
previously believed. Because diagnosis        not involve ventricular myocardium or the




272 Tumours of the heart - Cystic tumour of atrioventricular node
Cardiac sarcomas                                                                                                  A.P. Burke
                                                                                                                  H. Tazelaar
                                                                                                                                                      J.P. Veinot
                                                                                                                                                      R. Virmani
                                                                                                                  J.W. Butany                         H. Kamiya
                                                                                                                  D. El-Demellawy                  G. Watanabe
                                                                                                                  R. Loire                      D. Grandmougin
                                                                                                                  T. Geva                           M. Horimoto
                                                                                                                  F. Bonilla                           H. Hiraga
                                                                                                                  J.R. Galvin



Angiosarcoma                                            co-involvement of the right ventricle                    The predominant right-sided location
                                                        (6.5%), pericardium (6.5%), and the left                 allows for diagnosis by endomyocardial
Definition                                              atrium (0.9%) {1653}.                                    biopsy, generally out of reach of other
Angiosarcoma is a malignant tumour                                                                               sarcoma types (which have a predilec-
whose cells display endothelial differenti-             Clinical features                                        tion for the left atrium). Sometimes the
ation.                                                  Signs and symptoms                                       neoplasm remains undiagnosed in life
                                                        Clinical features reflect location, size and             due to the absence of specific symp-
ICD-O code                        9120/3                the extent of regional involvement, and                  toms.
                                                        the presence or absence of metastases
Synonyms                                                {259}. Most are initially silent. Because of             Imaging
Haemangioendothelioma,      malignant                   frequent pericardial involvement {1653},                 At echocardiography angiosarcomas
haemangioendothelioma,        haeman-                   dyspnoea is not an early symptom as is                   typically appear as an echogenic, nodu-
giosarcoma, haemangioendothelial sar-                   the case with other cardiac sarcomas.                    lar or lobulated mass in the right atrium.
coma, malignant haemangioma and                         The most common presenting symptom                       Pericardial effusion or direct pericardial
malignant angioendothelioma {1179}.                     is chest pain (46%) {259}. Right-sided                   extension/invasion are frequently seen
                                                        heart failure, often associated with hemo-               {66}. At MRI angiosarcoma also usually
Epidemiology                                            pericardium and supraventricular arrhyth                 appears as a heterogeneous, nodular
Angiosarcomas are the most common                       mias are also frequent {1128A, 1398A}. A                 mass in the right atrium. MRI imaging
malignant differentiated cardiac neo-                   significant number of patients present                   sequences sensitive for hemorrhage (T1
plasms {259,691}. They occur over a                     with or have co-existent haemorrhagic                    weighted images) may show areas of
wide age range (36 months to 80 years)                  episodes, coagulopathy, anaemia, per-                    hemorrhage which may be diffuse or
{259,1693} with a peak incidence in the                 sistent haematomas or easy bruisability                  nodular {65}. After administration of intra-
fourth decade. It occurs with equal fre-                {25}. Sometimes, early pericardial                       venous contrast (gadolinium-DTPA)
quency in men and women.                                involvement may lead to pericardial                      enhancement along vascular lakes may
                                                        biopsy during emergency surgical car-                    be seen which has been described as a
Localization                                            diac decompression for tamponade.                        “sunray” appearance {527}. Like echo-
It most often arises in the right atrium                Cardiac rupture may occur, but is rare.                  cardiography, MRI may also show peri-
near the atrioventricular groove (80%),                 Presentation with lung metastases is not                 cardial effusion or direct pericardial inva-
but has been reported in the other three                uncommon {23,186,2216}. In 10% of                        sion, though MRI is more sensitive than
chambers as well as in the pericardium                  cases, fever, weight loss, and fatigue                   echocardiography for distinguishing
{921,1654}. Left atrial involvement is                  remain unexplained for several months,                   between pericardial fluid and pericardial
unusual though it has been reported                     resulting in delayed diagnosis, large                    tumour. CT findings are similar to the MRI
{203,478,799}. In one series the right atri-            tumour size, and advanced stage when                     findings. CT usually shows a heteroge-
um was involved in 55.6% and showed                     surgery is performed.                                    neous, nodular mass in the right atrium




A                                                       B                                                       C
Fig. 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 the
lung, forming multiple haemorrhagic subpleural nodules (courtesy of Dr. William D. Edwards).


                                                                                                                                       Cardiac sarcomas 273
                                                                                                           Histopathology
                                                                                                           Over two-thirds of cardiac angiosarco-
                                                                                                           mas are well to moderately differentiated
                                                                                                           showing well-formed vascular channels
                                                                                                           and papillary structures. The vascular
                                                                                                           channels are irregular, anastomosing,
                                                                                                           and sinusoidal. The lining cells are usual-
                                                                                                           ly pleomorphic and atypical. They may
                                                                                                           form cord-like structures in which lumina
                                                                                                           are difficult to demonstrate. Mitoses are
                                                                                                           usually present {249,259,590}. The
                                                                                                           remaining third are poorly differentiated
                                                                                                           and composed predominantly of
                                                                                                           anaplastic spindle cells. In angiosarco-
A                                                                                                          ma with a focal or dominant spindle cell
                                                                                                           pattern, poorly formed vascular channels
                                                                                                           and extravascular red blood cells can
                                                                                                           usually be identified focally. Generous
                                                                                                           sampling may be necessary in order to
                                                                                                           identify diagnostic areas in such cases
                                                                                                           {249}. Often, metastatic as opposed to
                                                                                                           primary lesions, show areas of better dif-
                                                                                                           ferentiation. Angiosarcoma with a solid
                                                                                                           pattern of growth and individual cells
                                                                                                           having epithelioid features have been
                                                                                                           reported {2059}. In these cases the neo-
                                                                                                           plastic cells have eosinophilic cytoplasm
                                                                                                           with occasional cytoplasmic vacuoles.
                                                                                                           The nuclei in this variety are usually
                                                                                                           large, hyperchromatic and have promi-
B                                                                                                          nent eosinophilic nucleoli. The stroma
Fig. 4.25 Cardiac angiosarcoma. A Cardiac angiosarcoma with papillary features. Serpiginous and gaping     can be abundant and hyalinized.
vascular spaces lined by plump hyperchromatic endothelial cells. B Cardiac angiosarcoma with irregular
vascular spaces lined by atypical hyperchromatic, somewhat epithelioid endothelial cells.                  Immunoprofile
                                                                                                           Immunohistochemical staining is impor-
                                                                                                           tant for the definitive diagnosis of vascu-
with possible pericardial effusion or inva-          and hence a hemorrhagic pericardial                   lar lesions, especially those with poorly
sion. At CT angiosarcomas are usually                effusion is a frequent accompaniment.                 differentiated patterns in which vascular
low attenuation due to necrosis but may              While involvement of the tricuspid valve              channels are difficult to identify. Most
have focal high areas of attenuation due             and extension or invasion of the vena                 angiosarcomas express, to variable
to hemorrhage. CT may show a similar                 cavae is reported, involvement of the pul-            degrees, usual endothelial cell antigens
pattern of contrast enhancement as MRI.              monary artery and interatrial septum are              including factor VIII (von Willebrand fac-
With MRI or CT, the presence of a hem-               unusual. In rare instances, the pericardi-            tor), CD31 and CD34. Of these, CD31
orrhagic, irregular right atrial mass is             um is the sole site of involvement.                   gives the most consistent results, has
very suggestive of angiosarcoma, espe-                                                                     good specificity and excellent sensitivity
cially if accompanied by a pericardial                                                                     (approximately         90%)    {462,2119}.
effusion {66}.                                                                                             Vascular channels may be highlighted by
                                                                                                           the use of laminin and type IV collagen.
Macroscopy                                                                                                 Cytokeratin and epithelial membrane
Angiosarcomas usually form lobulated                                                                       antigen may be focally positive in con-
variegated masses in the right atrial wall,                                                                ventional angiosarcoma and may be dif-
protruding into the chamber. They range                                                                    fusely positive in epitheloid angiosarco-
from 2.0 cm to several centimeters. The                                                                    mas {2247}.
masses are classically dark, grey-brown
to black in colour and may resemble a                                                                      Electron microscopy
melanoma {249}, but tumours with less                                                                      With the wide availability of immunohisto-
well-developed vascular spaces may                                                                         chemistry, ultrastructural study is less
appear firm, yellow-white in colour, lack-                                                                 critical for diagnosis. The classic ultra-
ing the classic hemorrhagic appearance.              Fig. 4.26 Epithelioid angiosarcoma. Note the promi-   structural feature of endothelial cells, the
The pericardium is frequently involved               nent eosinophilic cytoplasm (arrows).                 Weibel-Palade body, is not demonstrable

274 Tumours of the heart - Sarcomas
in most neoplastic cells. However,                                                                   Epithelioid
pinocytotic vesicles, abundant interme-                                                              haemangioendothelioma
diate filaments, and a moderate amount
of rough endoplasmic reticulum and                                                                   Definition
Golgi apparatus may be identified.                                                                   Epithelioid haemangioendothelioma is a
Pericytes may be demonstrated adjacent                                                               vascular tumour composed of epithelioid
to tumour cells {1291}.                                                                              cells arranged in short strands or solid
                                                                                                     nests. The constituent endothelial cells
Differential diagnosis                                                                               are round or oval, contain small intracel-
In cases with a dominant spindle cell pat-                                                           lular lumina, and frequently infiltrate mus-
tern distinction from an unclassified spin-    Fig. 4.27 Epithelioid haemangioendothelioma.          cular walls of vessels.
dle cell sarcoma, fibrosarcoma or malig-       There are cords of tumor cells arranged circumfer-
nant fibrous histiocytoma may be diffi-        entially within a vessel wall. The cells show focal   ICD-O code                  9133/3
cult. The detection of endothelial vac-        vacuolization, representing intracytoplasmic vas-
uoles or papillary structures are helpful.     cular lumina.                                         Epidemiology
Immunohistochemical stains for laminin,                                                              Fewer than five have been reported in
type IV collagen and even reticulin stains     transition at the first base of codon 13,             the heart {26,249,1241}. Epithelioid hae-
may help highlight the vascular lumina         which resulted in one amino acid substi-              mangioendothelioma has been reported
{545}. The increasing incidence of             tution (Gly-13-Ser), in 2 relatively young            in association with myelodysplastic syn-
Kaposi sarcoma makes differentiation           patients (31 and 36 years old).                       drome {26}.
from the spindle cell areas of angiosar-
coma essential, though cardiac Kaposi          Prognosis and predictive factors                      Histopathology
sarcoma is usually metastatic.                 Cardiac angiosarcomas have an espe-                   The intracellular lumens of epithelioid
Pericardial angiosarcomas can be mis-          cially poor prognosis because they typi-              haemangioendothelioma may mimic the
taken for mesotheliomas {1277} and             cally present in the face of advanced                 vacuoles of adenocarcinoma, which may
clumps of reactive mesothelial cells may       disease {249}. In one study, 80% of                   be initially considered in the microscopic
be trapped in areas of an angiosarcoma.        patients had metastatic disease at the                differential diagnosis. Immuno-histo-
Stains for cytokeratin, calretinin, cytoker-   time of diagnosis and 90% survived less               chemical stains for factor VIII-related
atin 5/6 and CD31 can help to differenti-      than nine months {921}. A mean survival               antigen, CD31, or CD34 identify the cells
ate the two populations of cells.              of ten months after surgical excision, with           as endothelial. The differential diagnosis
                                               or without adjuvant therapy, has been                 also includes epithelioid haemangioma,
Genetics                                       reported in another study {823}. In soft              a tumour even rarer as a cardiac primary
Genetics studies involving cardiac             tissue angiosarcomas, morphologic fea-                {453}.
angiosarcomas are rare and they only           tures that have statistically correlated
analyze isolated patients with heart pri-      with poor outcome include age, large                  Prognosis
mary tumours. Cytogenetic analyses of          size and high proliferative (Ki-67) index             Approximately 10% of extracardiac hae-
cardiac angiosarcoma show no consis-           {478,590}. Metastases occur most fre-                 mangioendotheliomas develop metas-
tent chromosomal abnormality {590}. A          quently to the lung (70%), then liver. No             tases, and up to one third recur. The bio-
case of right atrial angiosarcoma demon-       significant correlation has been reported             logic behaviour of epithelioid haeman-
strated hyperdiploid clonal populations        between DNA ploidy patterns and clinical              gioendotheliomas of the heart is
with changes in chromosome number, as          outcome {590}.                                        unknown. They should be considered
follows: 55, XY, +der (1;17) (q10:q10),                                                              low-grade malignant, based on available
+2,+7, +8, +19, +20, +21, +22, as well         Treatment                                             data on histologically similar extracar-
as polysomy of chromosome 8 {2247}.            There are no randomized treatment trials,             diac tumours, and a case report of a
Other chromosomal changes reported             but patients are generally treated by a               tumour that developed distant metas-
are gains of 5pter-p11, 8p12-qter,             combination of surgery and radiation                  tases {1241}.
20pter-q12 and losses of 4p, 7p15-pter-y       with or without sarcoma-type chemothera-
and abnormalities involving 22q                py. Surgical resection is necessary, but
{310,590}. Molecular analyses on tumour        complete excision cannot be achieved in
tissues have focused on genetic alter-         most cases, because lack of a dissection
ations of TP53 and K-ras. The few reports      plane and myocardial encroachment of
available show that TP53 is more fre-          tumoural tissue. However, even partial
quently altered than K-ras. Mutations of       resection (with possible valve repair)
the TP53 tumour suppressor gene have           may provide some months of symptom-
been revealed by PCR-SSCP and                  free survival. However, local recurrence
sequencing studies and by immunohis-           is the rule, even when resection was
tochemical staining in up to 50% of            thought to be complete. Heart transplan-
tumours studied {662,1428,2247}. A K-          tation has been used to treat cardiac
ras mutation has also been documented          angiosarcoma, but without long-term sur-
in heart angiosarcoma {662}: a G-to-A          vival {1654, 2043}.

                                                                                                     Epithelioid haemangioendothelioma 275
A                                                     B                                                      C
Fig. 4.28 Malignant fibrous histiocytoma. A Primary malignant fibrous histiocytoma with ossesous differentiation (osteosarcoma). B Malignant fibrous histiocytoma
with osseous differentiation (osteosarcoma). C Large nodules in the right atrium.


Pleomorphic malignant fibrous                          In a recent review, 81% of 47 cases were                majority occur in the left atrium, where
histiocytoma (MFH) /                                   left atrial {1508}. The other reported loca-            they most often present like cardiac myx-
Undifferentiated pleomorphic                           tions included the pericardial space (3                 omas, they more commonly arise along
sarcoma                                                cases), right ventricle/ pulmonary valve                the posterior wall in comparison to the
                                                       (3 cases), right atrium (1 case), and left              septum {1056,1142,1526}.
Definition                                             ventricle (1 case) {1508}. Although the
Malignant fibrous histiocytoma or undif-
ferentiated plemorphic sarcoma is high-
grade malignancy showing fibroblastic
or myobroblastic differentiation and
areas of marked cellular pleomorphism.
Malignant fibrous histiocytomas and
fibrosarcomas represent a broad spec-
trum of mesenchymal tumours and the
degree of cellular pleomorphism is the
major distinguishing feature.

ICD-O code
Malignant fibrous                                      A                                                      B
histiocytoma                     8830/3

Synonym
Malignant fibrous histiocytoma is now
regarded as synonymous with undiffer-
entiated pleomorphic sarcoma, as many
tumours formerly classified as MFH have
been found to have evidence of myo-
genic or other more specific differentia-
tion.
                                                       C                                                      D
Epidemiology
Malignant fibrous histiocytoma, as histor-
ically defined, is the second most com-
mon malignant cardiac sarcoma in adults
and, if considered with all undifferentiat-
ed sarcomas represents the most com-
mon sarcoma. There is no gender
predilection and the mean age is around
45 years (range, 20-80 years). Rare
cases have been reported in infants.                   E                                                      F
                                                       Fig. 4.29 Malignant fibrous histiocytoma (pleomorphic undifferentiated sarcoma). A In this example, there
Localization                                           is a myxoid background and a prominent vascular pattern reminiscent of myxoid malignant fibrous histio-
Malignant fibrous histiocytoma tends to                cytoma found in soft tissue. B Malignant fibrous histiocytoma arising in left atrium where it initially mim-
be located in the left atrium of the heart,            icked a cardiac myxoma. Note mitotic activity. C Note pleomorphic growth pattern. D Malignant fibrous
most commonly the posterior wall and /                 histiocytoma with osseous differentiation (osteosarcoma). Note formation of the mature bone trabeculae.
or interatrial septum {1056,1142,1526}.                E Osteoid formation. F Cartilagenous differentiation.


276 Tumours of the heart - Sarcomas
Clinical features                            undifferentiated pleomorphic sarcomas
Most occur on the left side of the heart     with osteosarcomatous differentiation.
and cause signs and symptoms related         Virtually all osteosarcomas of the heart
to pulmonary congestion, mitral stenosis     reported thus far have occurred in the left
and pulmonary vein obstruction.              atrium. Like skeletal osteosarcoma,
Tumours may also present with metas-         areas of malignant giant cell tumour
tases and the lungs, lymph nodes, kid-       (giant cell malignant fibrous histiocy-
ney and skin are common sites.               toma), chondroid differentiation, and
Constitutional signs and symptoms may        osseous differentiation have been found
precede symptoms referable to the            to coexist in variable amounts in a single    A
heart. Diagnosis of cardiac sarcoma          lesion.
rests on echocardiography; MRI is help-
ful preoperatively to determine precise      Genetics
tumour size, location, and adjacent tis-     Genetic studies of cardiac sarcomas are
sues invasion, and post-operatively for      limited. In studies of extra cardiac malig-
assessment of excision and recurrence.       nant fibrous histiocytoma, the common
                                             signature of genetic alterations includes
Macroscopy                                   recurring low-level copy number increas-
Malignant fibrous histiocytoma typically     es at new sites on chromosome 7, and
presents as a soft or firm polypoid endo-    losses of chromosome 2 sequences
cardial based tumour. It may be sessile      {1546}. Genomic imbalance at chromo-          B
or pedunculated, simulating myxoma,          some 13 has also been observed, with          Fig. 4.30 A Myxosarcoma from the left atrium. Cut
but unlike myxoma, may form multiple         high gains for Xp and bands 1q21-22,          surface showing variable solid, soft and haemor-
masses not obviously part of the same        1p31, 3q27 and 9q3. The losses at chro-       rhagic regions. B Fibromyxosarcoma. A portion of
tumour {1142}. The mass may distend          mosome 13 were observed in a large            the tumor near the endocardial surface shows an
the atrium and impinge upon the mitral       proportion at regions 13q12-14 and            undifferentiated spindle cell sarcoma without
                                                                                           prominent vascularity or pleomorphism and an
valve. Extension into the pulmonary veins    13q21-22 {1131,1224}. Specific losses in
                                                                                           abundant proteoglycan matrix.
and lung parenchyma may be present           regions that harbour tumour suppressor
{1056} They may be uniform tan-white or      genes like INK4a (9p21) and RB1
variegated due to haemorrhage and            (13q14) have been revealed by Southern        Prognosis and predictive factors
necrosis. Calcification is uncommon.         blot and comparative genomic hybridiza-       For malignant fibrous histiocytoma and
                                             tion {1828}. RB1 gene is probably impli-      fibrosarcoma there is some evidence that
Histopathology                               cated in tumourigenesis of malignant          grading is useful in predicting survival,
Malignant fibrous histiocytoma or undif-     fibrous histiocytoma due to the high cor-     but the majority of patients with these
ferentiated pleomorphic sarcoma is a         relation between absence of RB1 protein       tumours die of either local or metastatic
diagnosis of exclusion, and immunohis-       expression and chromosome 13 losses           disease {731,952,1508}. The mean post-
tochemical studies are important in ruling   and mutations found in this gene {353}.       operative survival is 5-18 months. The
out metastatic myogenic, melanocytic         Mutations localized to the core domain of     cause of death may be related to
and neurogenic tumours as well as sar-       TP53 have been found by immunohisto-          metastatic disease, bulky intracardiac
comatoid carcinomas. Of the subtypes of      chemical and sequencing procedures            recurrences, or general debilitation.
malignant       fibrous       histiocytoma   {1982}, as have other abnormalities like
described in the soft tissue, the pleomor-   protein accumulation {1647}. TP53 muta-       Fibrosarcoma and
phic (greater than 90%) and giant cell       tions and accumulation of p53 protein         myxosarcoma
subtypes have been recognized in the         have been detected in tumours with
heart. The tumours are heterogeneous in      MDM2 gene amplification {1647}.               Definition
appearance and are variably cellular.                                                      Fibrosarcoma is a malignant tumour
The constituent cells may be spindled or     Treatment                                     composed of fibroblasts with variable
epithelioid and sometimes have abun-         Complete resection of malignant primary       amounts of intercellular collagen and a
dant eosinophilic cytoplasm. Intermixed      cardiac tumours can rarely be achieved,       classic herringbone architecture. Some
giant cells are common. A storiform          but palliative surgery is usually undertak-   fibrosarcomas with abundant myxoid
arrangement of tumour cells is common        en because many patients present with         stroma have been called myxosarcomas
and they usually have marked pleomor-        mechanical obstruction {731}. Adjunctive      but are not considered malignant vari-
phism. Mitotic activity is easy to find.     chemotherapy, radiation therapy or both       ants of cardiac myxoma. Tumours with
                                             are sometimes used {731}, however, the        marked pleomorphism, or a prominent
Osteosarcoma                                 optimal protocol and efficacy are unclear     vascular or storiform pattern are better
Undifferentiated pleomorphic sarcomas        {731,1508,1962,2043}. Patients with           classified as malignant fibrous histiocy-
demonstrate areas of osseous differenti-     unresectable primary malignant cardiac        toma.
ation in 15% of cases. There is debate as    tumours who are free of metastases may
to whether these tumours should be clas-     be considered for heart transplantation       ICD-O code
sified as extra skeletal osteosarcomas or    {731,1962,2043}.                              Fibrosarcoma                    8810/3

                                                                                                 Fibrosarcoma / myxosarcoma 277
Epidemiology
Fibrosarcoma represents 5-10% of all
cardiac sarcomas depending on the cri-
teria used for diagnosis. Fibrosarcomas
are less frequent, and occur over a
broader age range than malignant
fibrous histiocytoma, some having been
reported in children.

Localization
Fibrosarcomas are most common in the
left atrium, but have been reported to
arise in all chambers. Fibrosarcomas
may also infiltrate the pericardial space,
thus mimicking mesothelioma {1034}.

Clinical features
The clinical features of fibrosarcomas
have not been well-delineated from relat-
ed cardiac sarcomas such as malignant
fibrous histiocytoma (undifferentiated       Fig. 4.31 Embryonal rhabdomyosarcoma predenting as small cell undifferentiated tumor with cellular areas
pleomorphic sarcoma) as the classifica-      concentrated towards the surface.
tion of these lesions has not been stan-
dardized in large series. As with other
sarcomas, signs and symptoms vary            phasic synovial sarcoma, inflammatory                 Rhabdomyosarcoma
depending on the location of the tumour.     myofibroblastic tumours and localized
Because most occur on the left side of       fibrous tumours, and for the myxoid vari-             Definition
the heart, signs and symptoms related to     ant, other myxoid sarcomas (MFH,                      Rhabdomyosarcoma is a malignant
pulmonary congestion, mitral stenosis        leiomyosarcoma, etc.) and cardiac myx-                tumour with striated muscle differentiation.
and pulmonary vein obstruction are most      oma. The latter is generally distinguished
frequent. Rarely, cardiac fibrosarcoma       by the presence of myxoma cells, abun-                ICD-O code                       8900/3
may present with metastases in the           dant organizing hemorrhage, and
lungs, lymph nodes, skin, and kidney.        absence of mitotic figures and high cel-              Epidemiology
                                             lularity. Fibromas are easily distinguished           Rhabdomyosarcoma is a very rare sub-
Macroscopy                                   from typical fibrosarcoma by lack of cel-             type of cardiac sarcoma. In the past,
Fibrosarcoma typically presents as a soft    lularity and abundant collagen.                       before immunohistochemical documen-
polypoid tumour projecting into the                                                                tation of tumour histogenesis was routine,
chamber from whose walls they arise.         Prognosis and predictive factors                      it was stated that a large proportion of
They have a gross appearance similar to      See discussion on treatment of maligant               cardiac sarcomas were rhabdomyosar-
MFH {329}, but haemorrhage, necrosis,        fibrous histiocytoma. There is no proven              comas. However, in more recent series,
and variegation are less common.             difference in prognosis between cardiac               the proportion is less than 5% {250}, and
                                             fibrosarcoma and malignant fibrous histi-             in one recent series of cardiac sarcomas
Histopathology                               ocytoma as demonstrated in a meta-                    with rigorous immunohistochemical doc-
Fibrosarcoma of adult type is composed       analysis using actuarial methods {249}.               umentation, none of 24 was classified as
of spindle shaped cells arranged in                                                                rhabdomyosarcoma {509}.
sweeping fascicles that are often
arranged at angles to one another result-                                                          Localization
ing in a “herringbone” pattern. The nuclei                                                         Rhabdomyosarcomas occur anywhere in
are usually elongate with tapered ends                                                             the heart. Approximately 50% occur in
and darkly staining. Mitotic activity is                                                           the atria, and 50% in the ventricles. The
variable. In the myxoid variant tumour                                                             frequency of ventricular involvement is
cells spindling is less pronounced and                                                             greater than other cardiac sarcomas.
cells may take on a stellate or ovoid con-                                                         Contrary to sarcomas with fibro- or myofi-
figuration. However in all types pleomor-                                                          broblastic differentiation, they are not
phism is minimal and prominent vascu-                                                              usually intracavitary tumours, but are
larity is absent.                                                                                  more often mural.

Differential diagnosis                       Fig. 4.32 Embryonal rhabdomyosarcoma with rhab-       Clinical features
The differential diagnosis for the typical   domyoblasts containing abundant eosinophilic          Cardiac rhabdomyosarcomas are usual-
variant of fibrosarcoma includes mono-       cytoplasm.                                            ly of the embryonal variant and, there-

278 Tumours of the heart - Sarcomas
A                                                                                 B
Fig. 4.33 Leiomyosarcoma. A The tumour is cellular, composed of fascicles of relatively uniform cells. B Note tumour cellularity and focal necrosis.



fore, occur most frequently in children                genin greatly facilitates the diagnosis                 been detected in cardiac rhabdomyosar-
and young adults; it is the most common                {1630}. Desmin is also useful in docu-                  coma {662}.
primary cardiac malignancy in children.                menting     muscular      differentiation.
The mean age at presentation is approx-                Alveolar rhabdomyosarcoma, character-                   Treatment
imately 20 years, compared to 40-50                    ized by a collagenous stroma and a                      Surgery
years of age for other subtypes of car-                paucity of rhabdomyoblasts, has been                    Surgical resection of the tumour is usual-
diac sarcoma. Rhabdomyosarcoma is                      described in the heart generally as a                   ly indicated even if it is considered as
more likely than other primary cardiac                 metastatic lesion.Sarcoma botryoides,                   palliative to relieve obstruction to cardiac
sarcomas to involve the valves. The clin-              with characteristic grape-like structures               blood flow and to clarify the diagnosis
ical presentation, as with other cardiac               and a so-called cambium layer, a form of                {301,470,952}. Total orthotopic heart
tumours, depends on the cardiac loca-                  embryonal rhabdomyosarcoma, has also                    transplantation may offer relatively long-
tion.                                                  been described in the heart {760}.                      term survival {67,701,733} if there are no
                                                                                                               distant metastases.
Macroscopy                                             Differential diagnosis
Cardiac rhabdomyosarcomas are bulky,                   The differential diagnosis includes other               Chemotherapy
invasive tumours that may be grossly                   cardiac sarcomas, especially undifferen-                Although the outcome of chemotherapy
mucoid or gelatinous, similar to cardiac               tiated lesions and metastatic small round               on cardiac rhabdomyosarcoma has not
myxoma, or soft and necrotic, with varie-              cell tumours in children and young                      been fully studied, due to the rarity of the
gation and heterogeneity. They usually                 adults. Immunohistochemical stains are                  tumour, there have been advances in the
arise within the myocardium and are less               vital in identifying rhabdomyoblasts.                   treatment of soft tissue rhabdomyosarco-
likely than sarcomas with myofibroblastic              Adult cellular rhabdomyomas, in contrast                ma {423,529, 1194,1749} with a three-
or fibroblastic differentiation to be endo-            to rhabdomyosarcoma, lack significant                   year progression-free survival of approx-
cardial based, luminal tumours.                        mitotic activity, necrosis, and do not                  imately 65%. Neoadjuvant chemotherapy
                                                       express myogenin.                                       may optimize a surgical approach
Tumour spread and staging                                                                                      {1749}.
Sites of metastatic spread are, in order of            Electron microscopy
descending frequency: lungs, regional                  The diagnostic features are thick and thin              Radiotherapy
lymph nodes, central nervous system,                   filaments reminiscent of normal striated                Adjuvant radiotherapy is commonly
gastrointestinal tract, kidney, adrenals,              muscle. Internal A and I banding may or                 mandatory to preclude local relapse or to
thyroid, ovary, bone and pancreas.                     may not be present, but Z-bands are fre-                optimize the results of a surgical
                                                       quently well formed. Plentiful glycogen                 approach. However radiotherapy may be
Histopathology                                         granules and abundant mitochondria are                  used preoperatively to decrease tumor
Cardiac rhabdomyosarcomas are almost                   also present. Tumour nuclei are lobulat-                size and allow surgical resection.
exclusively embryonal. Embryonal rhab-                 ed, containing variable amounts of con-
domyosarcoma is small cell neoplasm                    densed chromatin. Occasionally, several                 Prognosis and predictive factors
with variable numbers of PAS-positive                  grids must be examined before rhab-                     Specific prognostic microscopic features
rhabdomyoblasts (tadpole or strap                      domyoblasts are identified.                             have not been devised for cardiac rhab-
cells). Well-differentiated embryonal                                                                          domyosarcomas. However, grading is
rhabdomyosarcoma has numerous tad-                     Somatic genetics                                        similar for other subtypes of cardiac sar-
pole-shaped rhabdomyoblasts. Nuclear                   At exon 1 of K-ras, a mutation at the first             comas, and includes an assessment of
staining with antibodies against myo-                  base of codon 13 (G to A transition) has                mitotic activity and necrosis {509}. The

                                                                                                                                 Rhabdomyosarcoma 279
A                                                                                 B
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.


prognosis is poor, with recurrence and                 oriented at sharp angle or 90° to one                   300,400,1466}. The true incidence has
eventual metastasis with death of the                  another. Inconstant characteristic fea-                 probably been underestimated, as
patient within months the rule {1944}. The             tures include the presence of cytoplas-                 molecular studies can now confirm the
mean survival rarely exceeds 12 months.                mic glycogen and perinuclear vacuoles.                  diagnosis in the monophasic variant,
                                                       Pleomorphic and giant cells may be                      which is the most common form in the
                                                       present. Zones of necrosis and mitotic                  heart. An association between cardiac
Leiomyosarcoma                                         figures are generally plentiful. Usual                  synovial sarcoma and asbestos expo-
                                                       immunohistochemical markers of neo-                     sure has been reported {1144}.
Definition                                             plastic cells are smooth muscle alpha
A malignant tumour composed of cells                   actin and desmin. Alpha actin also                      Localization
with distinct smooth muscle features.                  shows numerous normal little vessels in                 There is a predilection for the atria and
                                                       the tumour tissue. There may occasional-                pericardial surfaces.
ICD-O code                       8890/3                ly be aberrant expression of cytokeratin
                                                       and epithelial membrane antigen.                        Clinical features
Epidemiology                                           Demonstration of smooth muscle cell                     Clinical symptoms may arise from
Cardiac leiomyosarcoma is uncommon,                    derivation virtually confirms malignancy,               obstruction, embolism, and tamponade.
representing less 10% of cardiac sarco-                as leiomyomas remain undescribed in
mas. There is no sex predilection, and                 this location.                                          Macroscopy
most occur in patients between 40 and                                                                          Synovial sarcomas are bulky, infiltrative
50 years of age.                                       Treatment and prognosis                                 tumours that are typically firm and white.
                                                       Treatment consists of surgical excision,                Necrosis or hemorrhage may be present.
Clinical features                                      almost always incomplete. This may
Dyspnoea is the main clinical feature.                 allow some patients several months of                   Histopathology
Sometimes patients present with chest                  symptom free survival, typically less than              The classic lesion is biphasic, but the
pain, cough, atrial arrythmias, or haemo-              one year. Chemotherapy and radiation                    monomorphic variant is especially com-
ptysis.                                                therapy may provide palliation.                         mon in the heart. The spindle component
                                                                                                               resembles a fibrosarcoma, but alternating
Macroscopy                                                                                                     cellular and oedematous areas are typi-
Most of them are located in the left atrium            Synovial sarcoma                                        cal. The spindle cells are small, compact,
(posterior wall) and invade pulmonary                                                                          and often infiltrated by sparse mononu-
veins or mitral valve. But, tumours can                Definition                                              clear lymphoid cells. The epithelioid cells
arise elsewhere, including the right atri-             Synovial sarcoma is a biphasic tumour                   form clusters and nests, and occasional-
um and ventricle, or pulmonary valve or                composed of spindled and epithelioid                    ly larger gland–like spaces which may
trunk. The tumours tend to be firm, fleshy,            areas, characterized by X;18 chromoso-                  show branching. Immunohistochemically,
grey and sessile. They may present as                  mal translocations.                                     cytokeratin and epithelial membrane anti-
multiple intra-cavitary nodules.                                                                               gen are strongly expressed in the epithe-
                                                       ICD-O code                        9040/3                lioid cells. Staining for these markers in
Histopathology                                                                                                 the spindle cells may be very focal.
Leiomyosarcoma is composed of com-                     Epidemiology                                            Spindle cells express vimentin and occa-
pact bundles of spindle cells that pos-                Synovial sarcomas account for approxi-                  sionally smooth muscle actin. The cells
sess blunt-ended nuclei and are often                  mately 5% of cardiac sarcomas {173,                     do not express CD34.

280 Tumours of the heart - Sarcomas
A                                                     B                                                      C
Fig. 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 of
the 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).



Differential diagnosis                                 differential diagnosis. Unlike mesothe-                 either of two genes, SSX1 or SSX2, at
Distinction of synovial sarcoma from                   lioma, solitary fibrous tumour is generally             Xp11.2. This rearrangement of genes
mesothelioma, another biphasic tumour,                 lower-grade, usually expresses CD34                     produces a chimeric SS18 /SSX tran-
can usually be made on the basis of                    antigen, is less cellular and tends to have             script, which could be implicated in
tumour location (mesotheliomas do not                  alternating hyper- and hypocellular areas.              tumourigenesis {375}. The SS18/SSX
occur within the atria) and growth pattern                                                                     transcripts can be specific markers of
(synovial sarcoma is usually a circum-                 Somatic genetics                                        synovial sarcoma that can be detected
scribed solitary lesion while mesothe-                 Cytogenetically the reciprocal transloca-               by the reverse transcriptase-polymerase
lioma tends to grow diffusely over the                 tion t(X;18)(p11.2;q11.2) is seen in more               chain reaction (RT-PCR). The transcripts
pericardium. Additionally, the spindle cell            than 90% of soft tissue synovial sarco-                 can be identified in almost all synovial
areas of synovial sarcoma tend to be rel-              mas {1330}. This is considered to be the                sarcomas when there is adequate
atively monomophic. The X;18 transloca-                primary cytogenetic abnormality and                     tumour RNA {837}. This molecular diag-
tion may be confirmed on formalin fixed,               specific for synovial sarcomas.                         nostic method also can be applied to
paraffin embedded tissues and has a                    The breakpoints of the t(X;18) have been                paraffin-embedded tissue {747}.
high degree of sensitivity and specificity             cloned, and it has been shown that this
{1506}. Reactivity for calretinin has been             translocation results in fusion of SS18
described in both mesothelioma and syn-                gene (previously described as SYT or
ovial sarcoma, and is not helpful in the               SSXT) at the chromosome 18q11.2 to




                                                                                                                                     Synovial sarcoma 281
Cardiac lymphomas                                                                                G. Rolla
                                                                                                 F. Calligaris-Cappio
                                                                                                 A.P. Burke




Definition                                       a predisposing factor. However, the heart       may be the only findings. In additon to
Primary cardiac lymphoma (PCL) is an             is an uncommon site for immunodeficien-         echocardiography, MRI, and CT, nuclear
extra-nodal lymphoma involving only the          cy-related lymphoma. Most PCL arise in          medicine techniques may be useful pro-
heart and/or the pericardium. A less             immunocompetent patients. The median            cedures for the non-invasive assessment
restrictive definition includes small sec-       age of the reported cases is 62 years           of cardiac lymphomas. Gallium-67
ondary lesions elsewhere, with the vast          (range, 5-90 years) with a male-to-female       uptake is non-specific, though a marked
bulk of the tumour arising in the heart. It      ratio of 3:1.                                   accumulation in the heart without extrac-
is clinically defined as a lymphoma pre-         The clinical course is generally short,         ardiac uptake can suggest the diagnosis
senting as cardiac disease with the bulk         with a mean survival of 7 months (range,        of PCL {1680}.
of the tumour being intra-pericardial.           0-48 months).
Cardiac involvement by disseminated                                                              Diagnostic approach
non-Hodgkin lymphoma should be                   Clinical features                               When pericardial effusion is present its
excluded.                                        Signs and symptoms                              drainage may have both palliative and
                                                 The clinical course is generally acute in       diagnostic purposes. Lymphoma cells
Epidemiology                                     onset. There is no pathognomonic clini-         may be detected in serous fluid in up to
PCL is an uncommon malignancy,                   cal presentation and patients are gener-        88% of cases {308}.
accounting for 1.3% of primary cardiac           ally investigated because of chest pain,        When cytology is not available, the diag-
tumours and 0.5% of extranodal lym-              pericardial effusion, refractory heart fail-    nosis of PCL is usually assessed by
phomas {249,273,1679}. The published             ure, arrhythmia, or lightheadness and           explorative thoracotomy with cardiac
series account for about 80 cases, while         syncope due to a myxoma-like intracav-          mass biopsy. Recently, less invasive pro-
cardiac involvement in disseminated              itary mass {308}. Superior vena cava            cedures have been performed, such as
lymphoma has been documented in                  obstruction {363}, multiple pulmonary           transoesophageal echocardiography
nearly 20% of autopsy cases {1280}. The          emboli and infarction {1832} and hyper-         (TEE) guided percutaneous intracardiac
appearance of PCL in patients with AIDS          trophic cardiomyopathy {266} have also          biopsy {46,947}.
{1736} and in a kidney recipient {1667}          been reported as initial diagnosis in
suggests that immunodeficiency may be            patients with PCL. Complete atrio-ven-          Macroscopy
                                                 tricular block may be the major clinical        PCL may arise in either atrium or ventri-
                                                 presentation {1416}.                            cle. Usually the tumour is large, infiltrat-
                                                                                                 ing myocardium and extending into the
                                                 Imaging                                         right atrium and ventricle in the form of
                                                 Because the gross pathologic features of        multiple intracavitary polypoid nodules,
                                                 primary cardiac lymphoma are variable,          which may eventually obliterate the cavi-
                                                 the imaging findings are variable.              ties. The right atrium is involved in more
                                                 Cardiac lymphomas most commonly                 than 2/3 of patients. The pericardium is
                                                 manifest as circumscribed, nodular              usually thickened by white-greyish
                                                 masses in the myocardium, often with an         tumour infiltration. Pericardial effusion,
                                                 associated pericardial effusion. These          which is generally massive, may be iso-
                                                 findings are usually well seen at echocar-      lated (12.5% of cases) or associated with
                                                 diography, MRI, and CT. Lymphoma may            a heart mass (near half of cases) {737}.
                                                 also manifest as an ill-defined, infiltrative
                                                 mass, in which case, they are typically         Cytology
                                                 best depicted with MRI because of its           A diagnostic cytologic sample sample is
                                                 superior soft tissue contrast {66}. Internal    obtained in less than 20% of primary car-
                                                 imaging features and contrast enhance-          diac lymphomas (PCL) {1680}. It may be
                                                 ment patterns are very variable with car-       difficult to differentiate PCL from benign
                                                 diac lymphomas. Lymphomas may have              reactive lymphocytosis by cytology
                                                 high or low signal on MRI, may have sim-        alone. Immunocytochemical staining
                                                 ilar attenuation as muscle or lower atten-      {1724}, cytogenetic studies {1} and poly-
                                                 uation than muscle on CT, and may show          merase chain reaction {964} have been
                                                 increased, or decreased contrast                performed successfully to confirm the
Fig. 4.36 Cardiac lymphoma. Mulitofocal masses   enhancement. In some cases, pericar-            lymphoid lineage and detect the pres-
involving both atria and ventricular walls.      dial effusion or pericardial thickening         ence of a monoclonal population.

282 Tumours of the heart - Lymphomas
A                                                    B                                                    C
Fig. 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; immunophenotype
was 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.


Histopathology                                       Somatic genetics                                      response (mean follow-up 17 months;
Diffuse large B-cell lymphoma is the sub-            A complex abnormal karyotype contain-                 range 3-40 months). PCL should be
type most frequently observed (80% of                ing t(8;14) (q24;q32) has been reported               treated like other aggressive lymphomas
published cases). Non-cleaved small                  in a case of diffuse large B-cell lym-                arising in other primary sites.
cell lymphoma has been reported in a                 phoma mainly involving the heart with
few cases; the histopathology was                    cells which were CD5+ and CD20+ with
unspecified in the other cases. Recently             a c-myc rearrangement {1948}. In situ
two cases of diffuse large B-cell lym-               hybridization for EBER-1 was negative.
phoma with CD5 expression have been
reported {317}. This is a recently identi-           Prognosis and predictive factors
fied subgroup of diffuse large B-cell lym-           Late diagnosis appears to be a major
phomas, which differs for clinical charac-           factor in the poor outcome in PCL
teristics (elderly, female and extranodal            patients. Irrespective of the treatment
involvement) and aggressive clinical                 applied, 60% of the patients died of their
course {2181}. One case of Burkitt lym-              tumour 1.8 months after diagnosis {317}.
phoma in an immunocompetent patient                  Prompt anthracycline-based chemother-
has been described {317}.                            apy results in near 60% of complete




                                                                                                                              Cardiac lymphomas 283
Metastatic tumours to the heart                                                                    G. Rolla
                                                                                                   F. Calligaris-Cappio




Definition                                     tumor; haematogenously; via lymphatics;             and there is less frequent infiltration of
Malignant cardiac neoplasm with a non-         and rarely by intracavitary extension from          epi- and endocardium.
pericardial or myocardial primary site.        the inferior vena cava or pulmonary                 Leukemic and lymphomatous infiltrates
Metastatic tumors that infiltrate myocardi-    veins. Lymphatic spread is generally                are typically widespread, involving the
um are frequently accompanied by peri-         accompanied by involvement and                      epicardium (61%), and myocardium dif-
cardial metastases, especially in the          enlargement of pulmonary hilar or medi-             fusely. The left ventricle is involved in
cases of carcinomas, which additionally        astinal lymph nodes. Haematogenous                  55%, and right atrium in 54% of cases.
involve mediastinal lymph nodes.               spread is characterized by myocardial               Sarcomatous deposits are found within
                                               involvement.                                        the myocardium (50%), pericardium
Epidemiology                                   Epithelial malignancies typically spread            (33%), or both myocardium and peri-
In a series of 133 surgically resected car-    to the heart by lymphatics. Melanoma,               cardium (17% of cases). Valvular metas-
diac tumors, 14% were metastatic               sarcomas, leukemia and renal cell carci-            tases      are     uncommon         {764}.
{1411}. In a recent review, cardiac            noma metastasize to the heart by a                  Osteosarcoma, liposarcoma, leiomyosar-
metastases were present in 12% of              haematogenous route. Melanomas, renal               coma, unclassifiable sarcomas, rhab-
autopsies performed for widespread             tumours, including Wilms’ tumour and                domyosarcoma, neurofibrosarcoma, syn-
malignancy {12}. Primary tumors in             renal cell carcinoma, adrenal tumours,              ovial sarcoma, and maligant fibrous histi-
decreasing order of frequency include          liver tumours, and uterine tumours are              ocytoma have been reported to involve
carcinomas of the lung, lymphomas, car-        the most frequent intracavitary tumours.            the heart secondarily.
cinomas of the breast, leukemia, carcino-      Metastatic cardiac tumours affect the
mas of the stomach, malignant                  right side of the heart in 20-30% of                Pathologic findings
melanoma, hepatocellular carcinoma             cases, the left side in 10-33% of cases,            Metastatic deposits may be diffuse,
and carcinomas of the colon. The follow-       and show bilateral or diffuse involvement           multinodular, or consist of a single domi-
ing tumors have an especially high rate        in approximately 30-35% of cases. The               nant mass. Especially with carcinomas,
of cardiac metastasis if the incidence of      endocardium or chamber cavities are                 there may be diffuse studding and thick-
the primary tumor is considered:               involved in 5% of cases {1398}. The most            ening of the pericardial surfaces. This
leukemia, melanoma, thyroid carcinoma,         common epithelial malignancies to                   pattern can grossly be confused with
extracardiac sarcomas, lymphomas,              metastasize to the heart are carcinomas             mesothelioma, or benign fibrosing peri-
renal cell carcinomas, carcinomas of the       of the breast and lung. In most cases               carditis. The tumour burden in the heart
lung and carcinomas of the breast.             there is pericardial involvement with               is the highest with melanoma, as com-
These tumors all had a greater than 15%        superficial myocardial infiltration. The            pared to any other malignancy.
rate of cardiac metastasis in a large          valves and endocardium are usually                  Carcinomatous spread in the myocardi-
autopsy study {1398}.                          spared. Generally, the heart is not the             um is frequently most prominent in
The rate of cardiac involvement by             only organ involved, and metastatic                 subepicardial lymphatics, whereas
metastatic disease has not appeared to         deposits are usually present in extracar-           melanomas, sarcomas, renal cell carci-
change over a 14-year period, indicating       diac sites.                                         nomas and lymphoid neoplasms form
that current treatment modalities may not      The myocardium is involved in virtually             intramyocardial interstitial tumours. The
have a significant effect on the rate of       100% of cases of metastatic melanoma,               histopathologic distinction between pri-
metastatic malignancy to the heart.                                                                mary and metastatic sarcoma may be
                                                                                                   impossible upon surgical resection of a
Clinical features                                                                                  cardiac tumour. Most sarcomas metasta-
The cardiac location of the tumor greatly                                                          tic to the heart cause symptoms at their
affects the signs and symptoms. These                                                              primary site before cardiac symptoms
can include symptoms related pericar-                                                              are evident, however {764}. Although pri-
dial effusions, arrhythmias, or congestive                                                         mary sarcomas of the heart are uncom-
heart failure. Obstruction of the mitral or                                                        mon, extracardiac sarcomas presenting
aortic valve may cause syncope. Involve-                                                           as cardiac metastases are even rarer.
ment of the right heart and tricuspid
valves may give rise to right-sided failure.

Localization
Malignancies spread to the heart by            Fig. 4.38 Metastases of a large cell carcinoma of
direct extension, usually from mediastinal     the lung in the heart.


284 Tumours of the heart - Secondary tumours
Pericardial tumours                                                                                            A. Burke
                                                                                                               R. Loire
                                                                                                               R. Virmani




Solitary fibrous tumour                                 although diffuse mesothelial surface
                                                        involvement has been described.
Definition
An uncommon, spindle-cell, fibroblastic                 Histopathology
tumour which often shows a prominent                    Histologic variability is the rule and multi-
haemangiopericytoma-like vascular pat-                  ple growth patterns have been described.
tern.                                                   Most tumours will have a predominant
                                                        monomorphic spindle cell pattern resem-
ICD-O code                                              bling low-grade fibrosarcoma although
Solitary fibrous tumour          8815/1                 broad tumour cell fascicles are rare.                  A
                                                        Areas of hypercellularity typically alternate
Synonyms                                                with those that are less cellular. The less
Benign mesothelioma, fibrous mesothe-                   cellular areas can by myxoid or contain
lioma, submesothelial fibroma                           abundant collagen {459}. Typically the
                                                        nuclei of tumour cells are closely apposed
Localization                                            to collagen bundles. A haemangiopericy-
The most common locations, outside the                  toma-like vascular pattern may be con-
pleura, include the head and neck, espe-                spicuous, present in a small portion of the
cially orbit, soft tissue, especially                   lesion, or absent. The differential diagno-
abdomen, extremities, and meninges                      sis includes other monomorphic spindle
{233,1384,1473}. As with any lesion com-                cell tumours, including neurogenic                     B
mon to the pleura, there have been                      tumours, spindle cell mesotheliomas,                   Fig. 4.39 Mesothelioma of pericardium. A Note the
examples of solitary fibrous tumour                     monophasic synovial sarcoma, and                       extensive tumour encasing the pericardium. B In
                                                                                                               many cases, the pericardial mass is in continuity
reported in the pericardium and rarely                  fibrosarcoma {1311}. Recently, desmoid
                                                                                                               with pleural mesothelioma.
within the heart.                                       tumour of the pleura has been added in
                                                        the list of differential diagnostic consider-
Clinical features                                       ations {2151}. See pleural section for                 cific actin, desmin, CD31, CD117 (c-kit),
Clinical features are related to pericardial            additional information.                                S-100 protein calretinin, and inhibin
mass effect.                                                                                                   {596,772,1473,2127}.
                                                        Immunoprofile
Macroscopy                                              Solitary fibrous tumours are CD34 and                  Differential diagnosis
Solitary fibrous tumours tend to be well-               bcl-2 positive. They are consistently neg-             Sarcomatous mesotheliomas of the peri-
circumscribed, firm, fleshy or white                    ative for epithelial markers, muscle spe-              cardium are distinguished from solitary
                                                                                                               fibrous tumours by their diffuse growth
                                                                                                               pattern, and keratin and calretinin reac-
                                                                                                               tivity. On the other hand, solitary fibrous
                                                                                                               tumour may closely mimic monophasic
                                                                                                               synovial sarcoma and low- grade
                                                                                                               fibrosarcoma. Fibrosarcoma tends to be
                                                                                                               more architecturally monomorphic and
                                                                                                               negative for CD34. Monophasic synovial
                                                                                                               sarcoma has higher grade cytology,
                                                                                                               plumper nuclei and shows focal keratin
                                                                                                               reactivity. Endometrial stromal sarcoma,
                                                                                                               and metastatic granulosa cell tumour
                                                                                                               may be excluded by negative reactivity
                                                                                                               for cytokeratin, estrogen and proges-
                                                                                                               terone receptors, and inhibin.


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


                                                                                                                              Solitary fibrous tumour 285
A                                                     B                                                     C
Fig. 4.41 Pericardial mesothelioma. A The majority of pericardial mesotheliomas are epithelioid. B Strong expression of calretinin. C Strong expression of cyto-
keratin 7.


Prognosis and predictive factors                      patients with mesothelioma who have no                 Immunoprofile
The prognosis is generally good,                      known exposure history.                                The immunohistochemical profile of peri-
although recurrences and local spread                                                                        cardial mesothelioma is similar to that of
have been reported. Criteria for malig-               Clinical features                                      pleural mesothelioma. Expression of
nancy of pleural tumours include necro-               Signs and symptoms                                     mesothelial antigens, such as calretinin,
sis and a mitotic count of greater than 4             The mean age of patients with pericardial              and cytokeratins 5/6 are helpful in the
per 10 high powered fields, but the appli-            mesothelioma is about 45 years, with a                 diagnosis, as are negative reactions for
cability of these criteria to tumours in the          wide age range, including elderly, older               adenocarcinoma markers, such as carci-
heart and pericardium is unknown.                     children and young adults. The initial                 noembryonic antigen.
                                                      course is usually related to pericardial
                                                      effusions. Tamponade may eventually                    Electron microscopy
Malignant mesothelioma                                occur {1202}.                                          Ultrastructurally, mesothelioma cells from
                                                                                                             epithelioid areas contain branched,
Definition                                            Imaging                                                bushy microvilli. Cytoplasmic tonofibrils
Malignant mesothelioma arises from                    Echocardiography usually shows peri-                   are present in approximately 50% of
mesothelial cells or demonstrates                     cardial effusions and may show pericar-                tumours. Asbestos bodies may be identi-
mesothelial differentiation. The definition           dial thickening. However, because peri-                fied within pericardial mesothelioma, but
of primary pericardial mesothelioma stip-             cardium is at the periphery of the field of            are of no diagnostic utility.
ulates that there is no tumour present                view obtainable with echocardiography,
outside the pericardium, with the excep-              MRI or CT are usually necessary. MRI                   Differential diagnosis
tion of lymph node metastases.                        and CT usually demonstrate pericardial                 The distinction between mesothelioma
                                                      fluid as well as pericardial thickening                and pleural-based lung adenocarcinoma
ICD-O code                      9050/3                and/or pericardial masses {737}.                       can be quite difficult, and is generally
                                                                                                             based on immunohistochemical findings.
Epidemiology                                          Macroscopy                                             Distinction from reactive mesothelial cell
Mesothelioma of the pericardium repre-                Malignant mesotheliomas of the peri-                   proliferations may also be difficult; in
sents approximately 0.7% of malignant                 cardium can form bulky nodules that fill               comparison to reactive pleural mesothe-
mesotheliomas {831}. As with mesothe-                 the pericardial cavity. The tumour can                 lial proliferations, reactive pericardial
liomas in other sites, the incidence may              also spread diffusely over the pericardial             mesothelial cells may be more deeply
be increasing, due to the latency                     surface and completely encase the                      “invasive”. Reactive stromal cells may
between asbestos exposure and tumour                  heart. They can further encircle the great             also often attain bizarre and pleomorphic
development {1074}.                                   vessels and may obstruct the venae                     shapes, confusing the histopathologic
                                                      cavae.                                                 picture. Other malignancies that may be
Etiology                                                                                                     confused with mesothelioma include
Like pleural mesotheliomas, a large pro-              Histopathology                                         pericardial-based angiosarcoma, which
portion of mesotheliomas of the peri-                 Malignant mesotheliomas of the peri-                   may elicit a prominent mesothelial
cardium are induced by asbestos {1074}.               cardium resemble pleural mesothe-                      response, malignant solitary fibrous
Iatrogenically   induced     pericardial              liomas. Although the majority are of the               tumour      and      synovial    sarcoma.
mesotheliomas have been reported                      epithelioid type, forming tubules, papil-              Immunohistochemistry is invaluable in
decades after exposure to pericardial                 lary structures, and cords of infiltrating             such circumstances. Mesothelioma lacks
dusting with asbestos and fibreglass as               cells that can incite a desmoplastic                   the X;18 translocation of synovial sarco-
a treatment for angina pectoris.                      response, the sarcomatous variant is                   ma.
Therapeutic radiation for breast cancer               also common. Variants similar to those
and mediastinal lymphoma has also                     described in the pleura may also be seen               Prognosis and predictive factors
been implicated in rare patients.                     in the pericardium e.g. microcystic, ade-              The prognosis of pericardial mesothe-
However, there remains a subset of                    nomatoid, deciduoid {1649,1802}.                       lioma is poor. Fifty per cent of patients

286 Pericardial tumours
                                                      ed, over 90% within the pericardium, and             be the first symptom, due to acute
                                                      the remainder in the myocardium. The                 arrhythmia caused from the tumour’s
                                                      majority are pericardial teratomas {248},            interventricular location.
                                                      and the remainder are yolk sac tumours
                                                      {411,1178}. Reports of intrapericardial              Macroscopy
                                                      teratoma describing the presence of only             Cardiac teratomas may be massive,
                                                      one or two germ cell layers may repre-               measuring up to 15 cm. They have a
                                                      sent misclassified bronchogenic cysts.               smooth surface and are lobulated. The
                                                                                                           tumours are multicystic with intervening
                                                      Clinical features                                    solid areas. The tumours usually dis-
                                                      Patient age ranges from intrauterine life            place the heart and rotate it along its lon-
                                                      to 66 years {411}. Teratomas generally               gitudinal axis. Intrapericardial teratomas
                                                      occur in infants while adults tend to have           are usually located on the right side of
                                                      malignant germ cell tumours. Over 75%                the heart, displacing the organs to the
                                                      of cardiac teratomas occur in children               left and posteriorly; those located on the
                                                      under age 15. There is a slight female               left side will produce the opposite effect.
Fig. 4.42 Pericardial teratoma. T1-weighted spin      predominance. Symptoms include respi-                Teratomas are usually attached by a
echo MR image in the coronal plane showing large      ratory distress, pericardial tamponade,              pedicle to one of the great vessels with
pericardial teratoma (T). The right atrium (RA) is
                                                      and cyanosis. Occasionally mediastinal               arterial supply directly from the aorta.
compressed by the tumour.
                                                      teratomas in adults may secondarily
                                                      involve the pericardium.                             Histopathology
survive 6 months, and an exceptional                  Due to the routine use of fetal echocar-             Teratomas of the heart are similar to
patient may live as long as 48 months                 diography, an increasing number of peri-             extracardiac teratomas. A minority of
{248}.                                                cardial teratomas are being diagnosed in             germ cell tumours of the pericardium are
                                                      second and third trimester fetuses {1615,            yolk sac tumours {248,411,1792}.
Germ cell tumours                                     1786,2005}. Neonates may die at birth
                                                      from cardiac tamponade and cardiac                   Histogenesis
Definition                                            compression. Prenatal resection and                  The cell of origin of extragonadal ter-
A neoplasm of germ cell origin classified             intrauterine pericardiocentesis have                 atoma, including pericardial teratoma, is
by histologic type into seminoma (dys-                been successfully accomplished {1615,                the primordial germ cell. Although nor-
germinoma), embryonal carcinoma, yolk                 1935}.                                               mal germ cells migrate from the yolk sac
sac tumour (endodermal sinus tumour),                 Intramyocardial         teratomas       have         to the gonad, they may lodge early in
choriocarcinoma, and teratoma.                        occurred in the newborn period or in the             embryogenesis in midline structures
                                                      first 6 years of life {1615}. Most patients          such as the mediastinum.
Epidemiology                                          are symptomatic and present with con-
Approximately 100 cases of intrapericar-              gestive heart failure; rarely, a patient may         Treatment
dial germ cell tumours have been report-              be asymptomatic, or sudden death may                 Surgical excision is the only effective
                                                                                                           treatment for cardiac teratoma. Since the
                                                                                                           blood supply is usually from the root of
                                                                                                           the ascending aorta, the surgeon must
                                                                                                           perform a careful dissection and ligation
                                                                                                           of these vessels to prevent massive hem-
                                                                                                           orrhage.      Intracardiac     teratomas,
                                                                                                           because of their location in the interven-
                                                                                                           tricular septum, are more difficult to
                                                                                                           remove than pericardial teratomas.
                                                                                                           Malignant germ cell tumours require
                                                                                                           standard chemotherapy.


                                                                                                           Metastatic pericardial tumours

                                                                                                           A high percentage of pericardial biop-
                                                                                                           sies occur in patients in whom the diag-
                                                                                                           nosis of malignancy has not yet been
                                                                                                           made, either for life-threatening tampon-
                                                                                                           ade or to establish the cause of peri-
                                                                                                           carditis {1201,1499}. In about two-thirds
                                                                                                           of patients with positive pericardial biop-
Fig. 4.43 Yolk sac tumour. The patient was a young woman with a pericardial mass, detected incidentally.   sy, the clinical diagnosis is pericarditis,

                                                                                                                             Germ cell tumours 287
Table 4.03                                          the lung or an undetermined primary site.
Malignant tumours diagnosed at pericardial biopsy   Breast carcinoma, unlike lung carcinoma,
{1201}.                                             usually manifests as pericardial disease
                                                    only after the primary site is known. Other
 Tumour type           Number       Fraction        tumours found in pericardial biopsies
                                                    include lymphoma, melanoma, multiple
 Carcinoma             54           68%             myeloma, thymoma, metastatic semino-
 Adenocarcinoma        32           40%             ma {121,249,1398}. The sites of origin of
 Squamous cell         14           18%             tumours discovered initially at pericardial
 Large cell             7            9%             biopsy are shown in Table 4.03.
 Small cell             1            1%             The distinction between reactive              Fig. 4.44 Metastatic pericardial tumors. Gross large
 Lymphoma              12           15%             mesothelial hyperplasia and metastatic        metastatic nodules in cardiac chambers and
 Sarcoma                7            9%             carcinoma can be difficult, and is assist-    myocardium (renal cell carcinoma).
 MFH                    3            3%             ed by immunohistochemistry. The pres-
 Angiosarcoma           2            2%             ence of carcinoembryonic antigen,
 Leiomyosarcoma         1            1%             berEP4, B72.3 antigen, and Leu M1             with pericardial malignant lymphoma or
 Neurofibrosarcoma                                  favour carcinoma over mesothelial             with involvement by thymoma often fare
 Thymoma                5            6%             hyperplasia. Calretinin and cytokeratin       significantly better.
 Melanoma               2            2%             5/6 reactivity favour the diagnosis of a
                                                    mesothelial process.
 Total                 80           100%            The treatment of malignant pericardial
                                                    disease includes establishing a pericar-
                                                    dial window, sclerosis with tetracycline or
                                                    other agents, and radiation therapy
and in the remainder, tamponade. False              {1069}. Malignant pericardial effusions
negative biopsies may occur due to sam-             are generally a sign of rapidly progres-
pling, and it is not uncommon to have a             sive disease, necessitating emergency
positive cytology and a negative biopsy.            treatment. Patients with metastatic peri-
Most adenocarcinomas presenting as                  cardial disease have a mean survival of
pericardial metastases originate either in          4.3 months {1201}. In contrast, patients




288 Tumours of the heart

				
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