Abstract
This chapter surveys the entire spectrum of tumours that are described in the fetus, infant and child. The commoner tumours (rhabdomyoma, fibroma, teratoma, myxoma) are discussed in detail, but there is also extensive discussion of rarer tumours such as fatty tumours and vascular tumours and even rarer entities such as juvenile xanthogranuloma or inflammatory myofibroblastic tumour. A brief section is devoted to primary malignant tumours of the heart and to metastatic tumours. Finally, there is discussion of pseudoneoplasms that may be seen in children.
13.1 Introduction
Primary tumours of the heart in children are rare [1], with a reported incidence of 1 in 10 000 infant autopsies [2]. They may develop in utero. Rhabdomyoma, fibroma and teratoma account for the majority of cases. Malignant tumours are extremely rare, and only a few cases have been reported [3]. Symptoms depend upon the location and the size of the tumour. Murmur, arrhythmia, cyanosis, respiratory distress or cardiac failure are the presenting features in the neonatal period. In the fetus the presenting features are arrhythmia, cardiac failure and hydrops [4]. In spite of their benign histology they may have significant morbidity and even mortality [5].
13.2 Rhabdomyoma
Rhabdomyoma is the commonest fetal and neonatal primary cardiac tumour [6]. It may be single or multiple (Figure 13.1). If multiple, it is much more likely to be associated with tuberous sclerosis [7]. Tuberous sclerosis is an autosomal dominant condition caused by mutations in the genes TSC1 or TSC 2 that encode the proteins Hamartin and Tuberin respectively [8]. These proteins act as inhibitors of mTOR Complex 1, and hyperactivation of this pathway is thought to underlie the clinical manifestations of tuberous sclerosis [9]. Because spontaneous regression is well documented for rhabdomyoma [10], resection is not indicated unless there is persistent arrhythmia or haemodynamic compromise. The prognosis is good if not associated with tuberous sclerosis. When secondary to tuberous sclerosis, the survival of perinatally diagnosed cases is only of the order of 20% [11].
Rhabdomyomas are well circumscribed and lie within the myocardium (Figure 13.2). They may bulge into the ventricular cavity and cause obstruction of the ventricular outlet (Figure 13.3). Macroscopically they are pale tan in colour. Histologically, the tumour is composed of large cells with clear cytoplasm. The nucleus is connected by strands of cytoplasm to the cell membrane, giving rise to so-called spider cells (Figure 13.4). There is a variable amount of fibrous tissue dividing the tumour into lobules and there may be small foci of calcification (Figure 13.5), but this is never a prominent feature. By immunohistochemistry, rhabdomyoma cells express the muscle markers desmin, actin and myosin. There is focal staining of the cytoplasm for HMB45 [12]. Histiocytoid cardiomyopathy may cause confusion because of its multiple nodules, but the cytological appearance of the cells is quite different (Figure 13.6). A single case of an entity called localised nodular hypertrophy has been described in the right ventricular myocardium in a 20- to 21-week non-macerated stillbirth that mimics rhabdomyoma [13]. The significance of this report is, as yet, unclear.
Figure 13.2 Rhabdomyoma. A histological section from rhabdomyoma stained with Masson’s trichrome stain. The tumour cells are large with well-defined cell borders and central nuclei. The cytoplasm is clear and many of the nuclei are connected to the cell membranes by strands of cytoplasm to give the appearance of “spider cells”.
Figure 13.3 Rhabdomyoma bulging into ventricular lumen. Fetus aged 24 weeks. The heart is cut in a simulated long-axis echocardiographic view and shows a large rhabdomyoma of the free wall of the left ventricle bulging into the left ventricular cavity and occupying much of it.
Figure 13.4 A high-power histological section of rhabdomyoma showing spider cells. A mitotic figure is present in this field.
Figure 13.5 A histological section of rhabdomyoma showing small flecks of basophilic calcification. In contrast to cardiac fibroma where calcification is common, calcification is unusual in rhabdomyoma – and never extensive.
Figure 13.6 Comparison of cytology of rhabdomyoma and histiocytoid cardiomyopathy. A section from a case of histiocytoid cardiomyopathy to show their quite distinct morphology. The rhabdomyoma cells are large with clear cytoplasm. The histiocytoid cells are small and have finely vacuolated eosinophilic cytoplasm because of their content of mitochondria and lipid.
13.3 Fibroma
Fibroma is the second most common tumour of the heart in children [14]. It is especially common in the infant. It is almost always single. Cardiac fibroma has been described in association with naevoid basal cell carcinoma syndrome (Gorlin–Goltz syndrome) [15], an autosomal condition, the gene for which (PTCH1), is located on chromosome 9q22.3 and is a tumour suppressor gene encoding a transmembrane receptor for sonic hedgehog [16]. More recently, molecular genetic analysis of three cases of sporadic cardiac fibroma demonstrated homozygous loss of the PTCH1 gene locus in two and heterozygous loss in one, supporting a somatic role of the PTCH1 tumour suppressor gene in sporadic cardiac fibromas [17].
Fibroma is generally located in the interventricular septum or left ventricular free wall (Figure 13.7), but may be sited in either ventricular or even atrial wall and may cause obstruction of the ventricular outflow tracts resulting in hydrops or intrauterine death in the fetus, or cardiac failure post-natally. The tumour may induce cardiac arrhythmia, which is occasionally fatal [18].
Figure 13.7 Fibroma. Viewed from the epicardial surface, this heart containing a fibroma shows that the tumour extends to the epicardium and is closely related to the epicardial vessels.
The tumour is rounded and non-encapsulated and has a firm, white and whorled cut surface. It may achieve a size of up to 10 cm (Figure 13.8). It may surround the epicardial coronary arteries, precluding surgical removal. Histologically the tumour exhibits abundant collagen that contains uniform spindle cells (Figure 13.9). The cellularity is variable; some areas may be rather myxoid or resemble angioma, and cystic change is described (Figure 13.10) [19]. Calcification is also common (Figure 13.11). Mitotic figures may be seen in tumours in infants but are rare in older children. The margins of the tumour interdigitate with surrounding normal myocardium (Figure 13.12). By immunohistochemistry, the tumour cells are smooth muscle actin positive but are desmin negative [20].
Figure 13.8 Obstructive fibroma causing sudden death. Four-month-old male infant with no other abnormalities who died suddenly and unexpectedly. At post-mortem there was a large firm white tumour in the heart. This simulated four-chamber view of the heart shows a firm white tumour occupying much of the inferior and free walls of the left ventricle. In places the border of the tumour is well demarcated, but in others it blends imperceptibly with the surrounding normal myocardium.
Figure 13.9 Histology of fibroma. The tumour is composed of fibroblasts with wavy elongated nuclei and indistinct cell borders. The cells are arranged in roughly parallel fashion and there is abundant fibrillary interstitial collagenous fibrous tissue.
Figure 13.10 A focus of extramedullary haematopoiesis within a fibroma.
Figure 13.11 Calcification of fibroma. Flecks of calcification within the stoma of a cardiac fibroma. This is a common occurrence in fibroma.
The tumour does not show the same propensity to undergo spontaneous regression as rhabdomyoma [19], and if symptomatic, surgical resection is required. Cardiac transplantation may be the only satisfactory solution in the more complicated case.
13.4 Teratoma
These tumours are not common: among 22 congenital extragonadal teratomas reported from the University of California, San Francisco in 2005, only one was located in the heart [21]. Most teratomas of the heart occur within the pericardial cavity, usually attached to the epicardial surface (Figure 13.13) near the great arteries, but they may also be intramural (Figure 13.14) [22]. They are well recognised to occur in the fetus in utero, the Children’s Hospital of Philadelphia being able to report on eight cases of suspected intrapericardial fetal teratoma between 2008 and 2015 [23] with a median age of presentation of 26 weeks. The tumours are large and, in common with other congenital teratomas, have a multicystic cut surface (Figure 13.14), an appearance that permits them to be identified on echocardiography. Growth tends to be rapid. Histologically, they consist of the usual elements found in congenital teratomas (Figure 13.15), including immature elements [21]. Yolk sac elements may be present [24]. Presentation is with cardiac failure because of the compressive effect of the tumour. There may be pericardial effusion with cardiac tamponade. Surgical resection is required. For teratoma in the fetus over 28 weeks’ gestation an EXIT procedure may be employed. Successful resection at less than 28 weeks is reported, but before the onset of significant hydrops [23].
(A) Successful surgical removal in two pieces together measuring approximately 3.4 × 1.6 × 1.2 cm. The smooth endocardial surface contrasts with the irregular reception margin.
(B) The cut surface is mucoid with multiple small cysts. Histologically the tumour was largely mature with foci of immature neuroepithelium.
Figure 13.14 Cardiac teratoma surgical excision. One-day-old infant with antenatally diagnosed teratoma arising from right ventricle and protruding into right ventricular outflow.
13.5 Myxoma
Myxoma accounts for about one-tenth of all cardiac tumours in children. It is very rare in infancy, but has been described in the fetus [25]. Myxoma may occur in association with the Carney complex [26], a multiple neoplasia syndrome caused by inactivating mutations in the gene PRKAR1A on chromosome 17q24. The vast majority arise from the left atrium on the septum near the oval fossa. About 20% have multiple tumours. Constitutional symptoms are seen in 20% of patients and consist of weakness, malaise, fever and haematological symptoms such as anaemia, hypergammaglobulinaemia and increased sedimentation rate. Systemic symptoms appear to be related to IL-6 production by tumour cells [27]. The tumours are polypoid, lobulated and gelatinous (Figure 13.16). Thrombosis and haemorrhage are common, and they may be partly calcified. Histologically they consist of a myxoid matrix rich in glycosaminoglycans and contain stellate cells with scanty eosinophilic cytoplasm (Figure 13.17). They may contain foci of extramedullary haemopoiesis or bundles of smooth muscle. Calretinin stains the cells [28]. The cells also stain for vimentin, VEGF and VEGFR, alpha-1-antichymotrypsin and plakophilin. They are variably reactive with antibodies to S-100, SMA, desmin, alpha-1-antitrypsin, synaptophysin, NSE, Factor VIII, CD31 and CD34 [27].
(A) Section through a myxoma showing short runs of lepidic cells set in a myxoid matrix.
(B) A higher power view to show the lepidic cells.
Figure 13.17 Myxoma.
The tumours may result exceptionally in sudden death by obstruction of the ventricular outflow (Figure 13.18).
(A) Four-year-old boy, previously fit and well, who died suddenly following a mild febrile illness. At post-mortem he was found to have a large myxoma arising in the right ventricle and obstructing the right ventricular outflow like a ball valve.
Figure 13.18 Obstructing myxoma.
13.6 Vascular Tumours
The literature on vascular tumours of the heart is bedevilled with terminological confusion. Many of the publications are single case reports, and they employ the now discarded terms capillary haemangioma and cavernous haemangioma. Very few use the current International Society for the Study of Vascular Anomalies (ISSVA) classification [29] of vascular anomalies, or even its predecessor. Even in reports of tumours in infants, there are very few reports that have assessed GLUT-1 antibody staining of the lesions positively to confirm congenital infantile haemangioma [30].
At all events, vascular tumours of the heart are rare. They account for between 2% and 9% of all cardiac tumours [30, 31]. Approximately 25% of all cardiac haemangiomas occur in infants and children [32], and they may be detected in utero or at any age post-natally. Cardiac vascular tumours are usually sporadic. The presenting symptoms depend on location within the heart; arrhythmias or sudden death can occur if the tumour is present in the basal part of the ventricular septum; surgical resection is feasible in other locations. Some are associated with extracardiac haemangiomas [30]. A few exhibit the Kasabach–Merritt phenomenon [33].
Macroscopically, haemangioma may project into the cavity of either atrium or ventricle, or it may be largely intramural. The right atrium is the favoured location (Figure 13.19) [34]. Histologically, haemangioma comprises variable mixtures of small capillary sized vessels, large vessels with thin fibrous walls and thick-walled vessels. The stroma may be myxoid and may contain abundant fibrous and adipose tissue. The lesion may resemble an intramuscular haemangioma, although intramuscular haemangioma is now regarded as a venous malformation in the new ISSVA classification [35]. They express vascular markers CD34 and CD31 in the lesional endothelium, and some are positive for GLUT-1 [30]. “Cavernous haemangiomas” have been described in the mitral [36] and tricuspid valves. The tumours may regress (Figure 13.20).
(A) Incidental post-mortem finding of a nodule of tissue in the right ventricular outflow tract.
(B) Histological examination shows fibrous tissue containing multiple obliterated vascular spaces, most likely representing a regressed haemangioma (EvG stain).
Figure 13.20 Regression haemangioma.
Blood cysts of the cardiac valves are dealt with as non-neoplastic in the section on normal heart.
Epithelioid haemangioendothelioma, consisting of cords of epithelial-like endothelial cells set in a fibrous stroma, has been reported in infants, and kaposiform haemangioendothelioma is also described [33].
Lymphangioma affects predominantly the pericardium where it gives rise to pericardial effusion and may cause tamponade (Figure 13.21) [37]. They may also occur in the ventricular myocardium, atrium or atrioventricular region, and they commonly present with congestive heart failure, syncope and palpitations or with the effects of embolism.
Biopsy shows numerous thin-walled vascular channels with irregular smooth muscle in their walls and with focal collections of lymphocytes. The lesional endothelium was positive for the lymphatic endothelial marker D2–40.
13.7 Cystic Tumour of the Atrioventricular Node
Cystic tumour of the AV node is a benign, cystic mass located at the base of the atrial septum in the region of the AV node [38, 39]. It has been described from infancy throughout childhood but has not been described in the fetus. Microscopically, it is composed of solid and/or cystic structures of epithelial cells with a smaller population of neuroendocrine cells (Figure 13.22). The epithelial cells show immunohistochemical positivity for cytokeratins (CAM 5.2, AE1/AE3), CEA, EMA and bcl-2. The endocrine cell population is positive for chromogranin, synaptophysin and TTF-1. The lesional cells are negative for vimentin, calretinin, CD 31 and WT-1. It may be found as an incidental finding at autopsy or produce syncope or sudden death associated with complete heart block. Almost all published cases are diagnosed post-mortem. More recently, cases have been diagnosed ante-mortem and successfully treated by surgical excision.
(A) A histological section through the area of the AV node showing cystic spaces and nests of epithelial cells at the site of the node.
(B) A higher power view of the tumour showing nests of endocrine-like cells.
(C) Cystic AV node tumour showing a cyst lined by a double layer of epithelium.
Intracardiac teratoma may mimic it [40]. Cystic tumour of the AV node bears histological and immunohistochemical similarities to solid cell nests in the thyroid, and this has prompted some to postulate an origin from heterotopic ultimobranchial tissue [38].
13.8 Inflammatory Myofibroblastic Tumour
This is a tumour of intermediate biological potential with risk of recurrence (25%) and low metastatic potential (2%) [41], which in the past has also been called plasma cell granuloma, inflammatory pseudotumour and inflammatory fibrosarcoma. It is rare in the heart with fewer than 60 reported cases [42], and presentation is usually in children and young adults with approximately one-third of cases in infants. It arises in the cardiac chambers, usually protruding as a polyp from the endocardium of either atria or ventricle or the valves (Figure 13.23). It may present with sudden death sometimes from occlusion of a coronary artery (Figure 11.24) [43]. Histologically the tumour is composed of plump spindle cells in a variably collagenous stroma and with an inflammatory cell component of plasma cells and lymphocytes (Figure 11.25). The tumour may vary in appearance from area to area, being more compact in some areas, more myxoid in others and more collagenous in others. By immunohistochemistry the tumour cells are positive for vimentin, smooth muscle actin and muscle-specific actin in the majority of cases with variable positivity of ALK [44]. In contrast to cases in the lung where approximately 60% are ALK positive, only about 10% of cardiac cases show positivity for ALK.
Figure 13.24 Inflammatory myofibroblastic tumour. Epicardial coronary artery from the same case as in Figure 13.23 showing occlusion of its lumen by embolic tumour.
13.9 Juvenile Xanthogranuloma
Juvenile xanthogranuloma is the most frequent type of non-Langerhans cell histiocytosis. It most commonly presents in infancy and early childhood with lesions on the skin of the head, neck and trunk that appear abruptly and usually undergo spontaneous regression. Involvement of tissues other than skin, although rare, may occur in addition to the cutaneous form, or in isolation. The sites most frequently affected are the eye, deep subcutaneous tissues, lung and liver. Involvement of the heart is exceptionally rare, with only seven reports found in literature in the English language, all affecting infants [45]. It presents as a pericardial based mass (Figure 13.26A), usually with effusion. The cells stain positively for histiocyte markers (Figure 13.26B,C). Removal is the treatment of choice, and, if confined to the heart, the prognosis is good.
(A) A section through a pericardial-based tumour showing the dense inflammatory character of the tumour.
(B) Staining for CD68 demonstrates the histiocytic nature of the lesion.
