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\begin{document}

\title{PEDIATRIC CARDIAC TUMORS: ECHOCARDIOGRAPHIC IMAGING FEATURES -- A
PICTORIAL REVIEW}



\author[1]{Nathalie Jeanne Bravo-Valenzuela}%
\author[2]{Eliane Lucas}%
\author[2]{Nadinne Velloso Netto}%
\author[2]{Larissa Vieira da Conceicao}%
\author[2]{Natalia Pinheiro Duque Estrada}%
\author[3]{Maria Respondek-Liberska}%
\author[4]{Edward Araujo Júnior}%
\affil[1]{Sociedade Brasileira de Cardiologia}%
\affil[2]{Hospital Geral de Bonsucesso}%
\affil[3]{Uniwersytet Medyczny w Lodzi Klinika Kardiologii}%
\affil[4]{Universidade Federal de Sao Paulo}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Cardiac tumors (CT) in children are very rare lesions, but their
diagnosis is crucial for patient management. Echocardiography is the
most used cardiovascular imaging modality in clinical practice for the
initial diagnosis of CT in pediatric patients. Knowing the
echocardiographic characteristics of CTs can enable an increasingly
early diagnosis and the identification of its most likely etiology.
Primary CTs are the most frequent in children, with benign ones being
the most prevalent. Among benign CTs, the most frequent in fetuses and
neonates are rhabdomyomas and teratomas, while in older children, they
are rhabdomyomas and fibromas. In this article we describe the
echocardiographic characteristics of the main CTs in pediatric ages.%
\end{abstract}%



\sloppy


\textbf{Title: PEDIATRIC CARDIAC TUMORS: ECHOCARDIOGRAPHIC IMAGING
FEATURES -- A PICTORIAL REVIEW}

\textbf{Short title: PEDIATRIC CARDIAC TUMORS}

\textbf{AUTHORS}

\selectlanguage{ngerman}\textbf{Nathalie Jeanne Magioli Bravo-Valenzuela\textsuperscript{1,2} MD
PhD, Eliane Lucas\textsuperscript{3,4}MD MsC, Nadinne Velloso
Netto\textsuperscript{3} MD, Larissa Vieira da
Conceicao\textsuperscript{3}MD, Natalia Pinheiro Duque
Estrada\textsuperscript{3}MD,\textsuperscript{,} Maria
Respondek-Liberska\textsuperscript{5} MD PhD, Edward Araujo
Júnior\textsuperscript{6} MD PhD.}

\textbf{AUTHORS current e-mails}

Nathalie Jeanne Magioli Bravo-Valenzuela- njmbravo@cardiol.br

Eliane Lucas -- elianelucaslu@gmail.com

Nadinne Velloso Netto- netto.nadinne@gmail.com

Larissa Vieira da Conceicao- lala.vieira2015@gmail.com

Natalia Pinheiro Duque Estrada- naty\_duquestrada@hotmail.com

Maria Respondek-Liberska- maria.respondek-liberska@uni.lodz.pl

Edward Araujo Júnior- araujojred@terra.com.br

\textbf{INSTITUTIONS}

1- Curso de Pós- Graduacao em Cardiologia da SBC/INC/INCA (Cardio
Oncology), Rio de Janeiro, RJ, Brazil

2- Discipline of Pediatrics (Paediatric Cardiology), Faculty of
Medicine, Federal University of Rio de Janeiro (UFRJ), Rio de
Janeiro-RJ, Brazil

3- Service of Pediatric Cardiology, Federal Bonsucesso Hospital, Rio de
Janeiro-RJ, Brazil

4- Postgraduate Course in Pediatrics, Pediatric Cardiology, Central
Military Hospital, Brazilian Army (Hospital Central do Exército),
Brazil- Rio de Janeiro RJ, Brazil

5- Department of Prenatal Cardiology, Polish Mother's Memorial Hospital,
Research Institute, Medical University of Lodz, Poland

6- Department of Obstetrics, Paulista School of Medicine, Federal
University of São Paulo(EPM-UNIFESP), São Paulo SP, Brazil

\textbf{Corresponding author:}

Prof. Nathalie J M Bravo-Valenzuela, MD, PhD

Rua Bruno Lobo, 50, floor 3, Rio de Janeiro-RJ, Brazil Zip code:
21941-912

tel./fax: +55-21-3938-411 e-mail: njmbravo@cardiol.br

\textbf{Data availability statement:} not applicable (no new data
generated)

\textbf{Ethics approval statement:} no required

\textbf{Financing Source :} the present study had no external funding
sources.

\textbf{Potential Conflict of Interest:} none

\textbf{ABSTRACT}

Cardiac tumors (CT) in children are very rare lesions, but their
diagnosis is crucial for patient management. Echocardiography is the
most used cardiovascular imaging modality in clinical practice for the
initial diagnosis of CT in pediatric patients. Knowing the
echocardiographic characteristics of CTs can enable an increasingly
early diagnosis and the identification of its most likely etiology.
Primary CTs are the most frequent in children, with benign ones being
the most prevalent. Among benign CTs, the most frequent in fetuses and
neonates are rhabdomyomas and teratomas, while in older children, they
are rhabdomyomas and fibromas. In this article we describe the
echocardiographic characteristics of the main CTs in pediatric ages.

\textbf{Key words}

Cardiac Masses; Echocardiography; Screening; Imaging

\textbf{Introduction}

Cardiac tumors (CTs) are rarely found in clinical practice, and are
classified into primary and secondary according to their site of origin.
In the pediatric age group, CTs occur in 0.001--0.03\% of autopsy
findings, with primary CTs (PCTs) being the most prevalent and mostly
benign (1,2). The most frequent benign PCTs in fetuses and newborns are
rhabdomyomas, teratomas, and fibromas, while in older children, they are
rhabdomyomas and fibromas. In adults, myxomas are the most common benign
PCTs (3,4,5). As for malignant PCTs, sarcomas are the most frequent,
both in children and adults. In adults, secondary malignant CTs
(metastatic) are more frequent than primary ones, unlike in the
pediatric population (5, 6, 7, 8). Characteristics such as CT density,
number, and location help to suspect the type of CT (Fig1, Table 1). The
echocardiogram is an accessible, non-invasive test, being the most used
imaging method used for the initial evaluation of cardiac masses in
routine clinical practice. In this scenario, the analysis of CT aspects
by echocardiography and its association with patient age groups and
other epidemiological aspects can have a great impact on the therapeutic
approach and clinical evolution of these patients. Although rare, CTs
should be considered as a differential diagnosis with other types of
cardiac masses such as thrombi and vegetations. The objective of this
pictorial review is to describe the characteristics of echocardiographic
images of the main types of PCT found in the pediatric population,
providing tools for its diagnosis.

\textbf{BENIGN CTs}

Most (90\%) pediatric primary CTs (primary site: heart) are benign (3).
In the fetal and neonatal period, rhabdomyomas, teratomas, and fibromas
are the most frequent. In children and adolescents, rhabdomyomas and
fibroids are the most prevalent (2,3,7). Other rarer benign pediatric
PCTs are hemangiomas, myxomas, and hamartomas (2,6). Next, we will
describe the main echocardiographic characteristics of the most frequent
benign PCTs.

\textbf{Rhabdomyomas}

Rhabdomyomas are the most common benign PCT in children, constituting
45--60\% of tumors in this age group (2,3,7,8,9). In a retrospective
study that included 27,640 patients with PCTs, Beghetti \emph{et
al.}described that rhabdomyomas were diagnosed as multiple or single CTs
when associated with a family history of tuberous sclerosis or the
involvement of other organs (CNS, kidneys, and skin) (7,8). Rhabdomyomas
are homogeneous masses and variable in size. In general, they are
present as multiple, well-delimited masses (in \textgreater{}60\% of
these patients) or, less commonly, as a pedunculated mass in the cardiac
cavity (Figures 2 A and B/Video clip 1). They typically occur in
ventricular (intracavitary) cardiac chambers, both to the left and to
the right, with an equal distribution (9,10). Rhabdomyomas can also be
located in the interventricular septum. Occasionally, this CT can be
intramural.

Most patients do not have symptoms; however, depending on their
location, rhabdomyomas can cause arrhythmias (when located in the
atrioventricular region), heart failure (HF), and signs of low cardiac
output ( ventricular outflow tract obstructing the flow) (10). In cases
where there are hemodynamic repercussions, pharmacological treatment
(Everolimus- rapamycin inhibitor) or surgical treatment may be indicated
(7, 11, 12,13).

They usually occur in the fetal period or during the first year of life
(14), being hormone-dependent CTs that can grow in the fetal period
until the 32\textsuperscript{nd} week of pregnancy. The presence of
multiple cardiac masses on obstetric US and/or fetal echocardiography
should draw attention to the diagnosis of rhabdomyomas. In some cases,
the masses can be located in the ventricular outflow and/or inlet tracts
and be large in size. In such cases, blood flow obstruction may occur,
with risk of HF and fetal death. In the postnatal period, there may be a
reduction or even complete regression of tumor masses, especially in
early childhood. There is a strong association between rhabdomyoma and
tuberous sclerosis, especially in cases of multiple cardiac masses.
About 60--80\% of patients with rhabdomyomas have tuberous sclerosis
(6,7,15), which is a genetic syndrome with variable clinical
presentation, including cognitive deficit, seizures, multiple facial
angiofibromas, skin patches (hypochromic, ``coffee au lait''), multiple
retinal hamartomas, and cardiac rhabdomyomas, among other features. The
most common fetal and neonatal clinical presentation of tuberous
sclerosis is rhabdomyoma-type CT. Therefore, the presence of multiple
CTs in fetuses and children should draw attention to the diagnosis of
rhabdomyoma and its association with tuberous sclerosis (Fig 3). The
identification of mutations in the \emph{TSC1} or \emph{TSC2} genes is
sufficient for the diagnosis of tuberous sclerosis, and genetic research
should be requested in cases of rhabdomyomas (16,17).

\textbf{Fibromas}

Although rare, fibromas correspond to the second most common benign PCT
in pediatric patients, except in fetuses and neonates (2,7).

On echocardiography, these CT usually present as a large solid
myocardial mass (single tumor mass) that is well-delimited,
non-contractile, echogenic, and heterogeneous within the myocardium (Fig
4/ Video clip 2). They may have calcifications in their central portion
that are pathognomonic, reflecting a poor blood supply to the tumor.
Calcification is an important tool that makes it possible to
differentiate fibroma from rhabdomyoma within a single tumor mass. The
most common fibroma locations are the interventricular septum and the
ventricular free wall, while its extension into the ventricular cavity
can lead to obstruction and symptoms of HF. Alternatively, myocardial
location can lead to arrhythmias (3,19).

These tumors do not regress spontaneously and often require resection.
Surgical treatment for excision of the CT is recommended, and can be
subtotal in other to minimize the loss of myocardial mass. If the
evolution to myocardial failure or involvement of a large cardiac area
with impossibility of complete resection of the tumor occur, a heart
transplant is considered.

Patients with multiple basal cell carcinomas should be screened for
cardiac fibroids (Gorlin syndrome) (20). Gorlin syndrome is an autosomal
dominant disease caused by a mutation in the \emph{PTCH1} gene. It is
characterized by skeletal and developmental abnormalities, with a
tendency for neoplasms such as medulloblastomas, basal cell carcinomas,
and cardiac fibromas. In these cases, genetic counseling is crucial, and
diagnosis is carried out through DNA analysis, even from the prenatal
period (21).

\textbf{Myxomas}

Cardiac myxomas are the most common PCTs in adults, usually presenting
between the ages of 30 and 60 years and most frequently in women.
However, they are rare in children. Most of these PCTs (75--80\%) are
located within the left atrium, characteristically originating from the
middle portion of the atrial septum by a narrow pedicle, while 15--20\%
originate in the right atrium (22).

On echocardiography, myxoma usually presents as a single mobile and
heterogeneous (pedunculated) atrial mass (Fig 5). Polypoid myxomas are
larger with a smooth surface and a rough core, including cystic areas
due to hemorrhage and necrosis. Papillary myxomas tend to be smaller and
have an elongated appearance with multiple villi. Papillary myxomas are
associated with embolic phenomena, while polypoid myxomas tend to
obstruct blood flow, with possible symptoms of HF being the most
frequent (Fig 5 B and Video clip 3). Patients with myxomas may present
with systemic symptoms such as fever, weight loss, night sweats,
arthralgia, and exhibit laboratory abnormalities such as anemia and
elevations in inflammatory markers.

Cardiac myxomas may be associated with Carney complex, which is a
syndrome inherited in an autosomal dominant pattern (23). Carney complex
results in several neuroendocrine tumors and cardiac and cutaneous
myxomas associated with changes in skin pigmentation resulting from
mutations in the \emph{PRKAR1A} gene (Figure 6). Myxomas in this
syndrome occur at an earlier age and tend to recur more frequently
(24,25,26,27).

An atrial myxoma warrants resection due to the risk of cardiovascular
embolization, complications, and sudden death. Surgical resection is
associated with low operative mortality and good outcomes. A small
percentage of patients

(up to 5\%), typically those with a family history, show smaller tumors
or ventricular locations and are at risk of recurrence or new myxomas,
highlighting the importance of periodic follow-up.

\textbf{Teratomas}

Teratomas are PCTs in which 70\% of cases occur in childhood, being more
frequent in fetuses and neonates (3). As the main echocardiographic
characteristics of teratomas, we can cite large masses with a
non-homogeneous density and a cystic and multilobulated aspect, as they
contain all germinative layers (3, 28). Their most common location is
the pericardium, close to the base of the great arteries (adhered to the
aorta and pulmonary arteries), and the superior vena cava. In some
cases, extrinsic compressions of these vessels can occur (3,28). These
patients may have dyspnea and signs of HF. In general, pericardial
effusion is present, and may progress to cardiac tamponade, especially
in fetuses (6,28).

Teratomas are frequently detected on prenatal ultrasound or fetal
echocardiography, with a risk of fetal death from extrinsic compression
or cardiac tamponade (Fig 7). These fetuses may benefit from prenatal
intervention (3,28,29). Teratomas have a good postnatal prognosis after
curative surgical resection and, in general, show no recurrence in
long-term follow-up (7,30).

\textbf{Hemangiomas}

Hemangiomas are rare CTs and are most commonly located in the right
atrium and right ventricle. Depending on their location and size, they
can cause systemic venous congestion, right ventricular outflow tract
obstruction, elevated right ventricular end-diastolic pressure, and
irreversible right ventricular dysfunction. On electrocardiography, ST
segment abnormalities, signs of right ventricular hypertrophy, signs of
pre-excitation, and arrhythmias can be found. The presence of
pericardial effusion is prevalent in hemangioma cases (31). Remarkably,
this type of CT has the best prognosis due to the possibility of
spontaneous regression (32).

\textbf{Malignant tumors}

Malignant tumors account for about 15\% of CTs and are rather rare in
childhood (30). They typically show rapid growth, local invasion,
hemorrhagic pericardial effusion, and precordial pain. Among them, the
most prevalent are sarcomas and rhabdomyosarcomas.

\textbf{Sarcomas}

Sarcomas are the most common among malignant CT and are typically
diagnosed in the mid-4\textsuperscript{th} decade of life.
Undifferentiated sarcomas appear as a broad mass on echocardiography,
typically in the left atrium (which allows differential diagnosis with
myxomas), heterogeneous echogenicity, and hypoechoic areas, which
indicate tumor necrosis. The most common sarcoma in the heart is
angiosarcoma. It is often located to the right, especially in the right
atrium. Echocardiograms show a lobulated mass, clearly heterogeneous
with areas of necrosis and hemorrhage, and without a pedicle,
differentiating it from other tumors. Sarcomas tend to show direct
involvement with the pericardium, resulting in hemorrhagic effusion,
which may or may not cause tamponade.

Angiosarcomas tend to replace the cardiac wall of the right atrium and
fill it throughout the chamber. Depending on their location and
hemodynamic repercussions, they can show signs and symptoms of
pericardial precordial pain, obstruction, congestion, dyspnea, and
fatigue. Unfortunately, metastasis to the lung is common at diagnosis
and the prognosis is restricted, even after surgical approach, due to
recurrence and metastasis (3,31).

\textbf{Rhabdomyosarcomas}

Rhabdomyosarcomas are the 2\textsuperscript{nd} most common type of
malignant tumors and can appear in any cardiac structure, with no
preferred locations. They tend to occupy multiple areas and can cause
obstruction. They grow fast, involve the pericardium early, and result
in a poor prognosis (4,31).

Leiomyosarcomas, osteosarcomas, fibrosarcomas, and undifferentiated
sarcomas are other rarer types that have a very poor prognosis (3,21).

\textbf{Lymphomas}

In general, due to cardiac involvement in patients with Hodgkin's and
non-Hodgkin's lymphoma, however. Primary cardiac lymphomas show
increased incidence in immunocompromised patients, those at
post-transplantation, or those infected with HIV. These tumors are most
commonly diffuse large B cell lymphoma. On echocardiography, they are
homogeneous, infiltrative, leading to wall thickening and hemodynamic
restriction, with nodular masses occupying the cardiac chambers, mainly
the right ones, especially the right atrium (Fig 8; Video clip 4). The
atrioventricular region can be affected, causing the involvement of the
right coronary artery and pericardial effusion.

Transesophageal echocardiography is the best imaging technique and
should be performed when there is a need to identify this type of tumor.
Depending on its location, it can generate symptoms of inlet
obstruction, leading to vena cava syndrome, HF, and arrhythmias such as
complete atrioventricular block and embolism.

Diagnosis can be made by pericardial effusion cytology or echo-guided
biopsy. Diagnosis by cytology is the key to the prognosis of lymphoma,
which is usually much better than that of other primary CT, especially
if patients are eligible for adequate chemotherapy. Radiotherapy is less
favorable and surgical resection of the entire tumor is very difficult
(4,31).

\textbf{Mesothelioma}

Mesotheliomas represent half of the primary pericardial tumors, the
other half being benign (teratoma, fibroma, and lipoma). Their symptoms
include chest pain, cough, palpitation. These tumors form bulky nodules
within the pericardial cavity, circumventing the heart, mimicking
pericarditis, and cardiac tamponade (30). Echocardiography typically
reveals pericardial effusion and a tumor involving the heart, but a mild
mass may not be seen. The prognosis is restricted, although surgery and
radiotherapy can provide palliative benefits.

\textbf{Metastasis}

Cardiac metastasis is not uncommon, with an incidence of around
0.7--3.5\% in the general population, but reaching up to 7.1\% in people
with known malignancies (3). They can invade the heart by hematogenous
dissemination, or by contiguity, or via venous/ lymphatic route. Heart
metastasis is most common in primary breast and lung tumors, esophageal
carcinoma, malignant lymphoma, leukemia, and malignant melanoma (Fig 9).
Melanoma is more prone to cardiac metastasis due to its hematogenous
spread. The pericardium is more affected, with an effusion that can even
be asymptomatic. However, metastasis should be considered in any patient
with a known malignant disease and new cardiovascular symptoms.

Echocardiography should be performed as an initial diagnostic test to
assess the presence of metastatic implants, and it can be complemented
with other imaging tests. Unfortunately, metastatic cardiac disease
occurs in patients with already disseminated disease, making the
prognosis quite poor when identified (3,33).

\textbf{Differential diagnosis}

The main differential diagnosis of CTs is thrombi, which occur more
frequently on the right side of the heart and are related to a clinical
history of central venous catheter use (Fig 10 A) or structural heart
diseases with dilated cardiomyopathy (Fig 10 B). In general, cardiac
thrombus appears as mural mass or a pedunculated and mobile intraluminal
mass (Fig 10). Unlike CT, they are avascular and do not show increased
echogenicity on contrast-enhanced echocardiography (3,30,34,35).

Left ventricular (LV) diverticulum is another differential diagnosis
characterized by the image of a structure that connects to the
ventricular cavity by a narrow pedicle and presents asynchronous
contractility with the LV myocardium (Fig 11; Video clip 5) (3,36).

Other differential diagnoses are pericardial cysts and vegetations, the
latter being associated with a clinical history of fever and, in
general, the presence of structural heart disease (valvular disease or
shunt heart disease with communications between the left and right sides
of the heart) (Fig 12; Video clip

6 and 7) (3, 30,37). Vegetations generally appear as an echogenic mass
attached to atrial side of atrioventricular valves or ventricular side
of semilunar valves. Indeed, important features of vegetations on
echocardiography are: isoechoic to tissue, independent movement and
associated with valvular regurgitation (37,38,39).

So far, we are able to detect CT, to make diagnosis, to treat the
patients and to make a follow-up, but in this chain the missing link is
very first one: why and what is the cause of cardiac tumors. To answer
this question a good international cooperation is needed, but also
probably national data bases. Is this possible that air pollution may
take a role ? First such suggestion is coming from Poland (40).

\textbf{Conclusions:}

Although CTs are rare in the pediatric age group, their early diagnosis
can have an impact in the conduct and prognosis of these patients.
Primary CTs are most frequent in children, with a high prevalence of
benign CTs\textbf{.} Echocardiography is the most used cardiovascular
diagnostic test and provides important tools for an initial diagnosis.
Knowledge of the echocardiographic characteristics of pediatric CTs can
enable the identification of different types of CT and their
differential diagnosis with other images of masses such as thrombi,
contributing to treatment optimization (Figure 13).

\textbf{References}

1. Centofanti P, Di Rosa E, Deorsola L, Deorsola L, Dato GM, Patane F,
et al. Primary cardiac neoplasms: early and late results of surgical
treatment in 91 patients. Ann Thorac Surg. 1999;68:1236--41.

2. Uzun, O., Wilson, D.G., Vujanic, G.M. et al. Cardiac tumours in
children. Orphanet J Rare Dis. 2007; (2) 11:
1750-72/https://doi.org/10.1186/1750-1172-2-11.

3. Tao TY, Yahyavi-Firouz-Abadi N, Singh GK, Bhalla S. Pediatric cardiac
tumors: clinical and imaging features. Radiographics. 2014
Jul-Aug;34(4):1031-46. doi: 10.1148/rg.344135163. PMID: 25019440.

4. Pinede L, Duhaut P \& Loire R. Clinical presentation of left atrial
cardiac myxoma. A series of 112 consecutive cases. Medicine 2001; 80:
159--72. doi:10.1097/00005792-200105000-00002.

5. Sarjeant JM, Butany J \& Cusimano RJ. Cancer of the heart:
epidemiology and management of primary tumors and metastases. American
Journal of Cardiovascular Drugs 2003; 3: 407--21

6. Burke A,Virmani R. Pediatric heart tumors. Cardiovasc Pathol
2008;17(4):193--8.

7. Beghetti M, Gow RM, Haney I, Mawson J, Williams WG, Freedom RM.
Pediatric primary benign cardiac tumors: a 15-year review. Am Heart J
1997; 134(6):1107--14.

8. Chan HS, Sonley MJ, Moe\selectlanguage{english}s CA, Daneman A, Smith CR, Martin DJ. Primary
and secondary tumors of childhood involving the heart, peri- cardium,
and great vessels: a report of 75 cases and review of the literature.
Cancer 1985;56(4): 825--36.

9. Tzani A, Doulamis IP, Mylonas KS, Avgerinos DV, Nasioudis D. Cardiac
tumors in pediatric patients: a systematic review. World J Pediatr
Congenit Heart Surg 2017;8:624--32.

10. Penha JG, Zorzanelli L, Barbosa-Lopes AA, Aiello VD, Carvalho VO,
Caneo LF, Riso AA, et al. Tumores card\selectlanguage{ngerman}íacos em criança: análise
retrospectiva Arquivos Brasileiros de Cardiologia 2013; (100) 2:
120-126.

11. Stelmaszewski EV, Parente DB, Farina A, Stein A, Gutierrez A,
Raquelo-Menegassio AF, Manterola C, de Sousa CF, Victor C, Maki D, Morón
EM, de Abrantes FF, Iqbal F, Camacho-Vilchez J, Jimenez-Pavón J, Polania
JP, Thompson L, Bonanato L, Diebold M, Da Silva MVCP, Nashwan MWJ,
Galvani MAG, Idris OEA, Danos P, Ortiz-Lopez R, Mahmoud RAA, Gresse S,
Loss KL. Everolimus for cardiac rhabdomyomas in children with tuberous
sclerosis. The ORACLE study protocol (everOlimus for caRdiac
rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre,
placebo-controlled, double-blind phase II trial. Cardiol Young. 2020
Mar;30(3):337-345. doi: 10.1017/S1047951119003147. Epub 2020 Jan 27.
PMID: 31983379.

12. Demir HA, Ekici F,Yazal Erdem A, Emir S,Tunc\selectlanguage{english} B. Everolimus: a
challenging drug in the treatment of multifocal inoperable cardiac
rhabdomyoma. Pediatrics 2012;130(1):e243--e247.

13. Ebrahimi-Fakhari D, Stires G, Hahn E, Krueger D, Franz DN. Prenatal
Sirolimus Treatment for Rhabdomyomas in Tuberous Sclerosis. Pediatr
Neurol. 2021;125:26-31. doi: 10.1016/j.pediatrneurol.2021.09.014. Epub
2021 Sep 25.

14. Shi L, Wu L, Fang H, Han B, Yang J, Ma X, Liu F, et al.
Identification and clinical course of 166 pediatric cardiac tumors. Eur
J Pediatr 2017; 176: 253--60. https://doi.org/10.1007/s00431-016-2833-4.

15. Kocabas A, Ekici F, C\selectlanguage{english}etin II, et al. Cardiac rhabdomyomas associated
with tuberous sclerosis complex in 11 children: presentation to outcome.
Pediatr Hematol Oncol 2013;30:71--9.

16. Hinton RB, Prakash A, Romp RL, Krueger DA, Knilans TK; International
Tuberous Sclerosis Consensus Group. Cardiovascular manifestations of
tuberous sclerosis complex and summary of the revised diagnostic
criteria and surveillance and management recommendations from the
International Tuberous Sclerosis Consensus Group. J Am Heart Assoc. 2014
Nov 25;3(6):e001493. doi: 10.1161/JAHA.114.001493.

17. Lee KA, Won HS, Shim JY, Lee PR, Kim A. Molecular genetic, cardiac
and neurodevelopmental findings in cases of prenatally diagnosed
rhabdomyoma associated with tuberous sclerosis complex. Ultrasound
Obstet Gynecol. 2013 Mar;41(3):306-11. doi: 10.1002/uog.11227. PMID:
22791573.

18. Tyebally S, Chen D, Bhattacharyya S, Mughrabi A, Hussain Z, Manisty
C, Westwood M, et al. Cardiac Tumors: JACC CardioOncology
State-of-the-Art Review. J Am Coll CardioOnc. 2020; Jun 2 (2): 293-311.

19. Atallah J, Robertson M, Rebeyka IM, Dyck J, Noga ML. Antenatal
diagnosis and successful surgical removal of a large right ventricular
fibroma. Pediatr Cardiol 2006; 27(4): 493-496.

20. Mankad R and Herrmann J. Cardiac tumors: echo assessment. Echo Res
Pract. 2016 Dec; 3(4): 65-77.(DOI: 10.1530/ERP-16-0035).

21. Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome).
Orphanet J Rare Dis. 2008 Nov 25;3:32. doi: 10.1186/1750-1172-3-32.
PMID: 19032739; PMCID: PMC2607262

22. Grebenc ML, Rosado-De-Christenson ML, Green CE, Burke AP, Galvin JR.
From the archives of the AFIR: cardiac myxoma: imaging features in 83
patients. Radiographics 2002; 22: 673-689.

23. Ri\selectlanguage{english}os JC, Cha\selectlanguage{english}varri F, Morales G, et al. Cardiac myxoma with prenatal
diagnosis. World J Pediatr Congenit Heart Surg 2013; 4(2): 210-2.

24. Pack SD, Kirschner LS, Pak E, Zhuang Z, Carney JA, Stratakis
CA.Patients with the ``complex of spotty skin pigmentation, myxomas,
endocrine overactivity and schwannomas'' (Carney complex). J Clin
Endocrinol Metab. 2000; 85:3860--3865.

25. Iwata T, Tamanaha T, Koezuka R, Tochiya M, Makino H, Kishimoto I,
Mizusawa N, Ono S, Inoshita N, Yamada S, Shimatsu A, Yoshimoto K.
Germline deletion and a somatic mutation of the PRKAR1A gene in a Carney
complex-related pituitary adenoma. Eur J Endocrinol. 2015; 172:5--10.

26. Carney JA. Carney complex: the complex of myxomas, spotty
pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol
1995;14(2):90--8.

27. Borkar SS, Kamath SG, Kashyap N, et al. Carney complex: case report
and review. J Cardiothorac Surg 2011;6(1):25.

28. Respondek-Liberska MR. Fetal cardiac tumors. In: Ara\selectlanguage{ngerman}újo Júnior E,
Bravo-Valenzuela NJM, Peixoto AB, editors. Perinatal Cardiology- Part 2.
1st ed. Singapore: Bentham Science Publishers 2020;36-49.

29. Lacey SR, Donofrio MT. Fetal cardiac tumors: prenatal diagnosis and
outcome. Pediatr Cardiol 2007; 28(1): 61-67.

30. Mankad R, Herrmann J. Cardiac tumors: echo assessment. Echo Res
Pract. 2016; 3(4): 65-77.

31. Sharma J, Hirata Y, Mosca RS. Surgical repair in neonatal life of
cardiac haemangiomas diagnosed prenatally. Cardiol Young 2009; 19(4):
403-406.

32. Cartagena, AM, Levin, TL, Issenberg, H, Goldman, HS . Pericardial
effusion and cardiac hemangioma in the neonate. Pediatr Radiol 1993; 23:
384--385.

33. Huh J, Noh CI, KimYW, et al. Secondary cardiac tumor in children.
Pediatr Cardiol 1999;20(6): 400--3.

34. Ozbek N, Alioglu B, Avci Z, et al. Incidence of and risk factors for
childhood thrombosis: a single-cen- ter experience in Ankara, Turkey.
Pediatr Hematol Oncol 2009;26(1):11--29.

35. Choi SH, Jeong SI,Yang JH, et al. A single-center experience with
intracardiac thrombosis in children with dilated cardiomyopathy. Pediatr
Cardiol 2010; 31(2):264--9.

36. Ohlow MA. Congenital left ventricular aneurysms and diverticula:
definition, pathophysiology, clinical relevance and treatment.
Cardiology 2006;106 (2):63--72.

37. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke
criteria for the diagnosis of infective endocarditis. Clin Infect Dis
2000;30(4):633--638.

38. Sordelli C, Fele N, Mocerino R, Weisz SH, Ascione L, Caso P,
Carrozza A, Tascini C, De Vivo S, Severino S. Infective Endocarditis:
Echocardiographic Imaging and New Imaging Modalities. J Cardiovasc
Echogr. 2019;;29(4):149-55.

39. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore
T, Corey GR. Proposed modifications to the Duke criteria for the
diagnosis of infective endocarditis. Clin Infect Dis. 2000
Apr;30(4):633-8.

40. Wi\selectlanguage{polish}ę\selectlanguage{english}ckowska K, Pi\selectlanguage{polish}ą\selectlanguage{english}tek K, Respondek-Liberska M. Heart tumours in 33
fetuses - review of twenty-two years of the single-centre experience.
Prenatal Cardiology. 2016;(1):22-30.

\textbf{LEGENDS}

\textbf{Table}

Table 1- Typical characteristics of the most common pediatric primary
CTs.

\textbf{Figures}

Fig1- Pediatric primary cardiac tumors locations. Schematic image of the
heart with the most typical locations of where the more common different
types of pediatric primary CTs are positioned. LA: left atrium; RA;
right atrium; LV: left ventricle; RV: right ventricle.

Fig 2 -- Imaging of rhabdomyomas. Pediatric echocardiogram demonstrating
multiple ventricular masses (red arrows) with the appearance of
rhabdomyomas: (A) in the 4 chamber subcostal view (Video clip 1) and (B)
in the parasternal left ventricle (LV) view by scanning more apically
the LV. Note that the (increased) echogenicity of masses is different
from that of the myocardium of adjacent ventricular cavities. LA: left
atrium; RA: right atrium; ; Ao: aorta; RV: right ventricle; LV: left
ventricle; IVS: interventricular septum.

Fig 3- Rhabdomyoma in a case of tuberous sclerosis. Fetal echocardiogram
showing multiple masses (1, 2 ,3) in ventricular cavities and
interventricular septum in a case of rhabdomyomas and tuberous
sclerosis. LA: left atrium; RA: right atrium; Ao: aorta; RV: right
ventricle; LV: left ventricle; IVS: interventricular septum.

Fig 4- Fibroma. Transthoracic echocardiogram with the presence of a
large (single) homogeneous mass corresponding to the appearance of a
fibroma. The large single mass is detected in the left ventricle (LV)
free wall from the parasternal view by scanning the LV long (A/ Video
clip 2) and short-axis (B). The cardiac tumor was removed by cardiac
surgery and the histopathology confirmed the echocardiographic
diagnostic hypothesis. LA: left atrium; Ao: aorta; LV: left ventricle;
T: tumor (fibroma).

Fig 5- Left atrial myxoma. Transthoracic echocardiogram (apical 4chamber
view) demonstrates a large mobile mass (red arrow) in the left atrium
with irregular contours (A) and obstructing the left ventricle inlet
tract flow (B; Video clip 3). LA: left atrium; RA; right atrium; LV:
left ventricle; RV: right ventricle.

Fig 6- Left atrial myxoma (four chamber view) in a case of Carney
complex (A). Note the histopathological characteristics (red arrows
point to the myxoma cells) of this CT after surgical removal of this
cardiac tumor (B). LA: left atrium; RA; right atrium; LV: left
ventricle; RV: right ventricle.

Fig 7- Fetal teratoma. 3D Fetal echocardiogram with Power and Color
Doppler imaging demonstrating a teratoma in a fetus at 32 weeks of
gestation. Note the large pericardial mass (A) and pericardial effusion
(B). LA: left atrium; RA; right atrium; LV: left ventricle; RV: right
ventricle.

Fig 8 (Video Clip 4)- Lymphoma. Echocardiogram 2D imaging showing a
large nodular mass (lymphoma) in the right atrium (RA) cavity (red
arrow). The features of this mass in an adolescent patient infected with
the human immunodeficiency virus enabled the suspicion of this
diagnosis. LA: left atrium; RA; right atrium; LV: left ventricle; RV:
right ventricle; T: tumor (lymphoma).

Fig 9 - Transthoracic echocardiogram with a secondary cardiac tumor
(metastasis) in the aorta in an adult patient. Secondary cardiac tumors
are more frequent in the adult population than in the pediatric
population. Ao: aorta; Dao: descending aorta; T: secondary cardiac tumor
(red arrow).

Fig 10 - Cardiac thrombus. Transthoracic echocardiogram showing a
thrombus (red arrow): (A) in a the right atrium adhered to a catheter
and (B) in the LV apical wall. The first in a child with central venous
catheter and the latter in an adolescent with myocardial disease. RA:
right atrium; LA: left atrium; LV: left ventricle; T: thrombus (red
arrow).

Fig11-- Ventricular Diverticulum. Transthoracic echocardiogram (4
chamber view) in a child with left ventricular diverticulum (A). Observe
the color Doppler on the narrow pedicle demonstrating that this
structure communicates with the ventricular cavity (B/Video Clip 5). LA:
left atrium; LV: left ventricle; D: diverticulum (red arrow).

Fig 12- Mitral valve vegetation . Infective endocarditis in a pediatric
patient affecting the anterior cusp of the mitral valve on the atrial
side of this valve (A; Video clip 6). Mitral valve regurgitation is
detected using color Doppler (B; Video clip 7). LA: left atrium; LV:
left ventricle; M: mitral valve; a: anterior cusp; p: posterior cusp;
MR: mitral regurgitation; V: vegetation.

Fig 13- Echocardiographic approach of Pediatric Cardiac Tumors (PCT).

\textbf{Videos Legends}

Video 1- Rhabdomyomas. Apical four chamber view with color Doppler
showing large multiple masses located in ventricle chambers and
interventricular septum in a child with rhabdomyomas.

Video 2- Fibroma. Parasternal left ventricle (LV) long- axis view
showing a large single mass in LV in a pediatric case of cardiac
fibroma.

Video 3- Myxoma. Echocardiogram (apical 4chamber view) of a ten years
old female patient demonstrating a single large mobile mass ( myxoma) in
the left atrium with irregular contours. Note the inlet LV flow
obstruction during the diastole.

Video 4- Lymphoma. Note the nodular mass (lymphoma) occupying the right
atrium (RA) cavity in an adolescent patient.

Video 5- Fetal left ventricle (LV) diverticulum . Fetal echocardiogram
with color Doppler imaging showing the LV diverticulum (apical LV).

Video 6- Mitral valve vegetation. Transthoracic echocardiography imaging
of a mobile mitral valve vegetation attached to the anterior cusp.
Mitral valve vegetation is typically located to atrial side of its
cusps.

Video 7- Mitral valve regurgitation in a case of infective endocarditis.
2D with color Doppler imaging of vegetation with mitral regurgitation.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1--Pediatric-Cardiac-Tumors-(PCT)--locations/Figure-1--Pediatric-Cardiac-Tumors-(PCT)--locations}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5B----Atrial-myxoma-obstructing-the-left-ventricle-inlet--flow/Figure-5B----Atrial-myxoma-obstructing-the-left-ventricle-inlet--flow}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-11-B--Color-Doppler-imaging-of-LV-diverticulum--1-copy/Figure-11-B--Color-Doppler-imaging-of-LV-diverticulum--1-copy}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2B---Echocardiography-imaging-of-LV--rhabdomyomas/Fig-2B---Echocardiography-imaging-of-LV--rhabdomyomas}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2A--Multiple--rhabdomyomas-copy/Figure-2A--Multiple--rhabdomyomas-copy}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-3---Fetal-echocardiogram-in-a-case-of-rhabdomyomas/Fig-3---Fetal-echocardiogram-in-a-case-of-rhabdomyomas}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig--7A--3D-Fetal-echocardiography-Imaging--in-a-case-of-teratoma--copy/Fig--7A--3D-Fetal-echocardiography-Imaging--in-a-case-of-teratoma--copy}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5-A--Left-atrial-myxoma-(4-chamber-view)/Figure-5-A--Left-atrial-myxoma-(4-chamber-view)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-4A--LV-fibroma-(pasternal-LV-long-axis-view)--copy/Fig-4A--LV-fibroma-(pasternal-LV-long-axis-view)--copy}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-4B--LV-fibroma-(-pasternal-short-axis-view)/Fig-4B--LV-fibroma-(-pasternal-short-axis-view)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-6-B---Myxoma-cells--(histopathological--characteristics)/Figure-6-B---Myxoma-cells--(histopathological--characteristics)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-6A--Myxoma-in-a-case-of-Carney-Complex/Figure-6A--Myxoma-in-a-case-of-Carney-Complex}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-7B--Fetal-teratoma--with--pericardial-effusion--copy/Figure-7B--Fetal-teratoma--with--pericardial-effusion--copy}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-8--Right--atrial-Lymphoma/Fig-8--Right--atrial-Lymphoma}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-9---Aortic-secondary-CT-(metastatic)/Fig-9---Aortic-secondary-CT-(metastatic)}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figura-10-B---Thrombus-in-a-case-of-myocardial--disease/Figura-10-B---Thrombus-in-a-case-of-myocardial--disease}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-10-A---Right-atrial-trombus--adhered-to-a-catheter/Figure-10-A---Right-atrial-trombus--adhered-to-a-catheter}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-11-A--LV-diverticulum/Figure-11-A--LV-diverticulum}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-12-B/Fig-12-B}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-12-A--Mitral-valve-vegetation/Fig-12-A--Mitral-valve-vegetation}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-13--Echocardiograhic-approach-of--Pediatric-cardiac--tumors/Figure-13--Echocardiograhic-approach-of--Pediatric-cardiac--tumors}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/463068/articles/563136-pediatric-cardiac-tumors-echocardiographic-imaging-features-a-pictorial-review}

\selectlanguage{english}
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\end{document}

