the collaboration of Israel Meizner
IntroductionFetal tumors are rare, but they have important implications for the health
of both the fetus and the mother. The natural history and prognosis of
most fetal tumors are well known. Once a fetal tumor has been detected,
close surveillance by a multidisciplinary team of doctors is mandatory,
with anticipation and early recognition of problems during pregnancy,
labor and immediate postnatal life. When the sonographic diagnosis is
uncertain, fetal tissue biopsy may be necessary to obtain a histological
diagnosis. In rare cases, intrauterine treatment may be possible. Some
fetal tumors may be malignant and could metastasize to other fetal organs
and the placenta; maternal metastases in such cases are unknown. In contrast,
on rare occasions, maternal malignancies (melanoma, leukemia and breast
cancer) can metastasize to the placenta; in about half of the cases with
placental metastases, mostly with malignant melanoma, the tumor can metastasize
to fetal viscera.
and mechanisms of carcinogenesis
errors during embryonic and fetal maturation may result in embryonic tumors.
One hypothesis is that more cells are produced than are required for the
formation of an organ or tissue and the origins of embryonic tumors rest
in developmental errors in these surplus embryonic rudiments. Embryonic
tumors developing after infancy are explained by the persistence of cell
rests or developmental vestiges. Developmentally anomalous tissue (such
as hamartomas and dysgenic gonads) is a source of neoplasms in older children
and adults. When any of this developmentally abnormal tissue is present
at birth, it is inferred that the cells failed to mature, migrate or differentiate
properly during intrauterine life.
transformation of cells in tissue culture and in vivo carcinogenesis are
dynamic, multistep and complex processes that can be separated artificially
into three phases: initiation, promotion and progression. These phases
may be applied to the natural history of virtually all human tumors, including
embryonic ones. Initiation is the result of exposure of cells or tissues
to an appropriate dose of a carcinogen; an initiated cell is permanently
damaged and has a malignant potential. The initiated cells can persist
for months or years before becoming malignant. During the promotion phase,
initiated cells clonally expand. Promotion may be modulated or reversed
by a variety of environmental conditions. In the last phase, progression,
the transformed cells develop into a tumor, ultimately with metastasis.
Embryonic tumors can, therefore, be regarded as defects in the integrated
control of cell differentiation and proliferation. A genetic model of
carcinogenesis has also been introduced in an attempt to clarify the pathogenesis
and behavioral peculiarities of certain embryonic tumors. According to
this hypothesis, embryonal neoplasms arise as a result of two mutational
events in the genome. The first mutation is prezygotic in familial cases
and postzygotic in non-familial; the second mutation is always postzygotic.
of fetal and infantile neoplasms
neonatal and infantile tumors have a benign clinical behavior despite
histological evidence of malignancy. Examples include congenital neuroblastomas
and hepatoblastomas in the first year of life, and congenital and infantile
fibromatosis, and sacrococcygeal teratomas in the first few months of
life. The factors responsible for this ‘oncogenic period of grace’, which
starts in utero and extends through the first few months of extrauterine
life, are uncertain.
of neoplasia and congenital malformations
concept that teratogenesis and oncogenesis have shared mechanisms is well
documented by numerous examples. Probably, there is simultaneous or sequential
cellular and tissue reaction to specific injurious agents. The degree
of cytodifferentiation, the metabolic or immunological state of the embryo
or fetus, and the length of time of exposure to the agent will determine
whether the effect is teratogenic, oncogenic, both, or neither. Many biological,
chemical and physical agents known to be teratogenic to the fetus or embryo
are carcinogenic postnatally. Alternatively, a teratogenic event during
intrauterine life may predispose the fetus to an oncogenic event later
in life. This would explain neoplastic transformation occurring in hamartomas,
developmental vestiges, heterotopias and dysgenetic tissues. It is postulated
that the anomalous tissues harbor latent oncogenes which, under certain
environmental conditions, are activated, resulting in malignant transformation
of a tumor.
formal classification of fetal tumors does not exist. Apart from distinguishing
solid from cystic lesions, probably the best classification should be
by location. The main compartments of fetal tumors are the head and brain,
face and neck, thorax (including the heart), abdomen and retroperitoneum,
extremities, genitalia, sacrococcygeal region, and skin.
approach for prenatal diagnosis of fetal tumors should be based on three
sets of ultrasound signs: general signs, organ-specific signs and tumor-specific
signs. The general sonographic features, that should raise the suspicion
of an underlying fetal tumor, include:
Absence or disruption of contour, shape, location, sonographic texture
or size, of a normal anatomic structure;
Presence of an abnormal structure or abnormal biometry;
Abnormality in fetal movement;
is particularly important, because almost 50% of fetal tumors are accompanied
by this finding. The underlying mechanisms include interference with swallowing
(such as thyroid goiter or myoblastoma), mechanical obstruction (such
as gastrointestinal tumors), excessive production of amniotic fluid (such
as sacrococcygeal teratoma), and decreased resorption by lung tissue in
lung pathology. Intracranial tumors are also commonly associated with
polyhydramnios and the mechanism may be neurogenic lack of swallowing
or inappropriate polyuria.
signs include pathological changes within the tumor mass (calcifications,
liquefaction, organ edema, internal bleeding, neovascularization and rapid
changes in size and texture). Organ-specific signs are rare, but in some
cases they are highly suggestive of the condition (such as cardiomegaly
with a huge solid or cystic mass occupying the entire heart, suggesting
some cases, normal and abnormal sonographic findings may mimic fetal tumors.
Examples may vary from severe cases of bladder exstrophy (where the protruding
bladder mass appears as a solid tumor-like structure), to rare cases of
fetal scrotal inguinal hernia (where bowel loops occupy the scrotum, appearing
as huge masses).
from intracranial tumors (where the prognosis is generally poor), the
prognosis for tumors in other locations is variable and depends on the
size of the tumor (with resultant compression of adjacent organs), degree
of vascularization (with the risk of causing heart failure and hydrops),
and associated polyhydramnios (with the risk of preterm delivery).
tumors include teratomas, epidermoid, dermoid, germinoma, medulloblastoma,
meningeal sarcoma, lipoma of the corpus callosum, oligodendroglioma, gangliocytoma,
and glioblastoma, choroid plexus papilloma, tuberous sclerosis (Bourneville’s
disease), neurofibromatosis (Von Recklinghausen’s disease), and systemic
angiomatosis of the central nervous system and eye (Von Hippel–Lindau’s
tumors are exceedingly rare in children, and only about 5% arise during
fetal life; teratoma is the most frequently reported.
tumors are thought to derive from embryologically displaced cells. Brain
tumors have been produced in animals by the use of chemical and viral
teratogens. The relevance of these experiments to human brain neoplasms
brain tumor should be suspected in the presence of mass-occupying lesions
(cystic or solid areas), and a change in shape or size of the normal anatomic
structures (such as shift in the mid-line). Cystic tumors and teratomas
are usually characterized by complete loss of the normal intracranial
architecture. In some cases, the lesion appears as a low echogenic structure,
and it may be difficult to recognize. Hydrocephalus is frequently associated
with brain tumors and may be the presenting sign. The ultrasound appearances
of all intracranial tumors are similar and, therefore, precise histological
diagnosis from a scan is almost impossible. Possible exceptions are lipomas
(that have a typical hyperechogenic homogeneous appearance) and choroid
plexus papillomas (that appear as an overgrowth of the choroid plexus).
Identification of brain neoplasm associated with tuberous sclerosis, neurofibromatosis,
and systemic angiomatosis of the central nervous system and eye can be
attempted in patients at high risk; in most cases, however, antenatal
sonography is negative, at least in the second trimester.
a 250K clip of intracranial teratoma
depends on a number of factors, including the histological type and the
size and location of the lesion. Congenital intracranial teratomas are
usually fatal. The limited experience with the other neoplasms in prenatal
diagnosis precludes the formulation of prognostic considerations.
OF THE FACE AND NECK
is a very rare teratoma arising from the oral cavity or pharynx. Most
cases of epignathus arise from the sphenoid bone. Some arise from the
hard and soft palate, the pharynx, the tongue and jaw. From their sites
of origin, the tumors grow into the oral or nasal cavity or intracranially.
The tumors, which are usually benign, consist of tissues derived from
any of the three germinal layers; most of them contain adipose tissue,
cartilage, bone, and nervous tissue. Prenatal diagnosis is suggested by
the demonstration of a solid tumor arising from the oral cavity; calcifications
and cystic components may also be present. Differential diagnosis includes
neck teratomas, encephaloceles, and other tumors of the facial structures.
Polyhydramnios (due to pharyngeal compression) is usually present. A careful
examination of the brain is important because the tumor may grow intracranially.
The outlook depends on the size of the lesion and the involvement of vital
structures. Lesions detected antenatally have been very large. Polyhydramnios
has been associated with poor prognosis. The major cause of neonatal death
is asphyxia due to airway obstruction. Surgical resection with a normal
postoperative course is possible.
is a very rare benign tumor, which usually arises from the oral cavity.
The tumor occurs in females exclusively and it may be the consequence
of excessive production of estrogens by the fetal ovaries under human
chorionic gonadotropin stimulation. The ultrasound features are those
of a large solid mass protruding from the fetal mouth. Vascular connections
between the tumor and the floor of the oral cavity may be demonstrated
using color Doppler ultrasound. Polyhydramnios (due to pharyngeal compression)
is a rare tumor. Ultrasound features include a unilateral and well-demarcated
partly solid and cystic, or multiloculated mass, calcifications (in about
50% of cases), and polyhydramnios (in about 30% of cases due to esophageal
obstruction). The prognosis is very poor and the intrauterine or neonatal
mortality rate (due to airway obstruction) is about 80%. Survival after
surgery is more than 80% but, since these tumors tend to be large, extensive
neck dissection and multiple additional procedures are necessary to achieve
complete resection of the tumor with acceptable functional and cosmetic
goiter (enlargement of the thyroid gland) can be associated with hyperthyroidism
(the result of iodine excess or deficiency, intrauterine exposure to antithyroid
drugs or congenital metabolic disorders of thyroid synthesis), hypothyroidism
or an euthyroid state. Ultrasound diagnosis is based on the demonstration
of a solid, anteriorly located symmetric mass, which may result in hyperextension
of the fetal head. Polyhydramnios is common due to mechanical obstruction
of the esophagus. The prognosis depends on the basic cause of the goiter.
Most cases are in women with a history of thyroid disease. Fetal blood
sampling can aid in determining fetal thyroid status, especially in women
suffering from Grave’s disease where a transplacental transfer of drugs
or thyroid-stimulating antibodies may result in fetal goiter. Maternal
therapy usually corrects fetal hyperthyroidism. Direct fetal therapy in
cases of fetal hypothyroidism can be undertaken by amniocentesis or by
cordocentesis and this can result in resolution of the fetal goiter.
lung tumors have not been reported in the literature. Other lesions, which
are malformations, and which may appear as solid masses in the thorax,
include cystic adenoid malformation of lung and extralobar lung sequestration.
tumors (which include neuroblastoma and hemangioma) may cause mediastinal
shift, lung hypoplasia, hydrops and polyhydramnios (due to esophageal
(hamartoma) of the heart
(which represents excessive growth of cardiac muscle) is the most common
primary cardiac tumor in the fetus, neonate, and young child; the birth
prevalence is 1 per 10 000. In 50% of cases, the tumor is associated with
tuberous sclerosis (autosomal dominant condition with a high degree of
penetrance and variable expressivity). The ultrasound features are those
of a single or multiple echogenic masses impinging upon the cardiac cavities.
The prognosis depends on the number, size and location of the tumors.
The clinical spectrum varies from completely asymptomatic to severely
ill. The mortality rate in infants operated on within the first year of
life is about 30%. Up to 80% of the infants with tuberous sclerosis have
seizures and mental retardation, which are the most serious long-term
complications of the disease.
the majority of cases, the tumor is located in the right side of the heart.
It may reach a size that is 2–3 times that of the normal heart. The tumor
may be cystic or pedunculated. Pericardial effusion is always present
and results from rupture of cystic areas within the tumor, or from obstruction
of cardiac and pericardial lymphatic veins. Cardiac tamponade and hydrops
may develop and the prognosis is very poor.
OF THE ABDOMEN AND RETROPERITONEUM
hepatic tumors (hemangioma, mesenchymal hamartoma, hepatoblastoma and
adenoma) are extremely rare. All hepatic tumors may show the same sonographic
features: either a defined lesion (cystic or solid) is present or hepatomegaly
exists. Calcifications may appear, and both oligohydramnios and polyhydramnios
have been observed. The other tumors are very rare and little is known
about their natural history. Hemangiomata are histologically benign and
they regress spontaneously after infancy. However, occasionally, they
are associated with arteriovenous shunting, congestive heart failure and
hydrops, resulting in intrauterine or neonatal death.
is one of the most common tumors of infancy and is found in about 1 per
20 000 births. Neuroblastoma arises from undifferentiated neural tissue
of the adrenal medulla or sympathetic ganglia in the abdomen, thorax,
pelvis, or head and neck. Usually, the lesion is isolated, but occasional
metastasis before birth may occur. Sonographically, the tumor appears
as a cystic, solid, or complex mass in the region of the adrenal gland
(directly above the level of the kidney and under the diaphragm). Occasionally,
calcifications are present. Tumors arising from the sympathetic ganglia
may appear in the neck, chest, or in the abdomen. There may be associated
polyhydramnios and fetal hydrops. The tumor can metastasize in utero (placenta,
liver, or blood vessels). The prognosis is excellent if the diagnosis
is made in utero or in the first year of life (survival more than 90%),
but, for those diagnosed after the first year, survival is less than 20%.
nephroma (renal hamartoma) is the most frequent renal tumor, while Wilms’
tumor (nephroblastoma) is extremely rare. The sonographic picture in both
tumors is of a solitary mass replacing the normal architecture of the
kidney, and, in most cases, there is associated polyhydramnios. Cystic
areas may appear in both tumors. Mesoblastic nephromas are benign, and
nephrectomy is curative in the majority of cases. Wilms’ tumor is a genetically
heterogeneous group of malignant tumors and up to 60% of affected cases
are associated with genetic syndromes (such as Beckwith– Wiedemann syndrome).
Treatment of the tumor requires surgery, chemotherapy and sometimes radiotherapy.
OF THE EXTREMITIES
of the extremities include:
Vascular hamartosis; a malformation in which newly formed vessels proliferate;
Hemangioma, a combined lesion of both skin and internal organs. The Klippel–
Weber–Trenaunay syndrome should be considered in the differential diagnosis.
The hemangiomas may vary in size and location. Some authors do not consider
them to be true tumors, but rather suspect them to represent vascular
Lymphangioma, a cavernous lymphangioma, which involves the lymphatic vessels
and is related to cystic hygroma;
Sarcoma (mainly rhabdomyosarcoma); this should be distinguished from infantile
melanoma is a rare tumor capable of metastasizing into other organs including
the fetal liver, lungs and placenta.
sacrococcygeal region is the most frequent site of teratomas of the fetus.
teratoma is found in about 1 per 40 000 births. Females are four times
more likely to be affected than males, but malignant change is more common
tumor is thought to arise from totipotential cells in Hensen’s node. A
theory of ‘twinning accident’ with incomplete separation during embryogenesis
has also been proposed. The condition is sporadic but some cases are familial,
with autosomal dominant inheritance.
Sacrococcygeal teratomas usually appear solid or mixed solid and cystic
(multiple cysts are irregular in shape and size). Occasionally, the tumor
is completely cystic, and more rarely completely solid. Most teratomas
are extremely vascular, which is easily shown using color Doppler ultrasound.
The tumors may be entirely external, partially internal and partly external,
or mainly internal. Polyhydramnios is frequent, and this may be due to
direct transudation into the amniotic fluid and due to fetal polyuria,
secondary to the hyperdynamic circulation, which is the consequence of
arteriovenous shunting. Similarly, high-output heart failure leading to
hepatomegaly, placentomegaly and hydrops fetalis can occur.
a 250K clip of sacrococcygeal teratoma
teratoma is associated with a high perinatal mortality (about 50%), mainly
due to the preterm delivery (the consequence of polyhydramnios) of a hydropic
infant requiring major neonatal surgery. Difficult surgery, especially
with tumors that extend into the pelvis and abdomen, can result in nerve
injury and incontinence. The tumor is invariably benign in the neonatal
period but delayed surgery or incomplete excision can result in malignant
transformation (about 10% before 2 months of age to about 80% by 4 months).
© 2000 by Pilu, Nicolaides, Ximenes & Jeanty