++
Neonatal tumors differ in distribution from those found in older
children. Table 447-1 shows the distribution
of newborn tumors from a large published series.7 Overall,
teratoma is the most common neoplasm, whereas neuroblastoma is the
most common malignancy in newborns and infants in Western countries,8,9 followed
by leukemia, sarcoma, and brain tumors. By comparison, acute leukemia
is the most common cancer in newborns in a report from Asia.9
+++
Neonatal Germ
Cell Tumors
++
Germ cell tumors consist of a heterogeneous group of histologically benign
and malignant tumors which arise from primordial germ cells. All
subtypes can be seen in the neonate, although mature (benign) teratoma
is the most common with a reported incidence of 1 in 35,000 live
births.10
++
Mature (benign) teratoma is the most common germ cell tumor in the
newborn, comprising 37% to 52% of congenital tumors.11 Malignant
elements, usually endodermal sinus tumor (EST) are found in approximately
10% of teratomas in children under age 4 months,12 but
neither the degree of histologic immaturity nor the presence of malignant
elements has correlated with recurrence or progression to malignancy.11 After
age 4 months the malignancy rate of teratomas rises, reaching almost
100% at age 3 years.12 Mature teratomas are usually
extragonadal and midline, consistent with embryonic patterns of
germ cell migration.13 The most common anatomic site of
teratomas is sacrococcygeal, where these tumors may be primarily extrapelvic
(type 1), extra- and intrapelvic (type 2), or entirely intrapelvic (type
3). Other common areas are intracranial, orbital, nasopharyngeal,
neck, and anterior mediastinum.12 Extrapelvic sacrococcygeal
teratomas may be very large, resulting in intrauterine rupture, bleeding,
fetal death, or dystocia. Mortality is high, particularly if diagnosed
before 30 weeks’ gestation.11Caesarian section
should be done as soon as lung maturity is deemed adequate. In-utero
tumor debulking has been done in high-risk fetuses who cannot be
safely delivered.14 Postnatal therapy consists of complete
resection whenever possible.
++
The survival for fetal and neonatal teratoma has been reported
to be 53% and 85%, respectively, in a recent review.12 EST
is the most common malignant germ cell tumor of fetus and newborn.
Alpha feto-protein (AFP) levels are normally very high in newborn
and young infants up to levels of 150,000 ng/ml or more
and even higher in premature babies. AFP is cleared from the circulation
with a half-life of 5 to 7 days, reaching adult levels by about
9 months of age.15 Thus, only rising levels are clinically
useful in the early postnatal period. The range of normal serum AFP
values in term babies and in premature babies is shown in Tables 447-2 and 447-3.
Mature neonatal teratoma may recur locally as mature or immature
teratoma or, despite apparent complete resection, as pure EST up
to 36 months later.11,12,16 In a series from the Children’s Cancer
Group, 9 of 80 (11%) apparently completely resected mature
neonatal teratomas recurred locally, 2 as mature teratoma at age
6 months postresection and 7 as pure EST between ages 6 and 34 months.16 Malignant
recurrence was seen in a nasopharyngeal, mediastinal, and cervical
teratoma in addition to sacrococcygeal sites in another series,
suggesting that all mature teratomas in the newborn may contain
cells with a malignant potential.17 At the time of recurrence,
patients may present with metastatic disease and with extradural
spinal cord compression.18 The response to chemotherapy and
survival of EST is excellent, even for those with metastases at the
time of recurrence.19 All newborns with mature teratoma
at any site should be carefully followed with AFP measurements at
3 monthly intervals until 36 months of age.
++
++
+++
Neuroblastoma
in the Fetus and Newborn
++
Neuroblastoma (NB) is the most common malignancy in the neonate
and infant. Forty percent of neuroblastomas present in the first year
of life and 60% by age 2. There is a clear association
between age, site, and extent of NB. Infants less than 1 year of
age most commonly have localized disease arising equally from thoracic
and abdominal sites; older children tend to have disseminated disease
from an adrenal primary.20 Ninety percent of neonatal NB presents
with stage 1 or 4S disease with a good survival,1 but the
outlook may vary depending on tumor biology. Stage 4S NB is unique
to the neonatal/infancy periods and is characterized by
widely disseminated disease, often without an identifiable primary
tumor, which usually regresses spontaneously. (For a description
of neuroblastoma biology, see Chapter 457, “Neuroblastoma.”)
++
From a clinical point of view, the combination of biologic features with
clinical features such as stage and age has proven to be useful
in allocating patients to three risk groups, low, intermediate,
and high, with a 10-year probability of survival of 95%,
80%, and 30%, respectively. Although most infants
have low-risk disease, those with stage 3, 4, and 4S neuroblastoma
(NB) with MYCN amplified tumors have a significantly
worse survival rate than infants with stage 4 disease without MYCN amplification,
demonstrating that biology is more important than age or stage.21
++
Spontaneous regression is frequent in infants. Substantial increases
in the annual incidence rates of infant neuroblastoma was seen in
Japan22 and Canada23 when mass screening programs were
implemented, suggesting that many or most of the tumors detected
by screening would have undergone spontaneous regression and might
never have presented clinically. This suggests that such tumors
are able to respond to apoptotic mechanisms that prevent survival
of aberrant cells during development.1 The routine use
of fetal ultrasonography has also resulted in increasing detection
of an abdominal mass. Neuroblastoma (NB) is the second most common
abdominal mass detected by prenatal ultrasound, once renal lesions
are excluded. Differential diagnosis of a suprarenal mass in the
newborn includes adrenal hemorrhage, other adrenal tumors, and subdiaphragmatic
extrapulmonary lung sequestration. Most tumors detected prenatally
or by screening are of favorable stage and have favorable biology.24 NB
therapy depends on age, stage, and tumor biologic characteristics. A
current study is investigating whether perinatal localized tumors can
safely be managed with observation alone.20 By contrast,
newborns with stage III, IV, and IVS disease with poor prognostic
biological features have a very poor survival even with intensive
chemotherapy and autologous stem cell transplantation.
++
Stage IVS neuroblastoma in the neonate is potentially life-threatening. Two
separate studies have confirmed the increased risk, with only about
43% of neonatal patients with stage IVS NB surviving.8,25 The
cause of death is often massive and rapidly progressive liver enlargement
resulting in respiratory compromise, vena cava obstruction, and/or
gastrointestinal compression. A scoring system to help in therapeutic
decision making for such patients has been published.26 Any
sign of respiratory distress or inferior vena cava (IVC) compression
requires emergency therapy. Prompt referral to an oncology service
is necessary. Therapy includes chemotherapy with or without radiation
therapy, both of which may be life saving. Radiation is given at
a dose of 200 to 600 cGy using tangential fields and thereby sparing
kidney, gonad, and vertebral body, with minimal likelihood of significant
long-term sequelae.27 This therapy is necessary to deal with
immediate mechanical complications and does not necessarily have
to be continued after resolution of the immediate problem. Therapy
should include precautions against tumor lysis syndrome, which may
occur in young infants with stage IVS NB.
++
Congenital leukemia most commonly refers to leukemia diagnosed
within the first month of life, is most commonly of myeloid origin,
with acute monocytic and myelomonocytic leukemia being most prevalent.28 Epidemiologic
studies show that high birth weight increases the risk for congenital
leukemia and other childhood malignancies such as Wilms tumor (WT),
neuroblastoma (NB), and astrocytomas, possibly related to effects
of increased cell turnover and high levels of insulin growth factor,29 Low
birth weight and prematurity are associated with an increased risk
of development of WT but not leukemia.
++
Clinically, 50% of neonates with congenital leukemia
present with cutaneous infiltration, a rare finding in older children.28 Hepatosplenomegaly,
petechiae, and ecchymoses are common, and hyperleukocytosis, respiratory
distress, and meningeal involvement occur more frequently in this
age group. Approximately 10% of newborns with Down syndrome (DS)
present with circulating blasts resulting from transient myeloproliferative
disease (TMD). The blasts are clonal in origin and indistinguishable
from those of acute megakaryoblastic leukemia (AMKL). Organ infiltration
is commonly observed, particularly of the liver, spleen, heart,
and skin. The blasts usually disappear spontaneously within the
first 3 months of life, but 20% to 25% of these children
with DS and TMD go on to develop true AMKL.30 TMD may occur
in children without clinical DS but with extreme levels of mosaicism
on genetic testing. Conversion to true leukemia appears to be much
less frequent in these patients.Occasional cases of TMD
and subsequent AML have been reported in non-DS newborns.9 The
blasts of TMD and AMKL in DS are associated with somatic mutations
in the gene, GATA1, which encodes a myeloid transcription
factor, and an increased sensitivity to chemotherapeutic agents,
such as cytarabine.31,32GATA1 mutations
have been found in the Guthrie blood spot in infants who subsequently
developed AMKL, suggesting that mutations may occur early in hematopoietic
development, may be used as a specific marker for diagnosis of TMD
in DS neonates, and may serve as a marker for increased risk of
DS-related AMKL.33 Most patients with DS and TMD only require
observation, but about 15% present with life-threatening
complications including liver and cardiac failure, hyperviscosity
syndrome due to hyperleukocytosis, or respiratory impairment. These
newborns usually require chemotherapy; low-dose cytarabine is commonly used.30
++
Congenital acute lymphoblastic leukemia (ALL) is less frequent
than myeloid leukemia, but is biologically different and has a significantly
poorer prognosis than ALL in older children. Neonatal ALL is usually
B-lineage. Rearrangements of the MLL gene on 11q23
are observed in at least 80% of cases and are associated
with very poor prognosis. Most MLL rearrangements
in the newborn and young infant are due to a translocation of chromosomes
4 and 11, t(4 11)(q21;q23), and less commonly due to other translocations such
as t(9;11)(p22;q23) and t(11;19)(q23;p12). Analysis of MLL gene
rearrangements in identical leukemic twins suggests that the rearrangement
occurs prenatally and that leukemic cells are already present in
the peripheral blood at birth.34 A large study of more
than 200 infants showed no difference in outcome according to the
specific translocation, in contrast to outcomes observed in MLL-rearranged
ALL in older children.35 As in neonatal AML, there is an increased
frequency of poor prognostic features, such as hyperleukocytosis
and central nervous system (CNS) disease, whereas good prognostic
features such as hyperdiploidy and favorable cytogenetics are not
usually found.36 Identical 11q23 abnormalities have been
observed in secondary leukemia following treatment with epipodophyllotoxins
that inhibit the DNA topoisomerase II enzyme, resulting in the hypothesis that
maternal diet in pregnancy may contain foods with substances that
have a similar activity and that this may be important in the pathogenesis
of these infant leukemias.37
++
Many different chemotherapy regimens have been tried in neonatal ALL,
but induction failure rate is high and toxic mortality is frequent.
At present there is no evidence that myeloablative therapy with
hematopoietic stem cell transplant (HSCT) improves the outcome in MLL-rearranged
infant ALL, although this has not been properly evaluated in the
newborn patient. A Japanese study of 9 newborns with MLL-rearranged
leukemia showed that 2 of 5 who underwent stem cell transplant survived
compared, to 0 of 4 treated with chemotherapy alone; both survivors
were given total body irradiation (TBI) despite their young age.38 Total
body irradiation, shown to improve survival when used in conditioning
regimens for HSCT in older children with ALL, is usually not considered
an optimal approach in the neonate because of adverse growth and
cognitive sequelae. If cases of transient leukemia are excluded,
the prognosis is extremely poor for most infants with congenital
B-lineage or biphenotypic leukemia. By contrast, infants with AML
have comparable outcomes to those seen in older children, if treated
with the same intensive regimens.39
+++
Skin Nodules
in Neonatal Oncology
++
One of the intriguing differences between cancers in the neonate and
infant compared to what appears to be the same malignancy in older
children, is the tendency of the newborn to present with skin nodules.
The differential diagnosis of a newborn with multiple skin nodules,
often termed a “blueberry muffin” appearance,
includes congenital infections such as toxoplasmosis, rubella, cytomegalovirus,
and other herpes viruses (TORCHES), as well as several malignancies
such as congenital leukemia, lymphoma, and neuroblastoma. About
half the infants with congenital leukemia will have skin nodules
at presentation, and they may also be seen in newborns with Down
syndrome and transient myeloproliferative disease (TMD). Skin nodules
have also been described as a rare manifestation in other malignancies such
as rhabdomyosarcoma and adrenocortical carcinoma. In the fetus,
the skin functions as a transient hematopoietic organ and may revert
back to this function in the neonate and young infant if there is
a demand to increase blood cell production. In that capacity, the skin
may provide a microenvironment more permissive for malignant cell
growth.40
++
Histiocytic disorders may also cause skin nodules in a neonate. Congenital
self-healing reticulocytosis (Hashimoto-Pritzker disease) is a form
of skin histiocytosis presenting in the neonate. This condition
presents with a few scattered papules to multiple papules or vesicles
in the skin because of infiltration with Langerhans-type histiocytes
that contain Birbeck granules upon examination by electron microscopy.
The lesions may increase in number after birth, but will involute
spontaneously within a few months. Distinction from the skin manifestations
of infection, leukemia, and neuroblastoma is made on the basis of
skin biopsy, but distinction from the skin-only form of Langerhans
cell histiocytosis (LCH), can be considerably more difficult as
the cells are identical on immunohistochemistry. Because 50% of
skin-only LCH progresses to involve other organs within a few weeks
to months and may be life threatening, all newborns and infants
with skin-only LCH should be followed carefully clinically, but
without radiologic investigations.41
++
Brain tumors in the newborn comprise 5% to 12% of
neonatal tumors.42,43Association with Li-Fraumeni syndrome
was reported in 2 of 9 newborns in a Danish series. Other associations
reported included a history of previous fetal deaths, maternal irradiation,
maternal ingestion of anticonvulsants, and antiemetics, as well
as infections during pregnancy such as toxoplasmosis (glioma) and
chicken pox (medulloblastoma).44 About half are detected
prenatally. Postnatal clinical features include hydrocephalus, enlarged head
circumference, and asymmetric skull growth. Associated congenital
anomalies are common.45 Most frequent histologic diagnoses
are intracranial teratoma, low- or high-grade astrocytoma, medulloblastoma,
and primitive neuroectodermal tumor (PNET). The majority are supratentorial
tumors. Benign brain tumors are common in the neonatal period and
include choroid plexus papillomas (10–20% of infant
brain tumors), craniopharyngioma, and hemangioma. Intracranial teratoma
is the most common brain tumor in neonates and may present with
massive tumor, extension into orbit or neck, hydrocephalus, or as
an incidental finding in a stillborn fetus. Intracranial teratoma
has the worst survival of all perinatal teratoma, with 11% survival
in a recent review.45 Therapy of brain tumors includes surgical
resection and chemotherapy. The poor prognosis is usually the result
of the high surgical risk and the avoidance of radiation therapy
at this vulnerable age.
++
Retinoblastoma (RB) is the most common intraocular tumor of childhood.
It presents in infants and young children and may be present in
the newborn. All RB tumors show loss of function of the tumor suppressor
gene, RB1. RB1 mutations occur
in 60% of patients as somatic mutations, (mutations found
only in tumor cells) and in 40% as germ-line (inherited)
mutations. Patients with germ-line mutations in RB1 are
at a very high risk (90%) of a second mutation and bilateral
RB. Ninety-three percent of the RB1 mutations can
be identified in reference laboratories allowing molecular based
genetic counseling and screening.46 Of 46 neonates with
RB in one study, 42 had bilateral (familial) RB, 20 at presentation,
and 22 with asynchronous contralateral tumors developing later.
Thus, most RBs diagnosed in the neonatal period are the result of
inherited mutations in the RB1 gene.47
++
Early diagnosis is essential for survival and prevention of blindness. Early
stage RB is treatable with cryo- or laser therapy. Later diagnosis
may result in the need for enucleation sometimes with intensive
chemotherapy and radiation therapy. All infants less than 2 months
of age should undergo screening with a red pupil reflex test to
detect significant ocular abnormalities and RB.46,48 Half
the newborns with familial RB1 mutations were found
to have paramacular or macular tumors when delivered at 36 weeks
gestation.46Patients with a positive family history who
undergo early screening have been shown to have tumors diagnosed
at a younger age and with less extensive disease and have a better
ocular surviva.48 The best chance for preservation of
vision in patients with familial RB is making the diagnosis prenatally,
to prevent development of large tumors.46 Familial RB is
associated with a high incidence of second malignancy, particularly
if radiation therapy is given as part of the therapy,49 but
spontaneously developing tumors arising outside of the radiation
field are also well described.
+++
Newborn Kidney
Tumors
++
Nearly two-thirds of abdominal masses in the newborn arise from the
kidneys. The majority of these masses are non-neoplastic, such as hydronephrosis,
multicystic, dysplastic, and polycystic kidneys50 Neonatal
renal tumors are uncommon and represent less than 10% of
neonatal tumors (eTable 447.1). Benign congenital mesoblastic nephroma
(CMN) comprises 78% of neonatal kidney tumors. Three histologic
subtypes of CMN have been defined, the classic type comprising 24% of
cases, the cellular type 66% of cases, and a mixed type
with both classic and cellular histology 10% of cases.
Molecular characterization of CMN demonstrates a characteristic
translocation, t(12;15), in the cellular subtype of CMN.51 Wilms
tumor is much less common in this age group and accounted for only
4 of 27 newborn renal tumors in a National Wilms Tumor Study Group
(NWTSG) study of newborn renal tumors.52 An association
of WT with congenital anomalies includes sporadic aniridia, hemihypertrophy, Beckwith-Wiedemann
syndrome, and other overgrowth syndromes. Neonatal renal tumors
usually present as asymptomatic abdominal masses detected by prenatal
ultrasound or physical examination. Neonatal hypertension, hypercalcemia,
maternal polyhydramnios, and hydrops fetalis may occur. Polyhydramnios
is more common in CMN, which is also significantly associated with
preterm labor and prematurity, observed in 46% of newborns
with prenatally diagnosed renal tumors.53 Review of prenatal
ultrasound features showed no characteristics that distinguish CMN
and WT.51 CMN is treated by surgical removal and patients
have an overall excellent chance of survival. However, the cellular
form of CMN has been described to rupture, leading to peritoneal
contamination during surgery. For such patients, rigorous follow-up
is indicated and adjuvant chemotherapy may be required.
++
++
Neonatal WT is treated with primary excision followed by chemotherapy
at 50% of usual doses recommended for older children, because
of an increased risk of toxic deaths in very young infants. Reduction
of chemotherapy doses to 50% by the NWTSG resulted in 4-year
survival rates for the 256 babies with stages I, II, and III WT of
96%, 95%, and 90%, respectively.54 Subsequently,
the NWTS showed that children less than 24 months of age with small
(less than 500 gm), stage I favorable histology WT had an 86.5% disease-free survival
rate with resection alone.55 A review of prenatally detected renal
tumors confirmed an excellent prognosis, but many perinatal complications
were seen and close monitoring of all prenatal renal tumors is mandatory.53 Neonates
with nephrogenic rests in the contralateral normal kidney should
have prolonged monitoring with ultrasonography at 3 monthly intervals
to monitor for development of asynchronous tumors in the remaining
kidney.
++
Liver tumors in the neonate comprise approximately 5% of
tumors in the perinatal period.56 The most common primary
tumor is hemangioendothelioma (HE), followed by mesenchymal hamartoma,
and hepatoblastoma (HB). Secondary tumors include metastatic neuroblastoma,
renal tumors, and others such as endodermal sinus tumor (EST) and
choriocarcinoma.1 In Isaacs’s review, 162 (83.5%) newborn
liver tumors were benign, of which 117 were hemangioma/hemangioendotheliomas (HE)
and 45 mesenchymal hamartomas, whereas 32 (16.5%) tumors were
malignant.56
++
Liver tumors may be detected prenatally and may be associated
with anemia, hydramnios, or hydrops fetalis. Postnatal abdominal
distention, abdominal mass, and respiratory compromise may also
be seen. Radiologic investigations do not always reliably distinguish
benign from malignant tumors.57 HE may proliferate rapidly
after birth followed by slow involution over several years. Five
percent of unifocal and 49% of multifocal HE has associated
cutaneous hemangiomas. Congestive cardiac failure and consumptive
coagulopathy (Kasabach-Merritt syndrome) require urgent therapy, often
with surgical resection, corticosteroids, low-dose vincristine,
or interferon-α.56 However, interferon
therapy has been associated with a significant risk of spastic paraplegia
in young babies.
++
HB is the most common primary malignant liver tumor. Alpha feto-protein
(AFP) is usually increased in HB but the high levels found normally
in newborns can complicate the interpretation of this test in this
age group (Tables 447-2 and 447-3).
Therapy of HB consists of surgery and adjuvant chemotherapy; liver
transplantation may be required for HB not amenable to surgical
resection.58
++
The most common presentation of mesenchymal hamartoma is with
a multicystic or cystic and solid abdominal mass detected ultrasonographically
or clinically. The treatment is surgical removal. Death may occur because
of the rapid enlargement of a cystic mass causing respiratory distress
and compression of intra-abdominal blood vessels. Arteriovenous
shunting within the tumor may occasionally result in heart failure.56