Abstract
Malignant tumors diagnosed during the neonatal period are rarely encountered but extremely difficult to manage. Because factors such as drug absorption, metabolism, distribution, and elimination are affected by age and physiologic maturity, complications associated with the immature physiology of the neonate are common. Age-dependent maturation of the renal, hepatic, hematopoietic, and neurodevelopmental systems make the neonate particularly vulnerable to the deleterious effects of aggressive multimodal therapy involving extirpative surgery, chemotherapy, and radiotherapy. In addition, many neonatal malignancies differ from similar tumors in older children with respect to their biological behavior. These combined factors make tumors in the neonatal period a unique clinical domain and a domain in which most clinicians have little experience. The chapter provides an overview of the clinical presentation, diagnosis, and management of the most frequently seen, though rare, perinatal neoplasms.
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Introduction
Most solid tumors observed in early infancy are benign. Malignant tumors diagnosed during the neonatal period are rare. They account for only 2 % of all childhood cancers and have a reported incidence of 1: 27,000 live births in the United States [1]. Management of affected infants is extremely challenging. Because factors such as drug absorption, metabolism, distribution, and elimination are affected by age and physiologic maturity, complications associated with the immature physiology of the neonate are common. Age-dependent maturation of the renal, hepatic, hematopoietic, and neurodevelopmental systems make the neonate particularly vulnerable to the deleterious effects of aggressive multimodal therapy involving extirpative surgery, chemotherapy, and radiotherapy [2, 3]. Over the past three decades, the long-term effects of administering anti-cancer therapies to neonates have become increasingly evident [2–9]. An additional complicating factor is that many neonatal malignancies significantly differ from similar tumors in older children with respect to their biological behavior [10–12]. Certain benign tumors (e.g., sacrococcygeal teratoma) may have malignant potential and undergo malignant change if untreated. Other tumors that are histologically malignant (e.g., fibrosarcoma) may exhibit benign behavior. Some benign tumors may be life threatening because of their size, anatomic location, and impact on infant physiology. Congenital neuroblastoma may have an unpredictable course, with many tumors involuting spontaneously and others progressing to a fatal outcome. Due to the rarity of malignant neoplasms in neonates, existing treatment protocols are based on studies that predominantly comprise older children. As such, these protocols do not consider the unique aspects of treating perinatal tumors.
These combined factors make tumors in the neonatal period a unique clinical domain and a domain in which most clinicians have little experience. The aim of this chapter is thus be to provide a broad introduction to the most frequently seen, though rare, perinatal neoplasms.
Overview
Epidemiology and Clinical Presentation
Nearly 50 % of tumors occurring in neonates are observed at birth; another 20–29 % become evident within the first week of life [13, 14]. Although there is variation in the reported frequency of specific tumor diagnoses across neonatal series [15–20], teratomas and neuroblastoma account for approximately two thirds of reported neoplasms. Liver and renal tumors are considerably rarer. The most common finding on physical examination is a palpable mass. Nonspecific symptoms such as irritability, lethargy, failure to thrive, and feeding difficulties may indicate the presence of an occult neoplasm. Petechial hemorrhages and other hematologic abnormalities may indicate extensive bone marrow replacement by tumor cells such as neuroblastoma or leukemia (Fig. 11.1).
Neuroblastoma cells in bone marrow
The association between congenital abnormalities and tumors is well documented, with concurrence reported in as many as 15 % of neonatal tumors [17, 21, 22]. Many such associations are related to chromosomal defects, particularly trisomies 13, 18, and 21. An increased incidence of leukemia and retroperitoneal teratoma has been reported in neonates with Down syndrome [22] and teratomas are associated with regional and distal congenital anomalies such as cloaca, limb hypoplasia, and spina bifida [20].
Oncogenesis and Genetic Risk Factors
Many neonatal malignancies are inherited or occur spontaneously as the result of a de novo mutational event. The etiology of these tumors is likely multifactorial, including both genetic and environmental factors. Both genetically determined syndromes and constitutional chromosomal defects may result in an increased risk of malignancy. This includes single-gene malignancy-related syndromes and the familial associations of tumors [20]. Particular constitutional chromosome anomalies specifically favor neoplasms occurring in the fetal and neonatal period. These anomalies have been identified in retinoblastoma (13q) and nephroblastoma (11p) [23]. In patients with Denys-Drash syndrome, there is an association with genetic mutations located at 11p13 and WT1. These patients commonly have Wilms tumor. The specific site of the point mutation identified in most cases is located on the WT1 exon 9 [24]. Other examples of constitutional chromosomal anomalies associated with neoplasms include an increased risk of leukemia in patients with Down syndrome [25, 26] and a high frequency of poor-prognosis neonatal leukemia involving the 11q23 locus of the MLL gene. This specific genetic defect is rare in older children [27]. Genes that confer a higher risk of neoplasia by enhancing susceptibility to oncogenic factors are likely to exist and also appear to play a role in certain inherited syndromes. For example, there is an increased risk of hepatoblastoma and rhabdomyosarcoma in patients with Li-Fraumeni syndrome (p53 mutation) [20].
Environmental factors may also play a role in neonatal oncogenesis. A clear dose-related increase in tumor tendency following prenatal or neonatal radiation exposure has been reported [28]. Other possible associations include drugs taken during pregnancy, maternal infections and tumors, and environmental exposure to carcinogens. However, epidemiological data specifically examining these associations is limited, and it is difficult to draw unequivocal conclusions.
Diagnostic Investigations
Dramatic improvements in both prenatal and postnatal ultrasonography (US) and magnetic resonance imaging (MRI) have had a marked impact on perinatal diagnosis, management, and outcome [29–31]. Knowledge of the presence of a fetal tumor allows for timely counseling and close monitoring throughout pregnancy. Prenatal US has been particularly useful in identifying large sacrococcygeal or cervical teratomas that may complicate vaginal delivery or be responsible for intrauterine fetal demise or postnatal complications. US can also detect adrenal or thoracic masses in the fetus, providing useful information regarding both the nature of the mass and, in most cases, its origin. Fetal MRI can better characterize and delineate specific anatomic details and the extent of tumor involvement. These complementary imaging techniques, together with prenatal assessments, enable planning for the mode, timing, and location of delivery as well as postnatal management strategy. Fetal surgery and the ex utero intrapartum treatment (EXIT) procedure are useful in managing non-immune hydrops and congestive heart failure caused by neoplasms. In addition, EXIT to ECMO is appropriate for some patients, allowing a smoother transition from the in-utero state and time to allow postnatal lung development and stabilization of the hydropic infant [32]. Prompt tumor resection is then required. The EXIT procedure is also used to salvage infants with high-grade airway obstruction caused by tumors [33].
Contrast-enhanced computed tomography (CT) provides excellent postnatal images of most neoplasms, though it has limitations in evaluating intraspinal involvement and also has the disadvantage of emitting ionizing radiation. MRI, however, is particularly useful for evaluating tumors that involve the central nervous system or spinal canal. It is also extremely useful in the preoperative delineation of the vascular anatomy of the tumor and adjacent organs. Although limited information is available on the use of positron emission tomography (PET) in neonates, evidence suggests that it is helpful in determining cerebral glucose metabolism and, more importantly, it is useful in the management of selected pediatric patients with malignancy [34, 35]. PET used in conjunction with CT has recently been shown to have a limited role in early diagnosis; however, it plays an important role in initial staging, treatment response evaluation, and detection of metastatic disease in pediatric cancers [36].
Cytogenetics plays an important role in the diagnosis, risk stratification, and monitoring of patients with neonatal tumors. Most cancer cells are thought to have a high incidence of chromosomal changes and genetic mutations that frequently are identifiable and, in some cases, are prognostically significant. For example, N-myc amplification is a specific molecular marker that characterizes a subset of aggressive neuroblastomas that usually has a poor prognosis [37].
Therapeutic Interventions
Surgical Management
Although fetal surgery is occasionally considered for potentially lethal tumors causing non-immune hydrops, the vast majority of perinatal tumors are surgically managed postnatally. Surgical extirpation remains the definitive treatment modality in most neonates with solid tumors. The timing of surgery and the surgical strategies employed must take into account the physiologic and metabolic needs of the neonate. Avoidance of hypoglycemia and hypothermia, especially if significant fluid or blood replacement is required or prolonged exposure occurs are important considerations.
The impact of surgery on the subsequent growth and development of the neonate can be profound, especially when major tumor extirpations are extensive or resection of unaffected tissues integral for normal structure and function has occurred. In some patients, appropriate surgical management may result in impairment of gastrointestinal or bladder function, ambulation, or future sexual function, thereby creating life-long physical and emotional burdens for patients. Interrupting or traversing normal growth centers in order to resect tumors can have a profound effect on structural symmetry and function. For example, intrathecal tumor removal extending over several vertebral segments often results in some degree of post-laminectomy scoliosis later in childhood. Preserving function and structure without compromising survival is thus the paramount principle guiding contemporary surgical and multimodal treatment strategies. For many patients in whom a tumor is initially unresectable (e.g., those with stage 3 neuroblastoma) or involves important structures that should be preserved, the administration of several courses of preoperative chemotherapy has been extremely beneficial. This approach has allowed delayed complete primary resection with preservation of vital structures, thus improving surgical outcomes and quality of life.
Radiotherapy
Because many malignant tumors in childhood are radiosensitive, radiotherapy plays an important role in the management of advanced-stage tumors. In light of the scarcity of neonatal data, however, treatment parameters such as dosing schedules have been extrapolated largely from investigations of older children. Because the neonate experiences rapid growth of organs and structures, radiotherapy has a profound impact on subsequent development. The sensitivity and detrimental effects of radiation therapy on the central nervous system, skeletal growth, and visceral organs appear to be inversely related to the child’s age and directly related to the radiation dose [6].
In a seminal study of children younger than age 2, Meadows et al. [6] found that growth disturbances and musculoskeletal abnormalities were the most common late effects of radiation therapy. Approximately 85 % of patients had some degree of bone or soft tissue abnormality; this problem was most severe in children who had received thoracic or spinal irradiation. Other authors have documented a wide spectrum of significant late radiation effects, including scoliosis and severe bony deformities (70 %) and delayed physical development [14, 38]. Children receiving radiation to the cerebrospinal axis for leukemia or brain tumors reportedly experience major delays in cognitive development, and infants treated with cranial irradiation have a high incidence of learning disabilities and mental retardation [39, 40]. The severity of these disabilities is strongly correlated with radiation dose. As in older children, other significant late effects of radiation therapy in neonates include breast agenesis, aortic arch dysgenesis, second malignancies (particularly leukemias and breast and thyroid cancer), and chronic renal and hepatic insufficiency [40–44].
Chemotherapy
The lack of substantial pharmacologic data on newborns significantly complicates the administration of chemotherapeutic agents. Knowledge of drug interactions, metabolism and clearance, and toxicity are all areas of notable deficiency. As such, they remain the focus of intense ongoing discussion and contemporary investigation. In an overview of a workshop (2003) concerning cancer pharmacology in infants and young children, a significantly greater incidence of neurotoxicity for vincristine, hepatic toxicity for actinomycin D, and ototoxicity for cisplatin [45] was observed in infants and young children. For virtually all of these older agents and the newer camptothecin agents, the limited available data indicate that weight-based dosing in young children normalizes the drug clearance profiles and may improve the toxicity profiles, bringing them in line with that of older children [45].
During the course of the second National Wilms Tumor Study, the prescribed doses of actinomycin D, vincristine, and doxorubicin were reduced by 50 % due to observed excessive myelosuppression in infants younger than 1 year of age. Interestingly, reduction of dose did not compromise therapeutic effectiveness [46]. A similar dose reduction approach was followed in the Intergroup Rhabdomyosarcoma Study protocols [47]. Excessive drug-related toxicity has not been observed in infants with leukemia. Moreover, reduced dosage protocols have had a detrimental effect on clinical response and outcome [48].
Teratomas
Teratomas are embryonal neoplasms that contain tissues from at least two of the three germ layers (ectoderm, endoderm, and mesoderm). Although the etiology of these neoplasms is uncertain, three theories have been postulated, including the totipotent primordial germ cell theory, the primitive node theory, and the incomplete twinning theory [49]. Teratomas arise in both gonadal and extragonadal sites, with location thought to correspond to the embryonic resting sites of primordial totipotential germ cells. Tumor location correlates with the age of the patient. Teratomas occurring in infancy and early childhood are generally extragonadal, whereas those presenting in older children more commonly occur in the ovary or testis [50]. More than 50 % of teratomas are evident at birth and are most commonly seen in the sacrococcygeal area. Although more than one third of teratomas of the testis are recognized in the first year of life, these lesions are rarely diagnosed in the neonatal period. The sacrococcyx is also the most common extragonadal location irrespective of age (45–65 %) [51]. Cervicofacial and central nervous system tumors and tumors of the retroperitoneum are seen less frequently. Teratomas presenting in the mediastinum, heart, and liver are much less commonly seen. Excluding testicular teratomas, 75–80 % of teratomas occur in females. Approximately 20 % of tumors contain malignant components, the most common being endodermal sinus tumor [51]. Routine prenatal US at 18–20 weeks’ gestation identifies most teratomas present in neonates, irrespective of the anatomic location of the lesion.
A wide range of congenital anomalies is seen in association with teratomas, and the type of anomaly frequently depends on the tumor site and size. Single or combined malformations of the genitourinary tract, rectum, anus, vertebrae, and caudal spinal cord are sometimes found in patients with extensive sacrococcygeal teratomas [52–54]. Disfiguring cleft palate defects are found in newborns with massive cranial and nasopharyngeal teratomas [55]. Klinefelter’s syndrome is strongly associated with mediastinal teratoma. Teratomas may also form part of the Currarino triad (anorectal malformation, sacral anomaly, and a presacral mass) [56].
Teratomas can present as solid, cystic, or mixed solid and cystic lesions. Most teratomas that are present at birth consist of ectodermal and mesodermal components. Epidermal and dermal structures such as hair, sebaceous glands, sweat glands, and teeth are frequently present. Virtually all teratomas have mesodermal components, including fat, cartilage, bone and muscle. Endodermal components commonly seen include intestinal epithelium and cystic structures lined by squamous, cuboidal, or flattened epithelium [57]. Pancreatic, adrenal, and thyroid tissue, as well as mature and immature neuroepithelial and glial tissue is also frequently seen (Fig. 11.2).
Microphotograph of a benign teratoma showing differentiated cartilage, respiratory epithelium, mucinous epithelium, and salivary gland acini
Tumors are histologically classified as either mature or immature, with most pediatric teratomas classified as mature. These tumors exhibit an absence of coexisting malignant cells and little or no tendency to malignant degeneration. They nevertheless may be fatal if the airway is compromised or if vital structures such as the brain or heart are involved. Moreover, depending on location and size, even benign tumors may be inoperable and incompatible with extrauterine life.
Although useful tumor grading systems have been developed [58, 59], these systems are of limited use in regard to the fetus or newborn in that embryonic or immature elements may be appropriate for the stage of development [60, 61]. Regardless of tumor grade in these patients, immature teratomas are associated with a favorable prognosis, and only in rare cases does immature neuroglial tissue metastasize to adjacent lymph nodes, lungs, and other distant organs from an immature primary site [62, 63].
The most important predictor of recurrence in pediatric immature teratomas appears to be the presence of microscopic foci of yolk sac tumor [64]. Because they are small, these tumors may be missed by the pathologic sampling process. Such oversights may account for metachronous metastases after resection of the immature teratoma metastasis.
In general, the prognosis of neonates depends upon the resectability of the tumor and the presence of metastases or metastatic potential. Alpha-fetoprotein (AFP) is the principle tumor marker and is especially helpful in assessing the presence of residual or recurrent disease [65]. This assessment should, however, consider that neonates normally have a high AFP at birth, which rapidly dissipates due to its short half-life. In some patients, elevation of beta-human chorionic gonadotropin (β-hCG) indicates the presence of a component of choriocarcinoma [66].
Teratomas detected prenatally reportedly have a mortality rate three times higher than those diagnosed postnatally [49]; this higher rate is related to tumor location (head and neck involvement) and the presence or absence of hydrops. Regardless of tumor location, a fetus with hydrops has a poor prognosis.
Sacrococcygeal Teratoma
Clinical Presentation and Diagnosis
Sacrococcygeal teratoma (SCT) is the predominant teratoma as well as the most common extracranial neoplasms in newborns. The tumor has an estimated incidence of 1:20,000 to 1:40,000 live births and a female predominance ranging from 2:1 to 4:1 [67–69]. Ten percent to 20 % of patients with SCT have coexisting congenital anomalies such as tracheoesophageal fistula, imperforate anus, anorectal stenosis, spina bifida, genitourinary malformations, meningomyelocele, and anencephaly [70–72]. Also, many patients have significant structural abnormalities of juxtaposed organs resulting from displacement by a large teratoma.
The classification system currently used by the American Academy of Pediatrics Surgery Section (AAPSS) was developed by Altman et al. [73] in the early 1970s. This system divides SCTs into four distinct anatomic types that differ in the degree of intra- and extrapelvic extension (Fig. 11.3). Type I (46.7 %) is predominantly external with minimal presacral extension. Type II (34.7 %) arises externally and has a significant intrapelvic component. Type III (8.8 %) is primarily pelvic and abdominal but is apparent externally. Type IV (9.8 %) is presacral and has no external manifestation. These authors found that the incidence of malignant components not only correlated with anatomic type (8 % in type I vs. 38 % in type IV) but also with age at diagnosis and gender; however, the size of the tumor was unrelated. The rate of malignancy of tumors in older infants (>6 months) and children is significantly higher than that of the visible exophytic tumors seen in neonates. Malignant change is more frequent in males, particularly those with solid versus complex or cystic tumors [74, 75]. The most common malignant elements identified within sacrococcygeal lesions are yolk sac tumor and embryonal carcinoma (Fig. 11.4) [76].
Clinical staging of sacrococcygeal teratoma: (a1, a2) Stage I illustration and clinical photograph (b1, b2) Stage II illustration and clinical photograph (c) Stage III Illustration only (d1) Stage IV Illustration (d2) Intrapelvic tumor (d3) Secondary metastases in groin lymph nodes
Histology of an endodermal sinus tumor with alpha-fetoprotein stain
In countries where antenatal US screening is carried out, most large SCTs are diagnosed before birth. Uterine size larger than expected for a gestational date (polyhydramnios or tumor enlargement) is the most common obstetrical indication for initiating maternal-fetal US examination. US may reveal an external mass arising from the sacral area of the fetus (Fig. 11.5). The mass is composed of solid and cystic areas, with foci of calcification sometimes apparent. Most prenatally diagnosed SCTs are extremely vascular and can be seen on color-flow Doppler studies.
Antenatal maternal-fetal Doppler ultrasound of a 21-week gestation fetus with a sacrococcygeal tumor showing solid and cystic components. Black arrow marks vessel with high blood flow within the tumor on the Doppler image (Courtesy of Timothy Crombleholme, MD)
Fetal MRI has become an especially useful adjunctive imaging modality, as it provides important anatomic detail that may not be apparent on US alone. It may help define the pelvic component of SCT and its impact on other pelvic structures [77]. For neonates in whom fetal surgery is being considered, fetal MRI provides a broader field of view than US and may be helpful in operative planning. Additionally, in cases of cystic SCT, it may be helpful in excluding myelomeningocele from the differential diagnosis [78, 79].
Lumbosacral myelomeningocele is the most likely diagnosis to be confused with SCT. Lumbosacral myelomeningocele and cystic SCT may show similar findings on US. Since both are associated with elevated maternal levels of AFP, these levels are not helpful in distinguishing between the two entities. Other critical information gained from US includes the possible presence of abdominal or pelvic extension, evidence for bowel or urinary tract obstruction, assessment of the integrity of the fetal spine, and documentation of fetal lower extremity function [80]. Imaging of the fetal brain is helpful in establishing the diagnosis in that most fetuses with lumbosacral myelomeningocele have cranial signs such as Arnold-Chiari malformation [81]. When there is doubt, performing a fetal MRI can be extremely valuable in clarifying fetal anatomy and in making a definitive diagnosis (Fig. 11.6). Other soft tissue tumors that may mimic SCT include neuroblastoma, hemangioma, leiomyoma, and lipoma [81].
MRI of twin gestation at 21 weeks with one twin having a large sacrococcygeal teratoma (black arrow) associated with hydrops and high output failure (Courtesy of Timothy Crombleholme, MD)
Tumors can grow at an unpredictable rate to tremendous dimensions and may extend retroperitoneally displacing pelvic or abdominal structures (Fig. 11.7). Large tumors can cause placentomegaly, nonimmune fetal hydrops, and the mirror syndrome [82, 83]. These conditions are thought to result from a hyperdynamic state induced by low-resistance vessels in the teratoma. Without fetal intervention, high-output cardiac failure and hydrops resulting in fetal demise is almost certain. Thus, in a select subset of fetuses that meet specific criteria, restoring more normal fetal physiology may be achieved by surgical debulking of the SCT in utero [84].
Neonate with a large sacrococcygeal teratoma
Neonatal death may occur due to obstetric complications from tumor rupture, preterm labor, or dystocia [85–87]. Impending preterm labor from polyhydramnios or uterine distension from tumor mass may therefore require treatment by amnioreduction or cyst aspiration. Dystocia and tumor rupture can be avoided by planned cesarean section delivery for infants with tumors larger than 5 cm [82].
Antenatal diagnosis carries a significantly less favorable outcome than diagnosis at birth, and prognostic factors outlined in the current SCT classification system are not applicable to fetal cases. Although the mortality rate for SCT diagnosed in neonates is 5 % at most, that for fetal SCT is close to 50 % [82, 85, 86]. Results of most clinical series indicate that hydrops and/or polyhydramnios and placentomegaly portend a fatal outcome. The indication for maternal-fetal US has also been shown to be a predictive factor [85]. If SCT is an incidental finding on routine prenatal US, the prognosis is favorable at any gestational age. Many of these lesions are predominantly cystic and relatively avascular and can be managed postnatally with surgical resection. If US is initiated due to maternal indications, the outcome is much less favorable. Additionally, prematurity from polyhydramnios or cesarean section performed before 30–32 weeks’ gestation results in increased mortality [50]. In light of these factors, antenatal diagnosis requires referral to a high-risk obstetric center, with immediately available neonatal intensive care and qualified pediatric surgical and anesthesia expertise.
Postnatal diagnosis is determined by clinical findings on physical examination, serum levels of AFP and ß-HCG, and a number of radiographic imaging studies. Ninety percent of SCTs are noted at delivery, with a protruding caudal mass extending from the coccygeal region. These tumors are easily recognized and a diagnosis can generally be made by physical examination alone. Intrapelvic components can be diagnosed by a rectal digital examination. SCTs seen at birth are predominantly benign, and many are functionally asymptomatic.
Intrapelvic variants may have a delayed postnatal presentation [67, 73, 82]. They are typically noted in infants and children from ages 4–6 months to 4 years. In contrast to the SCTs seen in neonates, these tumors are located in the pelvis and have no external component. More than one third are associated with malignancy. Clinical presentation may include constipation, anal stenosis, or symptoms related to the tumor compressing the bladder or rectum and a palpable mass. Presacral tumors are associated with sacral defects and anorectal malformations (Currarino triad) [51].
Radiographs of the pelvis identify any sacral defects or tumor calcifications. CT with intravenous and rectal contrast material defines the intrapelvic extent of the tumor, identifies any nodal or distant metastases, and demonstrates possible urinary tract displacement or obstruction. CT imaging also identifies liver metastasis and periaortic lymph node enlargement. MRI is useful when spinal involvement is suspected or if the diagnosis is in doubt. A chest radiograph is useful in revealing obvious pulmonary metastases. Because chest CT is more reliable in picking up smaller metastatic lesions, it should be performed when there is a high index of suspicion.
Management Approaches
Advancements in antenatal diagnosis have given rise to the development of two primary fetal interventions in patients with teratomas—early delivery and open fetal surgery. Because these interventions are invasive to the fetus and may also cause maternal morbidity, they are, however, reserved for select cases in which the fetus develops progressive hydrops and shows evidence of high-output cardiac failure.
Operative Treatment
Fetal Surgery
SCTs are highly vascular tumors; a fetus with large lesions may thus develop high cardiac output failure, anemia, and ultimately, hydrops, with a mortality rate approximating 100 %. Signs of cardiac compromise are therefore an indication for surgery prior to 27–32 weeks’ gestation [88]. Since the first reported fetal resection of SCT in 1997 [89], this approach has resulted in a number of long-term survivors. Because in utero SCT resection commonly precipitates preterm labor, meticulous monitoring and tocolytic therapy during the immediate postoperative period is essential. Hospitalized patients undergo daily US and fetal echocardiography as indicated. Although signs of hydrops generally begin to resolve within several days of tumor resection, complete resolution may take weeks [30]. Since the intrauterine procedure is not designed to completely remove the teratoma, patients often require a second operation postnatally to remove the coccyx and any residual tumor mass. At surgery, the exophytic tumor is dissected free of the anus and rectum. The tumor is then removed by dividing it near the coccyx with a thick tissue-stapling device [30].
A rapidly enlarging macrocystic SCT results in polyhydramnios and placentomegaly, with associated mirror syndrome. Because this syndrome resembles severe preeclampsia and is life threatening to the mother, immediate delivery of the fetus or infant is essential.
Early Delivery
Serious or life-threatening complications are difficult to predict and often occur precipitously, making the third trimester of pregnancy extremely dangerous for a fetus with high-risk SCT. Unfortunately, the commonly accepted paradigm of watchful waiting frequently results in fetal death.
Based on published findings [88] as well as our own institutional experience, we have modified our treatment paradigm. This revised approach recognizes that rapid phases of tumor growth, early signs of internal hemorrhage, ominous changes in Doppler arterial wave forms, progression of placentomegaly or polyhydramnios, and early indications of maternal mirror syndrome are factors that should prompt consideration of early delivery. In the absence of hydrops, this approach is associated with good outcomes in appropriately selected fetuses with high-risk SCT [88].
Postnatal Intervention
The mainstay of treatment is complete surgical resection, with the exception of emergencies related to tumor rupture or hemorrhage that adversely affect the neonate’s hemodynamic status. The operative procedure can be undertaken on an elective basis early in the newborn period. The anatomic location of the tumor determines the operative approach. Tumors with extensive intrapelvic extension or a dominant abdominal component (type III or IV) are initially approached through the abdomen. A posterior sacral approach is sufficient for most type I tumors and type II tumors.
Operative goals include: (a) complete and prompt tumor excision. A significant delay may result in serious complications, including pressure necrosis, tumor hemorrhage, and malignant degeneration; (b) resection of the coccyx to prevent tumor recurrence; (c) reconstruction of the muscles of anorectal continence; and (d) restoration of a normal perineal and gluteal appearance [90, 91].
Initial control of the middle sacral and hypogastric arteries may be required to safely remove tumors in these fragile infants. The procedure is performed in a temperature-controlled environment, and infants are protected from heat loss with appropriate measures. The urinary bladder is catheterized and the operation is generally performed with the patient in a prone jackknife position, cushioned in a sterile foam ring. After skin preparation and sterile draping, a frown-shaped or inverted chevron incision is made superiorly to the tumor (Fig. 11.8a). This incision provides excellent exposure and keeps later wound closure some distance from the anal orifice. To delineate the rectum, the surgeon’s finger and/or a Hegar dilator also may be inserted 3 cm into the anal canal. After raising skin flaps off the tumor, the attenuated retrorectal muscles are carefully identified and preserved. The mass is mobilized close to its capsule, and hemostasis is achieved with electrocautery or ligatures. To retard heat loss, warm gauze pads are placed over the exposed dissection and the tumor mass. The main blood supply to the tumor usually arises from a primitive middle sacral artery or from branches of the hypogastric artery. After division of the coccyx from the sacrum, the vessels can be observed exiting the presacral space ventral to the coccyx. For patients with extremely large or vascular lesions in which excessive fluid shifts or hemorrhage may result in operative mortality, surgeons occasionally use extracorporeal membrane oxygenation (ECMO) in conjunction with hypothermia and hypoperfusion to facilitate better control of bleeding during resection [32].
Operative details (a) Position of the patient for surgery. The chevron incision is used. (b) Cross-section of tumor and excision of coccygeal segment to ensure complete incision (c) Postoperative cosmetic result
As failure to remove the coccyx is associated with a recurrence rate as high as 37 % [92], the coccyx is excised in continuity with the tumor (Fig. 11.8b). The tumor is dissected free from the rectal wall and the anorectal muscles are reconstructed. The levator muscles are attached superiorly, providing support to the rectum and positioning the anus in the normal location. A closed-suction drain may be placed below the subcutaneous flaps. The wound is then closed in layers with interrupted absorbable sutures. A urinary catheter is left in position for several days. To maintain cleanliness of the wound, the patient is kept prone for several days after surgery.
Premature newborns with large teratomas are challenging to manage. Due to lung immaturity, increased tumor vascularity, and poor tolerance of blood loss, surgical risks are high [93]. In these patients, devascularization and staged resection may be considered to avoid excessive blood loss. The fetus with a large SCT presents an even greater management challenge. As mentioned earlier, fetal hydrops and placentomegaly are associated with fetal demise.
The most serious complication of excision is intraoperative hemorrhage, and the major cause of mortality is hemorrhagic shock. One successful preoperative strategy for stabilizing patients with vascular tumors in which there is significant bleeding is to tightly wrap the teratoma with an elastic bandage. As a salvage approach for acute life-threatening hemorrhage, performing an emergent laparotomy and temporarily cross-clamping the distal abdominal aorta has been reported [94].
As with any surgical procedure, wound complications can occur. Resection of teratomas with significant intrapelvic and intraperitoneal extension may be associated with temporary or persistent urinary retention in the postoperative period, but these symptoms generally resolve. Although patients with small tumors usually have normal anorectal function, up to 40 % of premature infants with large SCTs and in whom the levator and gluteal muscles are severely attenuated, have fecal incontinence. Long-term bowel management strategies allow most patients to achieve socially manageable bowel function.
Adjuvant Chemotherapy
Detection of malignant elements necessitates adjuvant multiagent chemotherapy. The most active antineoplastic drugs include cisplatin, etoposide, and bleomycin. Reports indicate impressive survival after administration of intensive chemotherapy both in children with locally advanced disease and in those with metastatic disease [95–97]. Even with malignant transformation of SCT, reported survival is 88 % with local disease and 75 % with distant metastases [98]. Moreover, it appears that stage, extent of metastasis, and extension into bone have no prognostic significance when children are treated with platinum-based regimens [99].
For patients in whom the primary malignant tumor is unresectable, a course of multiagent chemotherapy is administered to facilitate subsequent resection. If a good tumor response is indicated by a diminishing serum AFP level, CT imaging, and a chest radiograph, resection is undertaken after several cycles of chemotherapy.
In patients with localized malignant recurrence, complete resection remains the cornerstone of salvage treatment. This is carried out in conjunction with adjuvant chemotherapy.
Chemotherapy also has been effective in the treatment of metastatic foci in the lungs and liver. However, to ensure removal of any malignant elements, residual lesions must be excised. Although radiation therapy is uncommon and used selectively, it may have a role in controlling unresectable disease.
Long-Term Outcomes
Patients diagnosed with SCT before 30 weeks’ gestation tend to have poorer outcomes and a higher likelihood of developing complications such as hydrops, placentomegaly, dystocia, and fetal demise [86]. For most patients diagnosed postnatally, the prognosis is favorable in regard to both survival and quality of life. Factors such as tumor maturity and morphology and degree of hemorrhage may also affect morbidity and outcome. When the diagnosis is made prior to 2 months of age or excision is performed prior to 4 months of age, the malignancy rate is 5–10 % [100, 101]. Additionally, cystic tumors, which are generally mature, carry a better prognosis. Complications related to hemorrhage, vascular steal, and malignancy are seen more frequently in patients with solid tumors.
The long-term survival of newborns who have undergone complete resection is generally excellent regardless of tumor histology [102]. Nevertheless, because all SCTs have a risk of local and/or distant recurrence, close follow-up at 3-month intervals for a 3- to 4-year period is essential. An 11 % tumor recurrence with mature teratoma and a 4 % recurrence with immature teratoma have been reported [71]. Although 43–50 % of these occurrences are malignant, the chemosensitivity of yolk sac (endodermal sinus) tumor results in a high survival rate. Serum AFP levels are monitored and physical examinations are performed. Special attention is given to rectal examination in that it may detect a presacral recurrence. When serum AFP levels do not fall appropriately, abdominal US is performed. When there is an index of suspicion, an abdominopelvic CT or MR imaging and a lung CT are performed. Recurrent tumor may be benign, but should be re-excised to minimize the long-term risk of malignant transformation.
Head and Neck Teratomas
Head and neck teratomas account for 5 % of all neonatal teratomas. These neoplasms have no sex or race predilection. They can occur in the brain, orbit, oropharynx, and neck.
Intracranial Teratomas
Intracranial teratomas account for approximately 50 % of all brain tumors in early infancy [67]. These tumors occur most commonly in the pineal region but also are found in the hypothalamus, ventricles, and suprasellar and cerebellar regions. Unlike intracranial teratomas in older children, most intracranial teratomas in neonates are benign. The most common presenting symptoms and findings are related to the presence of obstructive hydrocephalus. On imaging studies, these lesions may be suspected by visualizing midline or paraxial intracranial calcifications.
Although complete resection is the treatment of choice, many neonatal intracranial teratomas are not resectable. Palliative shunting to alleviate intracranial pressure and hydrocephalus has little long-term benefit. Moreover, in some infants, shunting has been associated with extracranial spread of tumor. The role and effectiveness of chemotherapy for this subgroup of patients are currently areas of investigation.
Long-term survival is predicated on complete tumor removal. Outcomes are significantly worse for patients with extensive intracranial involvement that is not amenable to complete resection; reported survival rates for these patients range from 15 to 20 % [103].
Cervical Teratomas
Cervical teratomas are extremely rare neoplasms, occurring with an estimated incidence of 1:40,000 to 1:80,000 live births. These lesions account for 2 % of all neonatal tumors and 3–6 % of teratomas [104, 105]. Both sexes are equally affected. Although most cervical teratomas are histologically benign, they frequently cause significant airway and esophageal obstruction in the perinatal period and are thus potentially fatal. Primary tumor sites include the tongue, nasopharynx, palate, sinus, mandible, tonsil, anterior neck, and thyroid gland.
Prenatal US is a reliable and essential diagnostic tool for detecting these lesions in utero, allowing for careful arrangement of the time, mode, and place of delivery (Fig. 11.9a). When large cervical teratomas are prenatally detected, findings generally reveal multiloculated irregular masses with both solid and cystic components [106]. Of cases detected prenatally, cystic lymphatic malformations are the most likely entity to be mistaken for cervical teratoma. Similarities in size, sonographic findings, clinical characteristics, location, and gestational age at presentation can make this distinction difficult [107]. Other lesions to be considered in the differential diagnosis include large branchial cleft cyst and congenital thyroid goiter. To delineate anatomy more clearly, fetal MRI is the diagnostic imaging study of choice. MRI provides a larger field of view than fetal US and more clearly defines tissue planes, permitting a clear distinction between teratoma and vascular malformations. Because fewer than 30 % of cervical teratomas are associated with elevated AFP levels, this assay is not particularly helpful in the differential diagnosis of fetal cervical masses [81]. Approximately one third of prenatally diagnosed cases are complicated by maternal polyhydramnios, which is thought to be due to esophageal obstruction and/or interference with fetal swallowing. There is a high incidence of preterm labor and delivery that may be secondary to increased uterine size resulting from polyhydramnios and/or tumor.
(a) Antenatal ultrasound of a cervical teratoma (b) Infant with a cervical teratoma causing respiratory distress
Cervical teratomas are generally large and bulky, often measuring 5–12 cm in diameter (Fig. 11.9b). Tumor masses greater than the size of the fetal head have been reported [107–109], as has involvement of the oral floor, protrusion into the oral cavity (epignathus), and extension into the superior mediastinum [108]. Massive lesions may cause dystocia, requiring a cesarean section to deliver the baby. Various anomalies occurring in association with cervical teratomas have been reported. These include craniofacial and central nervous system anomalies, hypoplastic left ventricle, trisomy 13, and a case each of chondrodystrophia fetalis and imperforate anus [104]. Mandibular hypoplasia also has been seen as a direct result of mass effect on the developing mandible [81].
Up to 50 % of cervicofacial teratomas have calcifications present and these are often seen more easily on postnatal plain radiographs. When calcifications are present in a partially cystic and solid neck mass, they are virtually diagnostic of cervical teratoma [106]. A postnatal CT scan or MRI is essential in delineating the anatomic extent and precise involvement of the neoplasm.
As shown in a number of series [104, 108–112], airway obstruction at birth is life threatening and associated with a high mortality rate. In patients with massive fetal neck masses, this is generally associated with a delay in obtaining an airway and ineffective ventilation. Delay in acquiring an adequate airway can result in hypoxia and acidosis and if longer than 5 min, can result in anoxic injury. In light of these concerns, most cervicofacial teratomas are definitively treated immediately after delivery, which preferably should take place at a tertiary care center with an expert perinatal team that includes a pediatric surgeon. Optimally, if a cesarean section is performed, maternal-fetal placental circulation should be maintained while an airway is secured. This is accomplished by employing an EXIT procedure; this allows time to perform procedures such as direct laryngoscopy, bronchoscopy, tracheostomy, surfactant administration, and cyst decompression, which may be required to secure the airway [81]. Because precipitous airway obstruction may occur due to hemorrhage into the tumor, orotracheal intubation is indicated in all patients, regardless of the presence or absence of symptoms.
In some reported series [112–114], infants have either had acute airway obstruction or lost a previously secure orotracheal airway within a few hours or days after delivery. Because early resection after stabilization is the most effective method of achieving total airway control, it is the treatment of choice. Delaying surgery can have other serious ramifications, including retention of secretions, atelectasis, and/or pneumonia due to interference with swallowing [54, 107]. Resection also removes the risk of malignant degeneration, which occurs at much higher frequencies (>90 %) in cases of cervical teratomas that are not diagnosed or treated until late adolescence or adulthood [115].
To minimize operative morbidity, dissection of the teratoma should begin in areas distant to important regional nerves. Cervical teratomas often have a pseudocapsule, which facilitates gentle elevation of the tumor out of the neck. If the tumor arises from the thyroid gland, the involved thyroid lobe is excised in continuity with the teratoma. As glial metastases may be present, any enlarged lymph nodes should be excised with the tumor. After excision, a drain is left in place for 24–48 h. Because tumors are often large, envelopment of vital anatomic structures in the neck is common. In some cases, complete tumor excision with acceptable functional and cosmetic results can be achieved only by staged procedures.
In contrast to the high incidence of malignancy (>60 %) in adults, malignant cervicofacial teratomas with metastases are comparatively uncommon in neonates, with a reported incidence of 20 % [104]. Despite the existence of poorly differentiated or undifferentiated tissue in the primary tumor, many infants remain free from recurrence following complete resection of a cervical teratoma. Such cases suggest that malignant biologic behavior is uncommon in this population [106, 107]. Reported findings show a number of consistent histologic patterns [104]. Neuroectodermal elements and immature neural tissue are the most commonly observed tissues in metastatic foci. In approximately one third of cases, the metastases are more differentiated but confined to regional nodes. Patients with isolated regional node metastases who are treated with excision of the primary tumor generally survive free of disease [51]. This supports the concept that the presence of metastases containing only differentiated tumor usually correlates with a good prognosis.
There are currently no chemotherapy guidelines for neonates with malignant cervical teratomas. Based on results of their series, however, Azizkhan et al. [104] recommend that this modality be reserved for infants with disseminated disease (undifferentiated lesions) and those who have invasive tumors and residual disease after resection.
Although cervical teratoma is generally a benign tumor, the possibility of malignant transformation mandates close surveillance for tumor recurrence. Serum AFP levels should be monitored at 3-month intervals in infancy and annually thereafter, with a rising level alerting the clinician as to the possibility of tumor recurrence. As previously discussed, AFP levels must be interpreted with caution and viewed within the framework of their natural half-life. Imaging studies twice a year for the first 3 years of life are also recommended. Since the thyroid and parathyroid glands may be removed or affected by tumor excision, the risk of temporary or permanent hypothyroidism must be considered. If these complications are encountered, they must be monitored and managed appropriately.
Retroperitoneal Teratomas
The retroperitoneum is the third most common extragonadal site, accounting for 2–5 % of all pediatric teratomas [116, 117]. Most lesions are observed in early infancy and 50 % are identified in the first year of life [67, 103]. Females are more commonly affected (2:1) than males. Infants generally present with a palpable abdominal mass. CT or MR imaging of the abdomen helps differentiate this neoplasm from the more commonly occurring neuroblastoma or Wilms tumor. Laparotomy or a minimally invasive laparoscopic approach is used for complete tumor resection; however, larger lesions are more likely to require an open procedure. Although an overall malignancy rate of 7 % has been documented in children with teratomas, approximately 24 % of retroperitoneal teratomas diagnosed during the first postnatal month have been found to be malignant, based on histology or clinical course [118]. Additionally, 30–40 % of tumors have histologically immature elements. Malignant recurrence has been reported in patients with benign retroperitoneal teratomas containing immature components. As such, malignant lesions and lesions containing high-grade immature elements should be treated with adjuvant cisplatin-based chemotherapy following resection [117].
Mediastinal Teratomas
The mediastinum is the second most common extragonadal site for teratomas in children; however, mediastinal teratoma is rarely diagnosed in the neonate. Although these lesions occasionally originate within the heart, the pericardium, or the posterior mediastinum, they most frequently arise in the anterior mediastinum. As with previously discussed teratomas, diagnosis with prenatal US has been reported; nevertheless, most mediastinal lesions are diagnosed postnatally by the presence of a mediastinal mass with calcifications on a plain radiograph. Infants may present with chronic cough, wheezing, or severe respiratory distress caused by airway compression. Surgical approaches vary, depending on the site and size of the lesion [119, 120]. Small lesions are amenable to video-assisted thoracic surgery (VATS), whereas lesions within the pericardium require sternotomy or resection. Rarely, cardiopulmonary bypass is required for successful excision.
Most lesions in infants are benign; however, about 20 % of resected tumors show immature elements on histologic examination [121]. Nonetheless, neonates with benign mature or immature mediastinal teratomas have identical outcomes following complete resection.
Neuroblastoma
Neuroblastoma arises from neural crest cells and can present anywhere along the sympathetic chain, including the adrenal medulla and sympathetic ganglia. It is the second most common tumor diagnosed in the neonatal period, with a reported incidence of 5–8 per million live births [122, 123]. It is also the most common neonatal malignancy, accounting for nearly one third of all malignancies diagnosed in newborns [122, 123]. Autopsy series of infants who have died from unrelated causes indicate an occurrence rate (in situ neuroblastomas) far exceeding the reported incidence of neuroblastoma [124, 125]. Most of these tumors are occult and known to regress spontaneously.
Up to 80 % of neuroblastomas have recognizable and abnormal chromosomal patterns. In most cases, the defect is found on chromosomes 1 and 17 [18]; however, other abnormalities have been identified at 4p, 6q, 9q, 10q, 11q, 12q, 13q, 14q, 16q, 22p, and 22q [126]. The most important of these abnormalities are N-myc amplifications, deletions of chromosome 1p, and aneuploidy [18, 127–129]. Amplification of the N-myc oncogene is associated with a more aggressive tumor type that often presents with advanced stage disease. As such, it is considered a critical prognostic factor [18, 127–129].
Clinical Presentation
The most common presentation of neonatal neuroblastoma is an abdominal mass arising from the adrenal gland. Primary lesions also can occur in the neck, mediastinum, retroperitoneum, and pelvis. Symptoms vary, depending on the anatomic location of the tumor, its physiology, and its mass effect. Nearly half of tumors have metastases at diagnosis, most commonly to the liver [130]. Hepatomegaly or massive abdominal distention associated with respiratory compromise may be the initial findings in patients with disseminated disease. These patients also may have skin nodules and bone marrow involvement (stage 4S).
Most neuroblastomas diagnosed during the neonatal period present as solid lesions, although cystic lesions have been described; such lesions may arise from an adrenal cyst or develop as a result of hemorrhage or degeneration within a solid neuroblastoma [131].
Diagnostic Evaluation
Antenatal
The routine use of antenatal US has increasingly identified the presence of adrenal tumors and other intraabdominal masses [132–135]. Fetal MRI may help distinguish neuroblastomas from other mass lesions. Unlike neuroblastomas diagnosed during the neonatal period, prenatally diagnosed lesions often have a cystic component [133]. More than 90 % of these cystic tumors arise in the adrenal grand, suggesting a link between perinatal tumors and the nodular collections of neuroblasts that are part of normal adrenal development [136]. Moreover, there is evidence that cystic tumors are caused by a disturbance in the natural course of neuroblastic nodule regression [136]. Most antenatally diagnosed cystic tumors are stage 1, 2, or 4S and usually have favorable biological characteristics. Evidence indicates that these lesions have a tendency to regress spontaneously [137].
Although increased urinary excretion of catecholamine metabolites is found in most children with neuroblastoma, a significant percentage of infants in whom there is a fetal diagnosis of intraabdominal neuroblastoma have negative markers, reflecting the presence of a nonfunctioning tumor [138, 139].. Catecholamine-secreting fetal tumors are sometimes recognized however, by the onset of maternal hypertension or pre-eclampsia appearing in the last trimester of pregnancy [140]. These offspring usually have either stage 4 or 4S disease or multiple metastases to the placenta [132].
Postnatal
Imaging studies may help to differentiate neuroblastomas from adrenal hemorrhage, renal masses, and intraabdominal extralobar sequestration. As most neuroblastomas secrete varying quantities of catecholamine metabolites such as vanillylmandelic acid (VMA) and homovanillic acid (HVA), these should be checked by random urine studies [141, 142]. Tissue diagnosis can be made by open biopsy; however, open biopsy should be avoided in neonates with massive liver involvement and in those who are high surgical risks due to impaired ventilation or concern about wound closure. In such patients, elevated urinary catecholamine levels and demonstrated bone marrow involvement are sufficient to confirm the diagnosis. Tissue samples also should be analyzed for amplification of the N-myc oncogene, chromosome IP, other tumor markers (e.g. TrK-A) and for ploidy, which significantly affect prognosis [127–129].
Because most neonatal neuroblastomas are low stage and may regress spontaneously, the Children’s Oncology Group (COG) has undertaken a prospective randomized study to determine outcomes associated with observation alone for adrenal lesions identified in neonates. Results indicate that lesions which do not show radiographic signs of progression can be managed with observation alone (i.e. without tissue diagnosis), with the expectation that spontaneous regression will occur (Unpublished results of COG study).
Staging requires CT or MRI scans of the primary lesion and suspected metastatic sites. A technetium or MIGB bone scan should be obtained to identify possible cortical bone metastases. PET scans may also be useful in evaluating metastatic disease [143, 144].
Patients are currently stratified into prognostic risk groups based on an assessment of biologic factors and tumor staging according to the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS) [145, 146].
Stage 4S Disease
Infants younger than 12–18 months of age often present with a pattern of metastatic disease (stage 4S) that is unique to this age group. Stage 4S infants have a small or undetectable primary neuroblastoma with metastases to the liver, skin, and bone marrow [147, 148]. The adrenal is the most common primary site. Skin lesions typically present as multiple bluish subcutaneous nodules. Stage 4S tumors exhibit particularly interesting biologic behavior. Most (75 %) of these tumors regress spontaneously during infancy [149, 150]. Frequently, however, newborns with massive hepatic involvement are subject to a wide spectrum of significant respiratory and cardiovascular problems that may be fatal.
Treatment and Prognosis
Treatment strategies are based on stage and biologic features. As most oncologic studies do not segregate neonates from the broader grouping of infants younger than age 1 year, information pertaining to both treatment and prognosis in this specific age group is scant. Overall survival rates of infants younger than age 1 year, however, are known to be significantly greater than those of older children. Neonates with high-risk disease do not have this survival advantage.
Stages 1 and 2
Most neonates with stage 1 or 2 disease have a favorable prognosis. Surgery alone is generally sufficient to control disease, and survival is nearly 100 % [130]. In patients with stage 2 disease without N-myc amplification, residual microscopic disease usually regresses without additional intervention.
Stages 3 and 4
The incidence of stage 3 and 4 tumors in neonates and infants younger than 1 year is lower than that in older children [147]. Infants with stage 3 disease generally undergo several cycles of combination chemotherapy followed by delayed primary resection. Those without N-myc amplification have an excellent prognosis and enjoy a 90 % event-free survival [151]. Infants with stage 4 disease without N-myc amplification do not fare as well. Although studies show variable survival rates, these rates exceed 50 % [152–154].
Infants with stage 3 or 4 disease and N-myc amplification are considered to be a particularly high-risk group, requiring more intensive high-dose chemotherapy and radiation therapy and possible stem cell rescue. Despite this approach, those with more than 10 copies of the N-myc oncogene may have rapidly progressive disease; only 30–40 % of these patients survive.
Stage 4S
The survival rate of infants with stage 4S disease is greater than 80 %, often without treatment [155, 156]. Most patients have favorable genetic and biologic factors, including high protooncogene Trk-A expression, absence of N-myc amplification, favorable histology, and no evidence of allelic loss of chromosome 1p [155].
Despite the high rate of spontaneous tumor regression, progressive hepatomegaly may lead to respiratory embarrassment or inferior vena caval compression. In these patients, low-dose radiation to the liver (1–1.5 Gy per day over several days, with a total dose of 6–12 Gy) and low-dose chemotherapy are used to accelerate tumor regression. As a measure of last resort, some surgeons have released the intraabdominal compartment syndrome by creating a ventral hernia, using a large silastic patch to cover the surgical defect.
Most deaths in stage 4S occur in infants younger than 2 months of age with severe symptoms due to hepatomegaly. As compared to older infants, this younger group exhibits less tolerance to therapy [148, 156].
Soft Tissue Sarcomas
More than 75 % of soft tissue masses in children younger than age 1 year are benign lesions of vascular or fibromuscular origin. Soft tissue sarcomas diagnosed during the neonatal period are extremely rare, accounting for approximately 10 % of all neonatal malignant tumors and only 2 % of all childhood sarcomas [157] (Fig. 11.10). Some soft tissue sarcomas in neonates have a better prognosis than in older children, and the distinction between benign and malignant tumors is less clear in the neonate [158]. These tumors fall into two diagnostic groups, including rhabdomyosarcoma (RMS) and an exceedingly rare and diverse group of tumors collectively referred to as non-rhabdomyosarcoma soft tissue sarcomas (NRSTS).
Clinical photograph of a neonate with a sarcoma of the knee with metastatic spread to groin and lymph nodes
Soft tissue sarcomas usually present as a mass on physical examination. Imaging studies such as US or MRI are used to assess evidence of local or distant spread; however CT scanning should be avoided because of the high radiation dose. In some patients, diagnostic bone marrow aspiration also may be used to rule out bone marrow involvement. In large tumors, incisional biopsy may be required to confirm the diagnosis. It is necessary to provide at least a cubic cm of fresh and unfixed tissue to the pathologist, allowing for cytogenetic studies, electromicroscopy, and conventional immunohistochemistry [158].
Soft tissue sarcomas differ in their natural history and their response to chemotherapy. As in older children, RMS in neonates is responsive to chemotherapy. Some NRSTS in neonates, however, are chemosensitive whereas others are not [159]. In view of the known long-term effects of radiotherapy, this should be used only as a treatment of last resort. Surgery plays a major role both in establishing the diagnosis and in tumor management, especially in neonates. Optimally, localized soft-tissues masses are treated by wide excision with a clear margin, if this can be achieved without compromising function, growth, or appearance [160].
Rhabdomyosarcoma
Although RMS is the most common soft tissue sarcoma in older children, it accounts for only a third of soft tissue sarcomas in the first month of life. Because less than 5 % of all RMS presents in patients younger than age 1, data pertaining to neonatal RMA is extremely limited. In an Intergroup Rhabdomyosarcoma Study reported in 1994, there were only 14 neonates in a study group of 3217 patients, an incidence of 0.4 % [47].
Two histologic types of rhabdomyosarcoma have been described: alveolar (ARMS) and non-alveolar RMS. These tumors differ in their clinical behaviors and are associated with distinct chromosomal translocations. The predominant histologic non-alveolar RMS subtype presenting in neonates is embryonal (ERMS). These lesions are associated with allelic loss of the 11p15 region [161].
Approximately half of neonatal RMS arises in the bladder, vagina, and testicular and sacrococcygeal regions [162]. A common characteristic of neonatal RMS is its aggressive biologic behavior, with 50 % of patients having widespread disease at the time of diagnosis [157]. Metastatic disease can appear in the lungs, lymph nodes, liver, bone marrow, bone, and brain.
The treatment of neonatal RMS includes both surgery and chemotherapy; however, some tumors are not resectable prior to preoperative chemotherapy. Chemotherapy regimens vary, depending on the specific site and stage of the tumor. Although combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide (VAC) has historically been considered the most effective chemotherapy regimen, this regimen has been modified to reduce long-term toxicity. Currently, neonates with low-risk RMS are treated only with vincristine and actinomycin D (VA), thus reducing the risk of myelosuppression, infertility, and second malignancies [158, 163]. Neonates with high-risk RMS undergo a more intensive regimen, with the addition of ifosfamide or anthracyclines. Complete resection of nonmetastatic primary tumors is recommended if it can be accomplished with acceptable morbidity and without impacting function.
Brachytherapy and conventional radiotherapy are reserved for infants with gross or microscopic residual disease. Prognosis depends on stage at presentation, histologic characteristics of the lesion, and the location of the primary tumor. Infants with embryonal histology and complete surgical resection do well, with cure rates higher than 90 % [164]. Those with primary tumors in the head and neck (except parameningeal) and genitourinary region enjoy this same favorable prognosis [164]. Infants with metastatic disease at diagnosis do not fare well, with a 5-year survival rate of less than 30 % [157, 165].
Non-rhabdomyosarcoma Soft Tissue Sarcomas
NRSTS are exceedingly rare, with published experiences consisting only of small series or case reports. These tumors comprise a wide spectrum of pathologies, including undifferentiated sarcomas, synovial sarcomas, liposarcomas, peripheral primitive neuroectodermal tumor (PNET), and infantile fibrosarcoma (IFS). A study conducted by the Children’s Cancer Study Group (n = 9) [157] found that 5 of 9 newborns with a range of NRSTS survived (mean followup 9 years). Primary tumor sites were the head and neck, extremities, and trunk. Tumor management was based on tumor location, biology, and resectability. Survivors had localized disease at the time of surgery. Four had complete surgical resections, and one had microscopic disease at the surgical site; this patient was treated with chemotherapy. All patients with unresectable regional or metastatic disease died despite adjuvant chemotherapy.
Infantile Fibrosarcoma
Infantile fibrosarcoma (IFS) is the most common soft tissue sarcoma in children younger than age 1. Its incidence is higher in the first 6 months of life, and approximately one third of tumors diagnosed before age 5 are diagnosed shortly after birth [166]. IFS often presents as visible enlarging soft tissue masses. These masses typically affect the extremities (66 %); however, they are also seen in the abdomen (21 %) and thorax (3 %) [167] and have been documented in atypical locations, such as the intestine, lung, kidney, and colon [168]. Although these tumors are histologically similar to fibrosarcoma occurring in adults, they differ significantly in their behavior, as they have a low metastatic rate and a 5-year disease-free survival greater than 90 % [169, 170]. IFS is characterized by the chromosomal translocation (t 12;15) involving the ETV6 and NTRK3 genes, which is not found in fibrosarcomas that occur later in childhood and which has a much worse prognosis [171, 172]. Spontaneous resolution of congenital fibrosarcomas has been documented [160].
Primary excision is the first line of treatment. Large bulky neoplasms that are not amenable to limb-sparing surgical procedures can be managed with a perioperative chemotherapy (VA) [167].This approach allows for delayed and less extensive resection that might otherwise result in significant mutilation or morbidity. In some cases, chemotherapy may even lead to complete remission, thus eliminating the need for excision. Although metastases are uncommon, local tumor control may be exceedingly difficult, with tumor recurrence reported as high as 40 % [157, 166, 173]. In general, prognosis is not adversely affected by local tumor recurrence or metastatic spread, although exceptions have been reported [174].
Renal Tumors
Congenital renal neoplasms are extremely rare in neonates, accounting for only 8 % of neonatal tumors [15, 16]. The most common tumor of the kidney in the neonate is congenital mesoblastic nephroma (CMN), which accounts for approximately 75 % of renal neoplasms in this age group [175]. This is followed by Wilms tumor, which has an incidence in neonates lower than 0.2 % [175, 176].
Congenital Mesoblastic Nephroma
Although congenital renal neoplasms are rare, CMN is among the most common to present during the first few months of life, accounting for 50 % of all renal masses in the neonate [177]. CMN is a benign mesenchymal renal tumor that is histologically characterized by the proliferation of spindle-shaped cells arranged in fascicles that separate normal renal parenchymal tissue. Two variants of CMN have been identified: classical and cellular (42–63 %) [178]. Both types can coexist in distinct areas of a given tumor. CMN typically presents as a palpable, non-tender abdominal mass (Fig. 11.11a, b); however, hematuria, hypertension, and vomiting can also occur. Although numerous authors have described the detection of CMN with prenatal US during the third trimester, there are no specific prenatal sonographic characteristics that reliably distinguish between CMN and Wilms tumor [179]. In most published series polyhydramnios has been detected.
(a) A 3-week-old infant with a congenital mesoblastic nephroma (b) Operative specimen
Fetal MRI is helpful in establishing an accurate prenatal diagnosis, offering better tissue contrast and definition of the relationship of the tumor to adjacent structures [180]. Postnatal imaging modalities such as MRI can be useful in making a more precise diagnosis but also are limited in distinguishing between the two tumors. Histology thus remains essential for establishing a definitive diagnosis [181].. Although most affected children have no associated abnormality, associations have been described for both histologic variants [182].
As most cases of CMN are confined to the renal capsule, nephroureterectomy is usually curative. In some patients, however, the growth pattern is one of local invasion and extension through the renal capsule. During the course of resection, these tumors may be particularly friable and prone to intraoperative bleeding and rupture [15, 183]. Despite these possible complications, a survival rate exceeding 90 % has been reported [15]. Metastases, which rarely occur, are managed with combination chemotherapy comprising vincristine, doxorubicin, and cyclophosphamide or iphosphamide [184, 185].
Wilms Tumor
Although rare, Wilms tumor is the most common renal malignancy in neonates. This tumor is thought to arise from nephrogenic rests that persist beyond 36 weeks of gestation [186]. Unlike CMN, Wilms tumor has a robust association with numerous genetic conditions. Both WAGR syndrome (Wilms, aniridia, genitourinary tract abnormalities, mental retardation) and Beckwith-Wiedemann syndrome (gigantism, omphalocele, macroglossia, hemihypertrophy) are associated with an increased risk of developing WT. These syndromes are associated with a loss of function of the WT1 gene at chromosome band 11p13 (WAGR) or WT2 at chromosome band 11p15 (BWS) [187, 188]. Fetal Wilms tumor may present as part of Perlman syndrome, which is characterized by familial nephroblastomatosis, fetal ascites, polyhydramnios, hepatomegaly, macrosomia, and Wilms tumor [189, 190]. Other associated anomalies include aniridia, hemihypertrophy, cryptorchidism, and hypospadias. Among patients with Wilms tumor who have no identifiable syndrome, approximately 40 % have abnormalities in expression of WT1 and WT2 [191]. This tumor affects both sexes equally [192].
Relatively few cases have been diagnosed antenatally, and as mentioned above, antenatal sonographic features of this tumor may be indistinguishable from those of CMN. Both CMN and Wilms tumor present as complex masses that may originate from and replace the entire kidney. Tumors are mainly solid, however, cystic regions may exist within the tumor. Wilms tumor may have a well-defined pseudocapsule. Fetal MRI provides clear anatomic definition of the extent of the tumor and its impact on adjacent structures. Postnatal MRI provides optimal preoperative imaging, however, histopathology is essential to confirm the diagnosis.
As with CMN, Wilms tumor in neonates usually presents as a non-tender abdominal mass. Important to note, 50 % of cases have hypertension, an important indication of the need for further evaluation [193]. Hematuria and hypercalcemia have also been reported [194], though they are not specific for this particular tumor. Most tumors are low stage and have favorable histology, however, metastatic disease can occur [176, 195]. The most common site of metastasis is the lungs.
For infants with unilateral Wilms tumor, the mainstay of treatment is nephroureterectomy for all tumors. In North America, stage II and higher tumors are treated with nephroureterectomy followed by combination chemotherapy with vincristine, dactinomycin, and doxorubicin (COG protocol). The SIOP (Societé Internationale D’oncologie Pediatrique) protocol for higher risk tumors is somewhat different, as it calls for upfront chemotherapy followed by nephroureterectomy [196].
Liver Tumors
Primary tumors of the liver are extremely rare, accounting for only 2 % of all pediatric tumors and 5 % of neoplasms occurring in the fetus and neonate [197]. They include a wide spectrum of benign and malignant lesions that occur with a distribution that is different from that in older children [198]. Most benign neonatal liver tumors are of vascular origin. Hemangiomas are the most common primary liver neoplasm, followed by mesenchymal hamartoma and hepatoblastoma.
Infantile Hepatic Hemangiomas
Hepatic hemangiomas follow a natural history similar to that of cutaneous lesions, and as with cutaneous lesions, they occur more commonly in females. Most hepatic hemangiomas are asymptomatic and incidentally discovered during imaging of the abdomen. Diffuse involvement of the liver is more often associated with severe complications during the proliferative phase, such as high output cardiac failure, hepatic dysfunction, abdominal compartment syndrome, and hypothyroidism. Significant symptoms or complications generally become evident during the first 3–4 months of life. Cutaneous hemangiomas are frequently the first indication of potential visceral involvement; however, hepatic and other visceral hemangiomas also can occur without cutaneous involvement [199].
Hepatic hemangiomas present variably, from tiny asymptomatic tumors that are detected incidentally to large (>5 cm in diameter) single or multiple tumors that may or may not be associated with high output cardiac states. Infants are frequently seen with a triad of hepatomegaly, anemia, and high-output cardiac failure [200]. A systolic bruit may occasionally be heard over the enlarged liver. In rare cases, progressive and massive liver enlargement may cause abdominal compartment syndrome, resulting in life-threatening visceral ischemia and ventilatory failure [201].
US of the liver in infants with multiple (>5) or solitary lesions is useful both for initial screening [202] and for followup on lesions that are well characterized. US demonstrates either a single lesion or multiple lesions with draining veins and often a dilated proximal abdominal aorta. There may also be signs of significant intrahepatic shunting. Antenatal US may detect large hepatic lesions [203].
MRI is the imaging technique of choice for completely defining the extent and location of hepatic hemangiomas and their relationship to vascular structures. Although imaging features vary, most lesions appear as focal or multifocal T2-hyperintense spheres with centripetal contrast enhancement and dilated feeding and draining vessels (Fig. 11.12a). Three atypical patterns have also been found, including focal mass lesions with a large central varix with or without direct shunts, focal mass lesions with central necrosis or thrombosis, and massive hemangiomatous involvement of the liver with abdominal vascular compression [204]. The latter pattern of massive replacement of liver is associated with abdominal compartment syndrome, hypothyroidism, and a high mortality rate. Hypothyroidism is attributed to high levels of type 3 iodothyronine deiodinase activity produced by hemangiomas; this activity inactivates circulating thyroid hormone [205]. Patients with diffuse liver hemangiomatosis should therefore undergo screening for hypothyroidism. Because an abnormal thyroid-stimulating hormone level may not develop until a hemangioma proliferates, repeat testing is indicated when lesions undergo considerable growth. For patients with diffuse hemangiomatosis, high-output cardiac failure, and compartment syndrome, the mortality rate exceeds 50 %.
(a) MRI of the liver demonstrating a large intrahepatic hemangioma (b) Operative photograph showing a large hemangioma of the liver in a 1-month-old infant
If embolic therapy is required, angiography should first be performed to clearly outline the vascular anatomy and aberrant shunting through the liver. Angiographic features of hepatic hemangiomas are variable, ranging from discrete hypervascular tumors to diffuse tumors with macroscopic arteriovenous, arterioportal, and portosystemic shunting [200, 206]. Because hepatic hemangioma and arteriovenous malformations are rheologically fast flow, they may be mistaken for one another; however, true arteriovenous malformations are extremely rare. Large solitary lesions diagnosed antenatally or soon after birth are likely to be congenital hemangiomas that are characterized by central necrosis of the lesion, capillary proliferation in the periphery of the lesion, and indistinct lesion margins due to abnormally large vessels extending into the adjacent liver tissue (Fig. 11.12b).
When imaging features are atypical and the diagnosis is unclear, incisional or excisional biopsies are extremely helpful in determining the pathology of a lesion and the most appropriate course of treatment. Differential diagnosis includes neuroblastoma, hepatoblastoma, and mesenchymal hamartomas, as well as a number of other neoplasms. Most infantile hepatic hemangiomas, including those detected incidentally on imaging studies, remain asymptomatic throughout their natural clinical course. Patients with focal lesions without high flow seen on Doppler US generally do not require treatment [204]. Patients with small, asymptomatic lesions should be followed with sequential physical examinations and US studies. Treatment should be reserved for infants with enlarged lesions that cause significant symptoms or complications.
Propranolol, a nonselective beta-blocker used for the management of infants with cardiovascular conditions, has become the preferred treatment for hepatic hemangiomas as well as other function or life-threatening hemangiomas [207]. Although the mechanism of action of propranolol remains speculative, it is thought to involve the down-regulation of vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF) gene expression and to trigger apoptosis of capillary endothelial cells. By using propranolol as our first-line therapy, we have achieved a response rate of greater than 90 %. Patients typically receive 3–4 mg/kg/day for up to 1 year, which generally corresponds to the proliferative phase. They are then weaned off the propranolol. Corticosteroids may be used adjunctively and in some patients the combined approaches have a synergistic effect. Patients who are critically ill are initially treated with both propranolol and corticosteroids. Once they are stabilized, propranolol alone is administered. Caregivers should be aware of possible adverse effects of propranolol, which include hypoglycemia, hypotension, and brachycardia. These may manifest in lethargy, labored breathing, and diaphoresis.
For lesions that are unresponsive to propranolol and steroids, vincristine is the current drug of choice. Because it is a vesicant, it is best delivered through central venous access. An initial weekly dose of 0.05–1 mg per m2 is administered by intravenous injection. This dose is then tapered, increasing the interval between injections depending on the clinical response. Treatment is administered for 4–6 months.
The angiogenesis inhibitor interferon-α is also occasionally used for lesions that are refractory to corticosteroid therapy. It is typically administered as a daily subcutaneous injection at a dosage range of 1–3 million units/m2. Because of its known neurotoxicity, particularly its association with spastic diplegia [208, 209], the use of interferon-α in children younger than age 1 year is generally avoided.
In patients with persistent high-output cardiac failure, angiography and embolization may be performed, with the latter being useful only if there are direct macrovascular shunts through the lesion. Because angiography and embolization are associated with risk of injury to the femoral access vessel or inadvertently embolized visceral vessels, it should be performed only by an interventional radiologist with skill and experience with these techniques in infants.
Other treatment options reserved for refractory lesions include surgical resection of large solitary lesions, hepatic artery ligation, and liver transplantation. Prior to contemporary pharmacologic therapy, resection of solitary lesions and embolization were frequently the only viable treatment options. Because they are associated with extremely high mortality, however, they are now infrequently performed. Although rarely done, hepatic artery ligation is associated with a survival rate of 80 % [210]. Liver transplantation is rarely performed and is reserved for patients in whom there is diffuse hepatic involvement and an imminent risk of death [211].
Mesenchymal Hamartomas
Hepatic mesenchymal hamartomas are benign tumors that typically present as a large, palpable, nontender cystic liver mass. They are more common (75 %) in the right lobe and have a slight male predominance. Lesions are generally diagnosed during the first 2 years of life, however, they are not uncommonly reported in the newborn [198]. The mass is usually encapsulated, although occasionally it can infiltrate into the hepatic parenchyma and cause respiratory distress or heart failure from arteriovenous shunting. Histologically, mesenchymal hamartomas are lined by bile duct epithelium. The phenotypic appearance of lesions may be either multi-cystic or with a dominant cyst. The cysts do not contain normal bile nor do they communicate with the biliary tree. The tumor stroma has a myxoid or fibrous appearance with combined vascular and biliary elements [212].
Aneuploidy has been documented by flow cytometry and balanced translocations between chromosome 11 and 19 t (11;19) (q13;q13.4) have been found by cytogenetic analysis; the latter finding is consistent with the possibility of a clonal genetic defect. Aneuploidy and karyotype changes are more commonly associated with malignant lesions and when found in mesenchymal hamartomas may indicate an inherent genetic instability [212].
Although lesions have been detected as early as the 19th week of gestation, they are more commonly found during the third trimester. They are sometimes pedunculated and their hepatic origin may be difficult to ascertain. Maternal AFP and β-hCG are sometimes elevated. Large tumors present a threat to the fetus, as they may lead to the onset of polyhydramnios and hydrops secondary to compression of the inferior vena cava and the umbilical vein. They may also cause rapid loss of fluid into the cysts. The volatile fluid shifts in these lesions may bring about premature labor.
Most lesions presenting postnatally are asymptomatic and appear as palpable abdominal masses in otherwise normal infants. Biochemical markers of liver function are generally normal. Although AFP may be elevated, it should return to normal following surgical resection.
The initial diagnostic modality of choice is US. This is followed by MRI or CT scans, which provide more information regarding anatomic details that are beneficial for surgical planning.
Although spontaneous tumor regression can occur, cases of massive local recurrence and later transformation to undifferentiated sarcoma have been reported [213, 214]. Thus, when feasible, complete surgical resection is the treatment of choice.
Hepatoblastoma
Hepatoblastoma is a rare embryonal neoplasm composed of malignant epithelial tissue with variable differentiation, most often with embryonal or fetal components [198]. It is the most frequently occurring liver tumor during the first year of life; however less than 10 % of these tumors occur in neonates [215].
A broad spectrum of congenital anomalies and malformation syndromes has been reported in association with hepatoblastoma. There is an increased incidence among patients with Beckwith-Weidemann syndrome, Li-Fraumeni syndrome, hemihypertrophy, and familial adenomatous polyposis [216–220]. There also is an increased incidence of hepatoblastoma in males (2:1) and premature infants [221, 222]; in the latter group, the risk increases as birth weight decreases [223].
Hepatoblastomas are occasionally detected prenatally by abdominal US and can cause polyhydramnios and stillbirth. Tumor rupture and massive hemorrhage have been described following delivery [224, 225].
Postnatally, hepatoblastoma presents with abdominal enlargement and hepatomegaly. AFP levels are elevated in most patients and are especially useful in monitoring disease status following treatment. The lungs are the primary site of metastasis, though bone and brain involvement can occur. US is useful in distinguishing solid from cystic masses. Hepatoblastoma generally appears as a large hyperechoic mass. Color Doppler imaging is also helpful in evaluating the involvement of the portal vein, hepatic veins, and the inferior vena cava. A CT or MRI liver scan is helpful in delineating the extent of the lesion and assessing its resectability. MRI scans in particular can clearly delineate the vascular anatomy of the liver in relationship to the tumor.
Complete surgical resection and subsequent chemotherapy with cytotoxic agents (e.g., cisplatin and doxorubicin) is the treatment of choice [226, 227]. For neonates with lesions that initially are not resectable, preoperative chemotherapy can be beneficial. For patients with unresectable tumors confined to the liver, hepatic transplantation is an option [211]. Prognosis is largely dependent on resectability. Approximately two thirds of patients with tumors that are initially unresectable can be rendered disease-free with several cycles of chemotherapy followed by surgical resection and subsequent postoperative chemotherapy [228, 229]. Despite preoperative chemotherapy, it is clear that hepatoblastoma is likely to be fatal without complete resection of the tumor [230].
Retinoblastoma
Retinoblastoma is a rare malignant tumor that arises from the embryonic neural retina and is estimated to occur in 1 in 15,000 to 1 in 34,000 live births [231]. Although it is believed to be congenital, it may not be observed at birth. Eighty percent of cases are diagnosed before the age of 3–4 years (mean, age 2). Bilateral tumors are estimated to occur in 20–30 % of affected children [232]. In this subgroup, the diagnosis typically becomes clinically apparent earlier (mean, age 12 months) [233].
Retinoblastoma develops in cells that that have mutations in both copies of RBI, the retinoblastoma locus, located on chromosome 13q14. The tumor is detected by absence of the normal red reflex when the infant’s eyes are examined with an ophthalmoscope. All newborns should thus be screened for this reflex and any infant with a family history of retinoblastoma should undergo a comprehensive ophthalmologic examination. These patients are particularly at risk for bilateral involvement.
When detected early, cure rates exceed 90 % [234, 235]. When disease is intraocular, laser therapy or cryotherapy is used either with or without adjuvant chemotherapy, depending on the size of the lesion. In selective cases, radiotherapy is also used to salvage vision. Extensive intraocular disease can be managed with enucleation [236]. Metastatic disease requires aggressive chemotherapy [237, 238].
References
Bader JL, Miller RW. US cancer incidence and mortality in the first year of life. Am J Dis Child. 1979;133:157–9.
Littman P, D’Angio GJ. Radiation therapy in the neonate. Am J Pediatr Hematol Oncol. 1981;3:279–85.
Reaman GH, Bleyer A. Infants and adolescents with cancer: special considerations, chap 15. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
Bhatia S, Landier W, Robison LL. Late effects of childhood cancer therapy. In: DeVita VT, Hellman S, Rosenberg SA, editors. Progress in oncology. Sudbury: Jones and Bartlett Publishers; 2002. p. 171–213.
Pintér AB, Hock A, Kajtár P, Dober I. Long-term follow-up of cancer in neonate and infants: a national survey of 142 patients. Pediatr Surg Int. 2003;19:233–9.
Meadows AT, Gallagher JA, Bunin GR. Late effects of early childhood cancer therapy. Br J Cancer Suppl. 1992;18:S92–5.
Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation therapy for Wilms’ tumor. Int J Radiat Oncol Biol Phys. 2000;46:1239–46.
Dreyer ZE, Blatt J, Bleyer A. Late effects of childhood cancer and its treatment, chap 49. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
Robison LL. The Childhood Cancer Survivor Study: a resource for research of long-term outcomes among adult survivors of childhood cancer. Minn Med. 2005;88:45–9.
Crom DB, Wilimas JA, Green AA, Pratt CB, Jenkins 3rd JJ, Behm FG. Malignancy in the neonate. Med Pediatr Oncol. 1989;17:101–4.
Campbell AN, Chan HS, O’Brien A, Smith CR, Becker LE. Malignant tumors in the neonate. Arch Dis Child. 1988;62:19–23.
Batcup G. Cancer in the very young child—pitfalls and problems for the pathologist. Br J Cancer. 1992;18(Suppl):S5–7.
Xue H, Horwitz JR, Smith MB, et al. Malignant solid tumors in neonates: a 40-year review. J Pediatr Surg. 1995;30:543–5.
Moore SW, Kaschula ROC, Albertyn R, Rode H, Millar AJW, Karabus C. The outcome of solid tumours occurring in the neonatal period. Pediatr Surg Int. 1995;10:366–70.
Dillon PW, Azizkhan RG. Neonatal tumors, chap 19. In: Andrassy RJ, editor. Pediatric surgery oncology. Philadelphia: WB Saunders Co; 1997.
Parkes SE, Muir KR, Southern L, Cameron AH, Darbyshire PJ, Stevens MC. Neonatal tumors: a thirty-year population-based study. Med Pediatr Oncol. 1994;22:309–17.
Halperin EC. Neonatal neoplasms. Int J Radiat Oncol Biol Phys. 2000;47:171–8.
Moore SW, Plaschkes J. Epidemiology and genetic associations of neonatal tumors, chap 70. In: Puri P, editor. Newborn surgery. 2nd ed. New York: Oxford University Press Inc; 2003.
Buyukpamukcu M, Varan A, Tanyel C, et al. Solid tumors in the neonatal period. Clin Pediatr. 2003;42:29–34.
Moore SW, Satgé D, Sasco AJ, Zimmermann A, Plaschkes J. The epidemiology of neonatal tumours: report of an international working group. Pediatr Surg Int. 2003;19:509–19.
Moore SW. Genetic and clinical associations of neonatal tumours. In: Puri P, editor. Neonatal tumours. New York: Springer; 1996. p. 11–22.
Altmann AE, Halliday JL, Giles GG. Associations between congenital malformations and childhood cancer: a register-based case-control study. Br J Cancer. 1998;78:1244–9.
Satgé D, Van Den Berghe H. Aspects of the neoplasms observed in patients with constitutional autosomal trisomy. Cancer Genet Cytogenet. 1996;87:63–70.
Coppes MJ, Campbell CE, Williams BR. The role of WT1 in Wilms tumorigenesis. FASEB J. 1993;7:886–95.
Holland WW, Doll R, Carter CO. The mortality from leukaemia and other cancers among patients with Down’s syndrome (Mongols) and among their parents. Br J Cancer. 1962;16:177–86.
Weinberg AG, Schiller G, Windmiller J. Neonatal leukemoid reaction. An isolated manifestation of mosaic Trisomy 21. Am J Dis Child. 1982;136:310–1.
Bresters D, Reus AC, Veerman AJ, van Wering AR, van der Does-van den Berg A, Kaspers GJ. Congenital leukaemia: the Dutch experience and review of the literature. Br J Haematol. 2002;117:513–24.
Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol. 1997;79:130–9.
Rahbar R, Vogel A, Myers LB, et al. Fetal surgery in otolaryngology: a new era in the diagnosis and management of fetal airway obstruction because of advances in prenatal imaging. Arch Otolaryngol Head Neck Surg. 2005;131:393–8.
Coleman BG, Adzick NS, Crombleholme TM, et al. Fetal therapy: state of the art. J Ultrasound Med. 2002;21:1257–88.
Sauvat F, Sarnacki S, Brisse H, et al. Outcome of suprarenal localized masses diagnosed during the perinatal period: a retrospective multicenter study. Cancer. 2002;94:2474–80.
Lund DP, Soriano SG, Fauza D, et al. Resection of a massive sacrococcygeal teratoma using hypothermic hypoperfusion: a novel use for extracorporeal membrane oxygenation. J Pediatr Surg. 1995;30:1557–9.
Mychaliska GB, Bealer JF, Graf JL, Rosen MA, Adzick NS, Harrison MR. Operating on placental support: the ex utero intrapartum treatment procedure. J Pediatr Surg. 1997;32:227–30.
Wegner EA, Barrington SF, Kingston JE, et al. The impact of PET scanning on management of paediatric oncology patients. Eur J Nucl Med Mol Imaging. 2005;32:23–30.
Rechnitzer C. Increased survival of children with solid tumours: how did we get there and how to keep the success going? Cancer Imaging. 2011;11(Spec No A):S65–9.
Kumar R, Shandal V, Shamim SA, et al. Clinical applications of PET and PET/CT in pediatric malignancies. Expert Rev Anticancer Ther. 2010;10:755–68.
Brodeur GM, Maris JM. Neuroblastoma, chap 31. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
Silber JH, Littman PS, Meadows AT. Stature loss following skeletal irradiation for childhood cancer. J Clin Oncol. 1990;8:304–12.
Meadows AT, Gordon J, Massari DJ, Littman P, Fergusson J, Moss K. Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet. 1981;2:1015–8.
Farwell JR, Dohrmann GJ, Flannery JT. Intracranial neoplasms in infants. Arch Neurol. 1978;35:533–7.
Littman PS, D’Angio GJ. Growth considerations in the radiation therapy of children with cancer. Annu Rev Med. 1979;30:405–15.
Guibout C, Adjadj E, Rubino C, et al. Malignant breast tumors after radiotherapy for a first cancer during childhood. J Clin Oncol. 2005;23:197–204.
Maier JG. Effects of radiation on kidney, bladder and prostate. In: Vaeth JM, editor. Frontiers of radiation therapy and oncology, vol. 6. Baltimore: Karger, Basel and University Park Press; 1972. p. 196–207.
Kraut JW, Bagshaw MA, Glatsein EJ. Hepatic effects of irradiation. In: Vaeth JM, editor. Frontiers of radiation therapy and oncology, vol. 6. Baltimore: Karger, Basel and University Park Press; 1972. p. 182–95.
Cancer pharmacology in infants and young children. Online summary of meeting sponsored by the Children’s Oncology Group (COG) and National Cancer Institute-Cancer Therapy Evaluation Program (CTEP), Arlington; 2003.
Morgan E, Baum E, Breslow N, Takashima J, D’Angio G. Chemotherapy-related toxicity in infants treated according to the Second National Wilms’ Tumor Study. J Clin Oncol. 1988;6:51–5.
Lobe TE, Wiener ES, Hays DM, et al. Neonatal rhabdomyosarcoma: the IRS experience. J Pediatr Surg. 1994;29:1167–70.
Reaman G, Zeltzer P, Bleyer WA, et al. Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children’s Cancer Study Group. J Clin Oncol. 1985;3:1513–21.
Isaacs Jr H. Perinatal (fetal and neonatal) germ cell tumors. J Pediatr Surg. 2004;39:1003–13.
Shamberger RC. Teratomas and germ cell tumors, chap 24. In: O’Neill JA, Grosfeld JL, Fonkalsrud EW, et al., editors. Principles of pediatric surgery. 2nd ed. St. Louis: Mosby; 2004.
Azizkhan RG. Teratomas and other germ cell tumors, chap 34. In: Grosfeld JL, O’Neill JA, Coran AG, Fonkalsrud EW, editors. Pediatric surgery. 6th ed. Philadelphia: Mosby Inc; 2006.
Bale PM. Sacrococcygeal developmental abnormalities and tumors in children. Perspect Pediatr Pathol. 1984;8:9–56.
Lemire RJ, Beckwith JB. Pathogenesis of congenital tumors and malformations of the sacrococcygeal region. Teratology. 1982;25:201–13.
Noseworthy J, Lack EE, Kozakewich HP, Vawter GF, Welch KJ. Sacrococcygeal germ cell tumors in childhood: an updated experience with 118 patients. J Pediatr Surg. 1981;16:358–64.
Gonzalez-Crussi F. Extragonadal teratomas. In: Atlas of tumor pathology. 2nd series. Washington, DC: Armed Forces Institute of Pathology; US Gov Priniting, 1982: fascicle 18.
Sen G, Sebire NJ, Olsen O, et al. Familial Currarino syndrome presenting with peripheral primitive neuroectodermal tumour arising with a sacral teratoma. Pediatr Blood Cancer. 2008;50:172–5.
Cushing B, Perlman EJ, Marina NM, Castleberry RP. Germ cell tumors, chap 36. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer. 1976;37:2359–72.
Robboy SJ, Scully RE. Ovarian teratoma with glial implants on the peritoneum. An analysis of 12 cases. Hum Pathol. 1970;1:643–53.
Isaacs Jr H. Germ cell tumors. In: Tumors of the fetus and newborn, Major problems in pathology series, vol. 35. Philadelphia: WB Saunders; 1997. p. 15.
Valdiserri RO, Yunis EJ. Sacrococcygeal teratomas: a review of 68 cases. Cancer. 1981;48:217–21.
Baumann FR, Nerlich A. Metastasizing cervical teratoma of the fetus. Pediatr Pathol. 1993;13:21–7.
Dehner LP, Mills A, Talerman A, Billman GF, Krous HF, Platz CE. Germ cell neoplasms of head and neck soft tissues: a pathologic spectrum of teratomatous and endodermal sinus tumors. Hum Pathol. 1990;21:309–18.
Heifetz SA, Cushing B, Giller R, et al. Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children’s Cancer Group. Am J Surg Pathol. 1998;22:1115–24.
Tsuchida Y, Endo Y, Saito S, et al. Evaluation of alpha fetoprotein in early infancy. J Pediatr Surg. 1978;13:155–62.
Schneider DT, Calaminus G, Göbel U. Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol. 2001;18:11–26.
Rowe MI, O’Neill JA, Grosfeld JL, Fonkalsrud EW, Coran AG. Teratomas and germ cell tumors, chap 30. In: Rowe MI, O’Neill JA, Grosfeld JL, Fonkalsrud EW, Coran AG, editors. Essentials of pediatric surgery. St Louis: Mosby-Year Book; 1995.
Magee JF, McFadden DE, Pantzar JT. Congenital tumors. In: Dimmick JE, Kalousek DK, editors. Developmental pathology of the embryo and fetus. Philadelphia: JB Lippincott; 1992. p. 235.
Schropp KP, Lobe TE, Rao B, et al. Sacrococcygeal teratoma: the experience of four decades. J Pediatr Surg. 1992;27:1075–9.
Goto M, Makino Y, Tamura R, Ikeda S, Kawarabayashi T. Sacrococcygeal teratoma with hydrops fetalis and bilateral hydronephrosis. J Perinat Med. 2000;28:414–8.
Rescorla FJ, Sawin RS, Coran AG, Dillon PW, Azizkhan RG. Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Children’s Cancer Group. J Pediatr Surg. 1998;33:171–6.
Werb P, Scurry J, Ostor A, Fortune D, Attwood H. Survey of congenital tumors in perinatal necropsies. Pathology. 1992;24:247–53.
Altman RP, Randolph JG, Lilly JR. Sacrococcygeal teratoma: american academy of pediatrics surgical section survey–1973. J Pediatr Surg. 1974;9:389–98.
Carney JA, Thompson DP, Johnson CL, Lynn HB. Teratomas in children: clinical and pathologic aspects. J Pediatr Surg. 1972;7:271–82.
Fraumeni Jr JF, Li FP, Dalager N. Teratomas in children: epidemiologic features. J Natl Cancer Inst. 1973;51:1425–30.
Hawkins E, Perlman EJ. Germ cell tumors, chap 10. In: Parham DM, editor. Pediatric neoplasia: morphology and biology. Philadelphia: Lippincott-Raven; 1996.
Garel C, Mizouni L, Menez F, et al. Prenatal diagnosis of a cystic type IV sacrococcygeal teratoma mimicking a cloacal anomaly: contribution of MR. Prenat Diagn. 2005;25:216–9.
Yoon SH, Park SH. A case of type III cystic sacrococcygeal teratoma. Pediatr Neurosurg. 2006;42:234–6.
Danzer E, Hubbard AM, Hedrick HL, et al. Diagnosis and characterization of fetal sacrococcygeal teratoma with prenatal MRI. AJR Am J Roentgenol. 2006;187:W350–6.
Shaaban AF, Kim HB, Flake AW. Fetal surgery, diagnosis, and intervention, chap 3. In: Ziegler MM, Azizkhan RG, Weber TR, editors. Operative pediatric surgery. New York: McGraw-Hill; 2003.
Bianchi DW, Crombleholme TM, D’Alton ME. Fetology: diagnosis and management of the fetal patient. New York: McGraw-Hill; 2000. Chap 111, Chap 116.
Flake AW. Fetal sacrococcygeal teratoma. Semin Pediatr Surg. 1993;2:113–20.
Kapoor R, Saha MM. Antenatal sonographic diagnosis of fetal sacrococcygeal teratoma with hydrops. Australas Radiol. 1989;33:285–7.
Hedrick HL, Flake AW, Crombleholme TM, et al. Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediatr Surg. 2004;39:430–8.
Bond SJ, Harrison MR, Schmidt KG, et al. Death due to high-output cardiac failure in fetal sacrococcygeal teratoma. J Pediatr Surg. 1990;25:1287–91.
Flake AW, Harrison MR, Adzick NS, et al. Fetal sacrococcygeal teratoma. J Pediatr Surg. 1986;21:563–6.
Musci Jr MN, Clark MJ, Ayres RE, Finkel MA. Management of dystocia caused by a large sacrococcygeal teratoma. Obstet Gynecol. 1983;62:10s–2.
Roybal JL, Moldenhauer JS, Khalek N, et al. Early delivery as an alternative management strategy for selected high-risk fetal sacrococcygeal teratomas. J Pediatr Surg. 2011;46:1325–32.
Adzick NS, Crombleholme TM, Morgan MA, Quinn TM. A rapidly growing fetal teratoma. Lancet. 1997;349:538.
Azizkhan RG. Neonatal tumors, chap 8. In: Carachi R, Azmy A, Grosfeld JL, editors. The surgery of childhood tumors. New York: Oxford University Press; 1999.
Fishman SJ, Jennings RW, Johnson SM, Kim HB. Contouring buttock reconstruction after sacrococcygeal teratoma resection. J Pediatr Surg. 2004;39:439–41.
Gross RW, Clatworthy Jr HW, Meeker Jr IA. Sacrococcygeal teratomas in infants and children: a report of 40 cases. Surg Gynecol Obstet. 1951;92:341–54.
Robertson FM, Crombleholme TM, Frantz 3rd ID, Shephard BA, Bianchi DW, D’Alton ME. Devascularization and staged resection of giant sacrococcygeal teratoma in the premature infant. J Pediatr Surg. 1995;30:309–11.
Teitelbaum D, Teich S, Cassidy S, Karp M, Cooney D, Besner G. Highly vascularized sacrococcygeal teratoma: description of this atypical variant and its operative management. J Pediatr Surg. 1994;29:98–101.
Göbel U, Schneider DT, Calaminus G, et al. Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol. 2001;19:1943–50.
Göbel U, Calaminus G, Schneider DT, Schmidt P, Haas RJ. Management of germ cell tumors in children: approaches to cure. Onkologie. 2002;25:14–22.
Rescorla F, Billmire D, Stolar C, et al. The effect of cisplatin dose and surgical resection in children with malignant germ cell tumors at the sacrococcygeal region: a pediatric intergroup trial (POG 9049/CCG 8882). J Pediatr Surg. 2001;36:12–7.
Misra D, Pritchard J, Drake DP, Kiely EM, Spitz L. Markedly improved survival in malignant sacrococcygeal teratomas—16 years’ experience. Eur J Pediatr Surg. 1997;7:152–5.
Calaminus G, Schneider DT, Bokkerink JP, et al. Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89. J Clin Oncol. 2003;21:781–6.
Donnellan WA, Swenson O. Benign and malignant sacrococcygeal teratomas. Surgery. 1968;64:834–46.
Waldhausen JA, Kolman JW, Vellios F, Battersby JS. Sacrococcygeal teratoma. Surgery. 1963;54:933–49.
Marina NM, Cushing B, Giller R, et al. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: a Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. J Clin Oncol. 1999;17:2137–43.
Azizkhan RG, Caty MG. Teratomas in childhood. Curr Opin Pediatr. 1996;8:287–92.
Azizkhan RG, Haase GM, Applebaum H, et al. Diagnosis, management, and outcome of cervicofacial teratomas in neonates: a Children’s Cancer Group Study. J Pediatr Surg. 1995;30:312–6.
Lack EE. Extragonadal germ cell tumors of the head and neck region: review of 16 cases. Hum Pathol. 1985;16:56–64.
Gundry SR, Wesley JR, Klein MD, Barr M, Coran AG. Cervical teratomas in the newborn. J Pediatr Surg. 1983;18:382–6.
Batsakis JG, Littler ER, Oberman HA. Teratomas of the neck. A clinicopathologic appraisal. Arch Otolaryngol. 1964;79:619–24.
Jordan RB, Gauderer MW. Cervical teratomas: an analysis, literature review and proposed classification. J Pediatr Surg. 1988;23:583–91.
Liechty KW, Hedrick HL, Hubbard AM, et al. Severe pulmonary hypoplasia associated with giant cervical teratomas. J Pediatr Surg. 2006;41:230–3.
Elmasalme F, Giacomantonio M, Clarke KD, Othman E, Matbouli S. Congenital cervical teratoma in neonates. Case report and review. Eur J Pediatr Surg. 2000;10:252–7.
Sbragia L, Paek BW, Feldstein VA, et al. Outcome of prenatally diagnosed solid fetal tumors. J Pediatr Surg. 2001;36:1244–7.
De Backer A, Madern GC, van de Ven CP, Tibboel D, Hazebroek FW. Strategy for management of newborns with cervical teratoma. J Perinat Med. 2004;32:500–8.
Langer JC, Tabb T, Thompson P, Paes BA, Caco CC. Management of prenatally diagnosed tracheal obstruction: access to the airway in utero prior to delivery. Fetal Diagn Ther. 1992;7:12–6.
Touran T, Applebaum H, Frost DB, Richardson R, Taber P, Rowland J. Congenital metastatic cervical teratoma: diagnostic and management considerations. J Pediatr Surg. 1989;24:21–3.
Buckley NJ, Burch WM, Leight GS. Malignant teratoma in the thyroid gland of an adult: a case report and a review of the literature. Surgery. 1986;100:932–7.
Mahour GH, Landing BH, Woolley MM. Teratomas in children: clinico-pathologic studies in 133 patients. Z Kinderchir. 1978;23:365–80.
Gatcombe HG, Assikis V, Kooby D, Johnstone PA. Primary retroperitoneal teratomas: a review of the literature. J Surg Oncol. 2004;86:107–13.
Auge B, Satge D, Sauvage P, Lutz P, Chenard MP, Levy JM. Retroperitoneal teratomas in the perinatal period. Review of the literature concerning a neonatal, immature, aggressive teratoma. Ann Pediatr (Paris). 1993;40:613–21.
Fagiana AM, Barnett S, Reddy S. Management of a fetal intrapericardial teratoma: a case report and review of the literature. Congenit Heart Dis. 2010;5:51–5.
Goldberg SP, Boston US, Turpin DA, et al. Surgical Management of intrapericardial teratoma in the fetus. J Pediatr. 2010;156:848–9.
Azizkhan RG. Perinatal tumors. In: Carachi R, Grosfeld J, Azmy A, editors. The surgery of childhood tumors. 2nd ed. Berlin: Springer; 2008. p. 145–67.
Isaacs Jr H. Perinatal (congenital and neonatal) neoplasms: a report of 110 cases. Pediatr Pathol. 1985;3:165–216.
Dehner LP. Neoplasms of the fetus and neonate. In: Naeye RL, Kissane JM, Kaufman N, editors. Perinatal diseases. International academy of pathology monograph number 22. Baltimore: Williams and Wilkins; 1981. p. 286–345.
Beckwith JB, Perrin EV. In situ neuroblastomas: a contribution to the natural history of neural crest tumors. Am J Pathol. 1963;43:1089–104.
Guin GH, Gilbert EF, Jones B. Incidental neuroblastoma in infants. Am J Clin Pathol. 1969;51:126–36.
Woods WG, Lemieux B, Tuchman M. Neuroblastoma represents distinct clinical-biologic entities: a review and perspective from the Quebec Neuroblastoma Screening Project. Pediatrics. 1992;89:114–8.
Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1991;9:581–91.
Brodeur GM, Maris JM, Yamashiro DJ, Hogarty MD, White PS. Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol. 1997;19:93–101.
Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313:1111–6.
Azizkhan RG, Haase GM, Coran AG, et al. Diagnosis, management and outcome of neuroblastoma in neonates: a Children’s Cancer Group study. 36th World Congress of Surgery abstract book; Lisban, Portugal, 1995. p. 134.
Richards ML, Gundersen AE, Williams MS. Cystic neuroblastoma of infancy. J Pediatr Surg. 1995;30:1354–7.
Jennings RW, LaQuaglia MP, Leong K, Hendren WH, Adzick NS. Fetal neuroblastoma: prenatal diagnosis and natural history. J Pediatr Surg. 1993;28:1168–74.
Ho PT, Estroff JA, Kozakewich H, et al. Prenatal detection of neuroblastoma: a ten-year experience from the Dana-Farber Cancer Institute and Children’s Hospital. Pediatrics. 1993;92:358–64.
Saylors 3rd RL, Cohn SL, Morgan ER, Brodeur GM. Prenatal detection of neuroblastoma by fetal ultrasonography. Am J Pediatr Hematol Oncol. 1994;16:356–60.
Acharya S, Jayabose S, Kogan SJ, et al. Prenatally diagnosed neuroblastoma. Cancer. 1997;80:304–10.
Nuchtern JG. Perinatal neuroblastoma. Semin Pediatr Surg. 2006;15:10–6.
Holgersen LO, Subramanian S, Kirpekar M, Mootabar H, Marcus JR. Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg. 1996;31:153–5.
Hosoda Y, Miyano T, Kimura K, et al. Characteristics and management of patients with fetal neuroblastoma. J Pediatr Surg. 1992;27:623–5.
Laug WE, Siegel SE, Shaw KN, Landing B, Baptista J, Gutenstein M. Initial urinary catecholamine metabolite concentrations and prognosis in neuroblastoma. Pediatrics. 1978;62:77–83.
Newton ER, Louis F, Dalton ME, Feingold M. Fetal neuroblastoma and catecholamine-induced maternal hypertension. Obstet Gynecol. 1985;65:49S–52.
Tuchman M, Morris CL, Ramnaraine ML, Bowers LD, Krivit W. Value of random urinary homovanillic acid and vanillylmandelic acid levels in the diagnosis and management of patients with neuroblastoma: comparison with 24-hour urine collections. Pediatrics. 1985;75:324–8.
Tuchman M, Ramnaraine ML, Woods WG, Krivit W. Three years of experience with random urinary homovanillic and vanillylmandelic acid levels in the diagnosis of neuroblastoma. Pediatrics. 1987;79:203–5.
Samuel AM. PET/CT in pediatric oncology. Indian J Cancer. 2010;47:360–70.
Melzer HI, Coppenrath E, Schmid I, Albert MH, von Schweinitz D, Tudball C, Bartenstein P, Pfluger T. I-MIBG scintigraphy/SPECT versus F-FDG PET in paediatric neuroblastoma. Eur J Nucl Med Mol Imaging. 2011;38:1648–58.
Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG TASk force report. J Clin Oncol. 2009;27:298–303.
Cohen SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report. J Clin Oncol. 2009;27:289–97.
D’Angio GJ, Evans AE, Koop CE. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet. 1971;1:1046–9.
Grosfeld JL, Rescorla FJ, West KW, Goldman J. Neuroblastoma in the first year of life: clinical and biologic factors influencing outcome. Semin Pediatr Surg. 1993;2:37–46.
van Noesel MM, Hahlen K, Hakvoort-Cammel FG, Egeler RM. Neuroblastoma 4S: a heterogeneous disease with variable risk factors and treatment strategies. Cancer. 1997;80:834–43.
Evans AE, Chatten J, D’Angio GJ, Gerson JM, Robinson J, Schnaufer L. A review of 17 IV-S neuroblastoma patients at the Children’s Hospital of Philadelphia. Cancer. 1980;45:833–9.
Matthay KK, Perez C, Seeger RC, et al. Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. J Clin Oncol. 1998;16:1256–64.
Strother D, Shuster JJ, McWilliams N, et al. Results of pediatric oncology group protocol 8104 for infants with stages D and DS neuroblastoma. J Pediatr Hematol Oncol. 1995;17:254–9.
Paul SR, Tarbell NJ, Korf B, et al. Stage IV neuroblastoma in infants: long-term survival. Cancer. 1991;67:1493–7.
Schmidt ML, Lukens JN, Seeger RC, et al. Biologic factors determine prognosis in infants with stage IV neuoblastoma: a prospective Children’s Cancer Group study. J Clin Oncol. 2000;18:1260–8.
Grosfeld JL. Neuroblastoma, chap 28. In: Grosfeld JL, O’Neill Jr JA, Coran AG, Fonkalsrud EW, editors. Pediatric surgery, vol. 1. 6th ed. Philadelphia: Mosby Inc; 2006.
Nickerson HJ, Matthay KK, Seeger RC, et al. Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children’s Cancer Group study. J Clin Oncol. 2000;18:477–86.
Dillon PW, Whalen TV, Azizkhan RG, et al. Neonatal soft tissue sarcomas: the influence of pathology on treatment and survival. J Pediatr Surg. 1995;30:1038–41.
Spicer RD. Neonatal sarcoma. Early Hum Dev. 2010;86:633–6.
Orbach D, Rey A, Oberlin O, et al. Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Committee. J Clin Oncol. 2005;23:4363–71.
Lloyd DA. Soft-tissue sarcoma. In: Puri P, editor. Chapter 78: Newborn surgery. 2nd ed. New York: Oxford University Press Inc; 2003.
Barr FG. Molecular genetics and pathogenesis of rhabdomyosarcoma. J Pediatr Hematol Oncol. 1997;19:483–91.
Raney Jr RB, Hays DM, Tefft M, Triche TJ. Rhabdomyosarcoma and the undifferentiated sarcomas. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia: JB Lippincott; 1989. p. 635–58.
Raney RB, Walterhouse DO, Meza JL, et al. Results of the Intergroup Rhabdomyosarcoma Study Group D9602 Protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol. 2011;29:1312–8.
Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001;19:3091–102.
Crist W, Gehan EA, Ragab AH, et al. The third intergroup Rhabdomyosarcoma study. J Clin Oncol. 1995;13:610–30.
Soule EH, Pritchard DJ. Fibrosarcoma in infants and children: a review of 110 cases. Cancer. 1977;40:1711–21.
Orbach D, Rey A, Cechetto G, et al. Infantile fibrosarcoma: management based on the European experience. J Clin Oncol. 2010;28:318–23.
Kogon B, Shehata B, Katzenstein H. Primary congenital infantile fibrosarcoma of the heart; the first confirmed case. Ann Thorac Surg. 2011;91:1276–80.
Blocker S, Koenig J, Ternberg J. Congenital fibrosarcoma. J Pediatr Surg. 1987;22:665–70.
Ninane J, Gosseye S, Panteon E, Claus D, Rombouts JJ, Cornu G. Congenital fibrosarcoma: preoperative chemotherapy and conservative surgery. Cancer. 1986;58:1400–6.
Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998;18:184–7.
Rubin BP, Chen CJ, Morgan TW, et al. Congenital mesoblastic nephroma t (12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol. 1998;153:1451–8.
Coffin CM, Dehner LP. Soft tissue tumors in first year of life: a report of 190 cases. Pediatr Pathol. 1990;10:509–26.
Salloum E, Flamant F, Caillaud JM, et al. Diagnostic and therapeutic problems of soft tissue tumors other than rhabdomyosarcoma in infants under 1 year of age: a clinicopathological study of 34 cases treated at the Institut Gustave-Roussy. Med Pediatr Oncol. 1990;18:37–43.
Hrabovsky EE, Othersen Jr HB, deLorimier A, Kelalis P, Beckwith JB, Takashima J. Wilms’ tumor in the neonate: a report from the National Wilms’ Tumor Study. J Pediatr Surg. 1986;21:385–7.
Ritchey ML, Azizkhan RG, Beckwith JB, Hrabovsky EE, Haase GM. Neonatal Wilms tumor. J Pediatr Surg. 1995;30:856–9.
Jones VS, Cohen RC. Atypical congenital mesoblastic nephroma presenting in the perinatal period. Pediatr Surg Int. 2007;23:205–9.
Knezevich SR, Garnett JM, Pysher TJ, et al. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. 1998;58:5046–8.
Giulian BB. Prenatal ultrasonographic diagnosis of fetal renal tumors. Radiology. 1984;152:69–70.
Yamamoto N, Yoshizako T, Uchida N, et al. Mesoblastic nephroma: a case report of prenatal detection by MR imaging. Magn Reson Med Sci. 2006;5:47–50.
Riccabona M. Imaging of renal tumours in infancy and childhood. Eur Radiol. 2003;13:L116–29.
Lakhoo K, Sowerbutts H. Neonatal tumours. Pediatr Surg Int. 2010;26:1159–68.
Leclair MD, El-Ghoneimi A, Audry G, et al. The outcome of prenatally diagnosed renal tumors. J Urol. 2005;173:186–9.
Gonzalez-Crussi F, Sotelo-Avila C, Kidd JM. Malignant mesenchymal nephroma of infancy: report of a case with pulmonary metastases. Am J Surg Pathol. 1980;4:185–90.
Ahmed HU, Arya M, Levitt G, et al. Part II: treatment of primary malignant non-Wilms’ renal tumours in children. Lancet Oncol. 2007;8:842–8.
Machin GA. Persistent renal blastoma (nephroblastomatosis) as a frequent precursor of Wilms’ tumor: a pathological and clinical review. Part 2. Significance of nephroblastomatosis in the genesis of Wilms’ tumor. Am J Pediatr Hematol Oncol. 1980;2:253–61.
Riccardi VM, Sujansky E, Smith AC, Francke U. Chromosomal imbalance in the Aniridia-Wilms’ tumor association: 11p interstitial deletion. Pediatrics. 1978;61:604–10.
Weksberg R, Squire JA. Molecular biology of Beckwith-Wiedemann syndrome. Med Pediatr Oncol. 1996;27:462–9.
Greenberg F, Stein F, Greisch MV, et al. The Perlman familial nephroblastomatosis syndrome. Am J Med Genet. 1986;24:101–10.
Perlman M. Perlman syndrome: familial renal dysplasia with Wilms’ tumor, fetal gigantism, and multiple congenital anomalies. Am J Med Genet. 1986;25:793–5.
Grundy P, Telzerow P, Moksness J, Breslow NE. Clinicopathologic correlates of loss of heterozygosity in Wilms’ tumor: a preliminary analysis. Med Pediatr Oncol. 1996;27:429–33.
Beckwith JB. Mesenchymal renal neoplasms of infancy. J Pediatr Surg. 1970;5:405–6.
Bianchi DW, Crombleholme TM, D’Alton ME, Malone FD, editors. Fetology. Diagnosis and management of the fetal patient. 2nd ed. New York: McGraw-Hill Co, Inc; 2010. Chap 116.
Glick RD, Hicks MJ, Nuchtern JG, et al. Renal tumors in infants less than 6 months of age. J Pediatr Surg. 2004;39:522–5.
Green DM, Breslow NE, Beckwith JB, Takashima J, Kelalis P, D’Angio GJ. Treatment outcomes in patients less than two years of age with small, stage I, favorable-histology Wilms’ tumors. A report from the National Wilms’ Tumor Study. J Clin Oncol. 1993;11:91–5.
Powis M. Neonatal renal rumors. Early Hum Dev. 2010;86:607–12.
Campbell AN, Chan HS, O’Brien A, Smith CR, Becker LE. Malignant tumors in the neonate. Arch Dis Child. 1987;62:19–23.
von Schweinitz D. Neonatal liver tumours. Semin Neonatol. 2003;8:403–10.
Douri T. Multiple cutaneous hemangiomas accompanied by hepatic hemangiomas. Dermatol Online J. 2005;11:21.
Boon LM, Burrows PE, Paltiel HJ, et al. Hepatic vascular anomalies in infancy: a twenty-seven-year experience. J Pediatr. 1996;129:346–54.
Mulliken JB, Fishman SJ, Burrows PE. Vascular anomalies. Curr Probl Surg. 2000;37:517–84.
Horii KA, Drolet BA, Frieden IJ, et al. Prospective study of the frequency of hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. Pediatr Dermatol. 2011;28:245–53.
Marler JJ, Fishman SJ, Upton J, et al. Prenatal diagnosis of vascular anomalies. J Pediatr Surg. 2002;37:318–26.
Kassarjian A, Zurakowski D, Dubois J, Paltiel HJ, Fishman SJ, Burrows PE. Infantile hepatic hemangiomas: clinical and imaging findings and their correlation with therapy. Am J Roentgenol. 2004;182:785–95.
Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med. 2000;343:185–9.
Kassarjian A, Dubois J, Burrows PE. Angiographic classification of hepatic hemangiomas in infants. Radiology. 2002;222:693–8.
Azizkhan RG, Cohen AP, Dasgupta R, Adams D. Vascular anomalies, chap 75. In: Ziegler M, Azizkhan R, Weber T, von Allmen D, editors. Operative pediatric surgery. 2nd ed. McGraw-Hill; China: 2014, in press.
Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr. 1998;132:527–30.
Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope. 2004;114:1231–6.
Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes of 115 patients with hepatic hemangioma. J Am Coll Surg. 2003;197:392–402.
Tiao GM, Alonso M, Bezerra J, et al. Liver transplantation in children younger than 1 year—the Cincinnati experience. J Pediatr Surg. 2005;40:268–73.
Makin E, Davenport M. Fetal and neonatal liver tumours. Early Hum Dev. 2010;86:637–42.
Stringer MD, Alizai NK. Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg. 2005;40:1681–90.
Ramanujam TM, Ramesh JC, Goh DW, et al. Malignant transformation of mesenchymal hamartoma of the liver: case report and review of the literature. J Pediatr Surg. 1999;34:1684–6.
Isaacs Jr H. Liver tumors. In: Isaacs Jr H, editor. Tumors of the fetus and newborn. Philadelphia: WB Saunders; 1991. p. 275–97.
Hartley AL, Birch JM, Kelsey AM, et al. Epidemiological and familial aspects of hepatoblastoma. Med Pediatr Oncol. 1990;18:103–9.
Berry CL, Keeling J, Hilton C. Coincidence of congenital malformation and embryonic tumours of childhood. Arch Dis Child. 1970;45:229–31.
Fraumeni Jr JF, Miller RW. Adrenocortical neoplasms with hemihypertrophy, brain tumors, and other disorders. J Pediatr. 1967;70:129–38.
Sotelo-Avila C, Gooch 3rd WM. Neoplasms associated with the Beckwith-Wiedemann syndrome. Perspect Pediatr Pathol. 1976;3:255–72.
Bodmer WF, Bailey CJ, Bodmer J, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987;328:614–6.
Ikeda H, Hachitanda Y, Tanimura M, Maruyama K, Koizumi T, Tsuchida Y. Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review. Cancer. 1998;82:1789–96.
Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a chance? J Pediatr. 1997;130:557–60.
Tanimura M, Matsui I, Abe J, et al. Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res. 1998;58:3032–5.
Cremin BJ, Nuss D. Calcified hepatoblastoma in a newborn. J Pediatr Surg. 1974;9:913–5.
Sinta L, Freud N, Dulitzki F. Hemoperitoneum as the presenting sign of hepatoblastoma in a newborn. Pediatr Surg Int. 1992;7:131–3.
Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: a report from the Children’s Cancer Group and the Pediatric Oncology Group. J Clin Oncol. 2000;18:2665–75.
Pritchard J, Brown J, Shafford E, et al. Cisplatin, doxorubicin and delayed surgery for childhood hepatoblastoma: a successful approach—results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol. 2000;18:3819–28.
Fuchs J, Rydzynski J, Hecker H, et al. The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma: a report from the German Cooperative Liver Tumour Studies HB 89 and HB 94. Eur J Pediatr Surg. 2002;12:255–61.
Fuchs J, Rydzynski J, von Schweinitz D, et al. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report form the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer. 2002;95:172–82.
Gonzalez-Crussi F, Upton MP, Maurer HS. Hepatoblastoma: attempt at characterization of histologic subtypes. Am J Surg Pathol. 1982;6:599–612.
Salim A, Wiknjosastro GH, Danukusumo D, Barnas B, Zalud I. Fetal retinoblastoma. J Ultrasound Med. 1998;17:717–20.
Donaldson SS, Egbert PR, Lee WH. Retinoblastoma. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia: Lippincott; 1993. p. 683–96.
Shields JA, Shields CL. Update on retinoblastoma. Semin Ophthalmol. 1990;5:183–92.
Shields JA, Shields CL. Current management of retinoblastoma. Mayo Clin Proc. 1994;69:50–6.
Dudgeon J. Retinoblastoma: trends in conservative management. Br J Ophthalmol. 1995;79:104.
Lamkin TD, Gamis AS. Neonatal oncology, chap 16. In: de Alarcon PA, Werner E, editors. Neonatal hematology. New York: Cambridge University Press; 2005.
Doz F, Neuenschwander S, Plantaz D, et al. Etoposide and carboplatin in extraocular retinoblastoma: a study by the Société Française d’Oncologie Pédiatrique. J Clin Oncol. 1995;13:902–9.
Pratt CB, Fontanesi J, Chenaille P, et al. Chemotherapy for extraocular retinoblastoma. Pediatr Hematol Oncol. 1994;11:301–9.
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Azizkhan, R.G., von Allmen, D. (2016). Perinatal Tumors. In: Carachi, R., Grosfeld, J. (eds) The Surgery of Childhood Tumors. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-48590-3_11
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