Prenatal Diagnosis of Neuroblastoma

A 39-year-old gravida 3, para 1 pregnant person presented to our Fetal Care Program at 30 weeks’ gestation with a trichorionic triamniotic triplet gestation with a suspected suprarenal mass in triplet B. Their past medical history was notable for suboptimally controlled asthma, anemia, and a history of pre-eclampsia in her prior pregnancy. Her past surgical history was unremarkable. A routine fetal anatomic survey ultrasound at 19 weeks’ gestation revealed a suspected left urinary tract dilation of 5 mm in triplet B with normal male genitalia, but no masses were noted. A fetal ultrasound at 28 weeks’ gestation identified a left suprarenal echogenic mass with small cystic areas in triplet B. The pregnancy was also significant for triplet A with mild to moderate cardiac left ventricular dilation with reduced function noted at 27 weeks’ gestation as well as an enlarged nuchal translucency of triplet B at the 99th percentile at 12 weeks’ gestation. She had multiple admissions to the hospital for threatened preterm labor. The patient’s family history was notable for a son with dilated cardiomyopathy of unknown etiology requiring medical management. The parents had known consanguinity and were distant cousins.The initial ultrasound at our center at 30 weeks’ gestation confirmed the presence of a 1.7 × 1.5 × 1.9–cm left suprarenal mass, consistent with a neuroblastoma (Figure 1). There were no additional abnormal findings on the anatomy of triplet B, although limited by the gestational age. At 30 weeks’ gestation, a fetal magnetic resonance imaging (MRI) was performed to further characterize the suprarenal mass, which demonstrated a left suprarenal mass measuring 2.5 × 1.2 × 1.5 cm, felt most likely to be a neuroblastoma based on signal intensity on different MR sequences (Figure 2). Given the triplet gestational and fetal anomalies, the patient underwent serial ultrasound imaging in which the mass remained stable and was last imaged at 32 weeks and 6 days’ gestation, measuring 3.2 × 2.4 × 3.6 cm (Figure 3).The incidence of fetal neuroblastoma is 1 in 10 000 to 1 in 100 000 live births.1 Neuroblastomas are the most common extracranial solid tumor of childhood and account for 50% of fetal adrenal masses.2 They are more common in white infants as compared with Black, Asian, Hispanic, or American Indian infants and are slightly more common in males than females.2,3 The term neuroblastoma encompasses a group of neuroendocrine tumors that originate from neural crest progenitor cells and include a spectrum of neuroblastic tumors including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas.2 Given their origin, they can occur anywhere along the sympathetic nervous system; however, the majority arise from the adrenal glands.4 The adrenal glands embryologically develop from both the mesoderm and the ectoderm; the mesoderm forms the cortex and the ectoderm forms the medulla.5 The neural crest is of ectodermal origin, and these cells migrate from their initial position to aggregate in the vicinity of the primitive blood vessels. Aberrant signaling throughout this process, along with likely epigenetic influence, can result in the development of a neuroblastoma.6,7The differential diagnosis for a fetal mass within the abdomen is broad, and the approach to narrowing the differential includes ultrasonography and evaluation of specific characteristics. At our institution, pregnant individuals with suspected or confirmed fetal anomalies are referred to our Fetal Care Program for further evaluation, multidisciplinary care, and counseling. Through this clinic, patients and families interact with the care teams that will facilitate diagnosis and management in the pregnancy, at time of delivery, and in the postnatal period including maternal-fetal medicine, radiology, genetic counseling, neonatology, social work, and any additional relevant pediatric subspecialists.For those with ultrasound findings suspicious for fetal neuroblastoma, we arrange consultation with neonatology and pediatric hematology/oncology to prepare patients for the infant evaluation and prognosis. Additionally, the multidisciplinary team recommends a plan for additional antenatal care including imaging including MRI, mode and timing of delivery, and anticipated care needs at time of delivery and in the postnatal period, which is recorded in the electronic medical record for seamless communication among care teams at delivery.Our patient with trichorionic triamniotic triplet gestation met with the neonatology team to discuss both the management of prematurity for all of the triplets and postnatal evaluation of suspected adrenal neuroblastoma for triplet B. A consultation with pediatric hematology-oncology was offered; however, the patient was unable to complete this prenatally. Therefore, a postnatal consultation was planned. Although fetal neuroblastomas are usually sporadic, some families have a predisposition to hereditary neuroblastomas, and there are some biologic and molecular markers for neuroblastoma. As a result, the patient was offered genetic counseling but was unable to attend the consult and declined prenatal genetic screening. Given the triplet gestation and suspected fetal adrenal neuroblastoma, we recommended delivery at our tertiary care center with the availability of neonatologists and pediatric hematologists.On follow-up ultrasound at 33 weeks’ gestation, findings were similar, with the fetal left suprarenal mass measuring 3.2 × 2.4 × 3.6 cm. Antenatal testing remained reassuring. The pregnant patient developed gestational hypertension and was admitted shortly after her 33-week ultrasound for delivery planning and blood pressure monitoring. At 34 weeks 1 day’s gestation, she underwent an uncomplicated, planned cesarean section, which was attended by the neonatology team secondary to prematurity.Triplet B was a well-appearing male neonate with birthweight 1990 g, less than the first percentile, and Apgar scores of 8 and 9 at 1 and 5 minutes of age, respectively. After 10 minutes of mask continuous positive airway pressure for mild respiratory distress, he transitioned to room air and was admitted to the Neonatal Intensive Care Unit, as were the other 2 neonates, given their gestational age and enteral feeding support needs. After delivery, the maternal patient was transferred to the postpartum unit, where she recovered well without complications and was discharged on postoperative day 4.Pediatric Hematology/Oncology was consulted soon after the delivery for triplet B. A renal bladder ultrasound on day of birth redemonstrated a 2.5 × 2.5 × 2.4–cm mass abutting the superior right kidney with minimal internal vascularity, concerning for an adrenal neuroblastoma. They recommended sending urinary homovanillic acid (HVA) and vanillylmandelic acid (VMA) levels. These resulted as VMA 29 mg/gCr (normal 0–27 mg/gCr) and HVA 49 mg/gCr (normal 0–42 mg/gCr). Pediatric Hematology/Oncology recommended observation with repeat imaging at 6 weeks of age and consideration of an iodine-131-meta-iodobenzylguanidine (MIBG) scan. The placental pathology resulted negative for metastases. His course in the neonatal intensive care unit was otherwise uneventful. He progressed well with enteral feedings, remained stable in room air, required a short course of phototherapy, and was discharged home at age 22 days.He was seen by Pediatric Hematology/Oncology at age 2 months, at which time repeat ultrasound imaging demonstrated progression of his left suprarenal mass to 5.8 × 4 × 5.6 cm, from 2.5 × 2.5 × 2.4 cm, with new mass effect from the lesion causing slight inferior displacement of the left kidney. Additionally, there was a hypoechoic mass noted on the right hepatic lobe measuring 5.0 × 3.0 × 5.0 mm, concerning for metastasis. Given this, a computed tomography scan of the chest, abdomen, and pelvis as well as an MIBG scan and repeat HVA and VMA urinary levels were recommended, and he was readmitted to the hospital to complete the workup. The computed tomography scan redemonstrated the left adrenal mass measuring 5.7 × 4.5 × 4.9 cm, in addition to a specific liver lesion (Figure 4). The urinary VMA and HVA had uptrended to 101 mg/gCr and 122 mg/gCr, respectively. The MIBG scan demonstrated uptake in the left adrenal mass but no other sites of disease (Figure 5). Pediatric surgery was consulted and recommended left adrenalectomy, liver biopsy, and lymph node sampling, which was completed at age 3 months. The pathology of the left adrenal mass demonstrated poorly differentiated neuroblastoma with clear margins and metastatic neuroblastoma in a left renal hilar lymph node and confirmed that the hepatic lesion was consistent with neuroblastoma. Overall, given the poor differentiation, age younger than 18 months, no N-MYC amplification, and favorable genomics (whole chromosome gains in absence of segmental chromosomal aberrations), his case was determined to be overall favorable, and outpatient management with laboratory and imaging surveillance were recommended.Unfortunately, at age 5 months, he developed an increased number and size of hepatic metastatic lesions and had increasing urinary HVA and VMA levels. Ultimately, he underwent chemotherapy and completed 2 cycles of carboplatin and etoposide. After chemotherapy, imaging demonstrated interval improvement of his liver lesions, and urinary VMA and HVA levels decreased. A repeat MIBG scan after chemotherapy demonstrated no uptake at the surgical bed from the left adrenalectomy and no new areas of uptake other than the already known liver lesions. The decision was made to discontinue chemotherapy and monitor. At age 1 year, he had no ultrasonographic evidence of disease, and as of age 3 years, he has had no evidence of recurrence.Prenatally diagnosed neuroblastoma most commonly involves the adrenal gland. Other less common locations include the posterior mediastinum or the sympathetic neural chain.1 On prenatal ultrasonography, adrenal neuroblastomas appear as a well-encapsulated cystic or solid mass that can be differentiated from the adjacent kidney and other structures.3 After identification of a potential adrenal neuroblastoma, it is important to assess the contralateral adrenal gland to evaluate for prominent adrenal glands vs a discreet mass. More than half of adrenal neuroblastomas are located within the right adrenal gland.8 Color fetal Doppler assessment can be used for further evaluation; however, there is no pattern of vascularization that is pathognomonic.5 In fact, peripheral flow, no flow, and internal vascularization have all been reported in the literature.2,3,5 However, evidence of a single feeding artery is more common in a subdiaphragmatic bronchopulmonary sequestration (BPS).9 For this reason, BPS is considered in the differential for adrenal neuroblastoma alongside adrenal hemorrhage, duplicated renal collecting system, and other less common causes.10 Additionally, a BPS is more common on the left and tends to present at an earlier gestational age, such as in the second trimester. Often, the adrenal gland can be visualized separately from a BPS. Fetal MRI can be used to further differentiate neuroblastoma from the other possibilities.11 Specifically, an adrenal hemorrhage will have no color flow within the mass on ultrasound, but on MRI, blood products can be noted to be bright on T1-weighted images and dark on T2-weighted images. Finally, it is important to differentiate the surrounding organs including the bowel and kidneys. A duplicated collecting system including a hydronephrotic upper pole can be mistaken for a suprarenal mass; thus, it is important to differentiate the adrenal gland separately and look for a ureterocele in the bladder.Approximately 75% of congenital neuroblastomas are located in the adrenal gland; however, they can arise anywhere along the sympathetic nervous system, and neuroblastomas in the pelvis (<5%), retroperitoneum, posterior mediastinum (approximately 20%), thoracic cavity, and neck (<5%) have been reported in the literature.8 For neuroblastomas located in the neck or thoracic cavity, prompt neonatal assessment is necessary to ensure airway patency and evaluation for Horner syndrome. Although rare, if congenital intraspinal neuroblastomas occur, they necessitate early evaluation for spinal cord compression, which can present as immediate neurologic deficits such as permanent paralysis or loss of bowel or bladder function.12 These rarer forms of congenital neuroblastomas may similarly benefit from additional evaluation with a fetal MRI to delineate the extent of involvement and help narrow the differential diagnoses for masses in those anatomic locations.13Additionally, congenital neuroblastomas typically present as an isolated mass; however, congenital metastatic neuroblastoma has been reported. The most common site of metastasis is the liver, which can present as either diffusely infiltrating or discrete masses. Neuroblastomas are the most common fetal malignancy to involve the placenta.14 Although most fetal neuroblastomas are incidental findings on ultrasonography, metastatic involvement of the placenta is associated with symptoms of catecholamine excess in the pregnant person, fetal hydrops, and pre-eclampsia.12 Similarly, very large masses may also predispose to fetal hydrops. The proposed pathophysiology for hydrops include direct compression of the fetal vasculature or precipitation of high-output heart failure in the setting of a highly vascular tumor bed.15Congenital neuroblastoma is considered sporadic without known hereditary genetic causes. There are reported genetic, molecular, and serum biomarkers reported in infants and children with neuroblastoma.16 Specifically, familial neuroblastoma has been reported in families with mutations in the anaplastic lymphoma kinase gene and paired-like homeobox 2b gene.17 These account for 1%–2% of pediatric neuroblastoma; additionally, these genes have been implicated in sporadic, nonfamilial neuroblastoma. Further, Li-Fraumeni syndrome, Hirschsprung disease, and neurofibromatosis type 1 have all been associated with neuroblastoma, but there are no reports linking these disorders to congenital neuroblastoma.2When a neuroblastoma is diagnosed prenatally, serial ultrasounds are performed throughout the pregnancy to assess for evolution of the neuroblastoma (including size) as well as the development of fetal hydrops. Delivery of a fetus with suspected neuroblastoma is recommended to occur within a tertiary care center to allow for immediate assessment and care. As long as there are no additional contraindications, vaginal delivery is appropriate for these cases and an outright cesarean delivery is not recommended. However, cesarean delivery can be considered to prevent rupture or soft tissue dystocia for very large cystic adrenal masses.Congenital neuroblastomas, defined as those diagnosed by 1 month postnatal age, have a good prognosis with a 5-year survival rate of 90%.16 This is in contrast to pediatric neuroblastomas, which tend to have a less favorable prognosis.17 The International Neuroblastoma Staging System is used for the staging of neuroblastoma in neonates and children. Additionally, the International Neuroblastoma Risk Group Stating system was introduced in 2009 as a consensus approach to pretreatment risk stratification. When further prognosticating, cystic neuroblastomas in the perinatal period have higher rates of detection on ultrasonography, decreased incidence of metastasis, lower tumor marker levels, and favorable histologic features and biological markers.8,18Initial evaluation in the neonatal period, if congenital neuroblastoma is suspected, includes a physical examination, laboratory evaluation as described below, and imaging starting with ultrasound in the case of abdominal or retroperitoneal mass. If the site of the neuroblastoma is the neck or the thoracic cavity, or if it arises from the paravertebral sympathetic ganglion, it is important to evaluate for the acute symptoms mentioned above. Evaluations should include assessment for metastases. Congenital neuroblastomas are most likely to be stage I or II, but may be 4S (special) stage metastatic disease,16 which includes dissemination to the liver, skin, and/or bone marrow, and can present as a critically ill neonate with abdominal distension secondary to the liver metastasis who may require intubation for respiratory compromise. Skin findings can include subcutaneous nodules.10 Notably, 4S neuroblastoma may still spontaneously regress.16When compared with neuroblastomas in older children, the approach to congenital neuroblastoma treatment tends to be less invasive given the potential for spontaneous regression. Factors associated with spontaneous regression include lack of MYCN amplifications, no loss of chromosome 1p, and a near triploid number of chromosomes.19Postnatally, laboratory evaluation should include blood samples for complete blood counts, biochemistries (including both liver and renal function tests), lactate dehydrogenase, neuro-specific enolase, ferritin, urine catecholamine metabolites (HVA and VMA), and free serum cortisol. VMA and HVA are elevated in more than 90% of neuroblastomas and therefore can be helpful in confirming the imaging-based diagnoses.18 The serum markers can be used in addition to the staging systems for prognostication and treatment response. Specifically, lactate dehydrogenase levels greater than 1500 U/L, neuron-specific enolase greater than 100 ng/mL, ferritin greater than 142 ng/mL, and urine VMA to HVA ratio less than 1 have been associated with more adverse outcomes.13 Additionally, if a family history of neuroblastoma has been reported, genetic screening for the ALK and PHOX2B mutations could be completed in consultation with a genetic counselor.In addition to postnatal laboratory evaluation, an imaging evaluation should be performed, including an initial ultrasound and an MRI within the first 9 weeks of age to exclude regional or metastatic involvement. For asymptomatic neonates with a small mass and a low-stage adrenal neuroblastoma, a biopsy is typically avoided in favor of careful observation, as these are more likely to spontaneously regress and biopsy carries risks.19 In one study, 83 infants aged younger than 6 months with stage I small adrenal masses (defined as 3.1 cm or less) were observed instead of biopsied. Surgical intervention was reserved for those with growth, disease progression, or increasing urine catecholamines. Although only 19% received surgery, all patients were alive at 2 years of follow-up.20 Therefore, most favor deferring surgical intervention in favor of observation with serial urine catecholamines for low-risk patients10 with stage I small, solid adrenal tumors less than 3.1 cm, or cystic tumors less than 5 cm.19 Patients in the intermediate risk category often receive chemotherapy followed by surgical resection. The chemotherapeutic agents utilized include carboplatin, cyclophosphamide, doxorubicin, and etoposide with a variable number of cycles.19 Finally, high-risk disease, which encompasses 8%–10% of infants, is associated with a poor prognosis, with 2- to 5-year survival rates of approximately 30%.10 Treatment within this group includes 4 phases: (1) Induction: chemotherapy and surgical resection; (2) Consolidation: myeloablative therapy and stem cell transplant; (3) Postconsolidation: radiation therapy; and (4) Maintenance: eradication of minimal disease.19Congenital neuroblastomas detected prenatally typically present as an isolated mass, and a majority involve the adrenal gland.Congenital neuroblastomas are typically sporadic and not associated with underlying genetic conditions.Neonatal evaluation includes imaging, laboratory studies such as catecholamine metabolites, and consultation with pediatric hematology-oncology specialists.Not all adrenal neuroblastomas require biopsy or intervention; small, low-stage adrenal neuroblastomas in asymptomatic neonates are likely to spontaneously regress.American Board of Pediatrics Neonatal-Perinatal Content SpecificationsKnow the importance and limitations of ultrasonographic findings of common fetal anomalies including congenital heart disease.Know the clinical, laboratory, and imaging features and management of neuroblastoma in the newborn.