A male trichorionic triamniotic triplet is born at 34 weeks' gestation via cesarean section. His prenatal course was significant because a 19-week fetal anatomic sonogram found a left suprarenal mass with cystic areas. At 30 weeks’ gestation, the mass measured 1.7 x 1.5 x 1.9 cm on fetal sonogram. Fetal magnetic resonance imaging (MRI) was obtained (Figure 1). The infant appears well at delivery and has Apgar scores of 8 and 9 at 1 and 5 minutes of age, respectively.
Figure 1: Fetal MRI at 30 weeks’ gestation showing coronal (A) and sagittal views (B) (yellow arrows). Image from: Ryan K, Haag M, Kim A, Sohaey R, Fiest C, Dukovny S. Prenatal diagnosis of neuroblastoma. Neoreviews. 2025:26(1):e66-72.1
In addition to obtaining postnatal renal and bladder ultrasonography, which of the following diagnostic evaluations is the most appropriate next step?
- Bone marrow biopsy
- Paired urine and serum osmolalities
- Plasma metanephrine levels
- Urinary hyaluronic acid level
- Urinary homovanillic acid and vanillylmandelic acid levels
Answer: E. Urinary homovanillic acid and vanillylmandelic acid levels
Explanation:
The presence of a suprarenal mass in this preterm infant should raise suspicion for congenital neuroblastoma because of the unilateral presentation, the appearance in early gestation, and the cystic appearance on fetal MRI.2 Congenital neuroblastomas occur between 1 in 10,000 and 1 in 100,000 live births and are the most common extracranial solid tumor of childhood.3 Neuroblastomas account for 50% of fetal adrenal masses and 20% of all neonatal malignancies.4 They arise early in gestation, with some detectable as early as 19 weeks on fetal sonogram as described in this case.5 Most are detected by fetal ultrasonography between 33 and 36 weeks of gestation.6 These masses are best characterized by fetal MRI, which can show either a solid mass or one with cystic components as shown in Figure 1.7 On fetal MRI, the mass is hypointense on T1-weighted sequences and hyperintense on T2-weighted images as noted in this case.8
Congenital neuroblastomas arise from primordial neural crest cells (Figure 2). Because of their embryonic origin, they can develop anywhere in the sympathetic chain. Sixty-five percent occur in the abdomen, and most are localized to the adrenal glands.2 Other locations include the neck and pelvis, though these locations are less common than the abdomen. Initial laboratory testing for an infant with a suspected neuroblastoma should include a complete blood count, electrolyte panel, liver function tests, and renal function tests. Most neuroblastomas secrete catecholamines, which are metabolized to homovanillic acid (HVA) and vanillylmandelic acid (VMA). These metabolites (Option E) can be detected in the urine,8 making them a good choice as an initial screening test. A urinary VMA-to-HVA ratio of less than 1 is a poor prognostic marker with lower survival; because HVA is an early metabolite in the catecholamine pathway, a lower ratio is suggestive of a biochemically primitive neuroblastoma, which is more aggressive and more likely to have metastasized at presentation.9
Figure 2: Illustration of the normal fate of neural crest cells, which differentiate into chromaffin cells of the adrenal gland and neurons of the peripheral nervous system. If there is abnormal cell signaling of MYCN and ALK or abnormal transcription factors, tumor formation may result. Image from: Minakova E, Lang J. Congenital neuroblastoma. Neoreviews. 2020;21(11):e716-727.2
Ultrasonography is the best initial postnatal imaging modality for the initial assessment of a prenatally diagnosed suprarenal mass. This can be followed by MRI to further delineate the extent of the mass and detect the presence of bony metastases. If there are bony metastases, a bone marrow biopsy (Option A) can be completed instead of a biopsy of the mass to obtain a tissue diagnosis, but this procedure is invasive and should be completed if noninvasive urine HVA and VMA levels are abnormal. A meta-iodobenzylguanidine (MIBG) scan (Figure 3) is recommended for further evaluation of metastases if a detected mass is >1 cm in size or if urine catecholamines are elevated3. MIBG scans are highly sensitive for infantile neuroblastomas. However, there is a high risk of false-negative results if used in isolation for diagnosis, because only 70% of congenital neuroblastomas will be visualized using this imaging modality. 3. They are therefore not the recommended first-line imaging modality for diagnosis of congenital neuroblastoma.
Figure 3: Postnatal metaiodobenzylguanidine (MIBG) scan showing MIBG uptake in the left adrenal gland without metastatic disease. Image from: Ryan K, Haag M, Kim A, Sohaey R, Fiest C, Dukovny S. Prenatal diagnosis of neuroblastoma. Neoreviews. 2025;26(1);e66-72.1
Some neonates with congenital neuroblastoma may be asymptomatic. If the tumor is in the adrenal gland, there may be hypertension and tachycardia due to both compression of the renal artery and catecholamine release. Neuroblastomas located in the neck may cause stridor, respiratory distress, or congenital Horner syndrome.10
Wilms tumor is a key differential diagnosis for the patient in this case. These arise directly from the kidney rather than from the adrenal gland (Figure 4).11 Urinary hyaluronic acid levels (Option D) are elevated in patients with Wilms tumor but not in those with neuroblastoma.12 Other clinical features may be present in patients with Wilms tumor if it occurs as part of a syndrome, such as Beckwith-Wiedemann syndrome with overgrowth and WAGR syndrome with Wilms tumor, aniridia, genitourinary tract abnormalities, and a range of developmental delays. Wilms tumor metastasizes to the lung, and therefore, a CT scan of the chest should be performed if one is suspected as part of the staging process.13
Figure 4: Coronal computed tomography (CT) image of a child with a left-sided Wilms tumor (asterisk). Wilms tumors present as large abdominal masses that arise directly from the kidney and, as in this image, can displace the intraabdominal organs. Image adapted from: Allen-Rhoades W, Whittle SB, Rainusso N. Pediatric solid tumors of infancy: an overview. Pediatr Rev. 2018;39(2):57-67.11
Several other important differential diagnoses should be considered for fetal abdominal masses. These must be considered when determining the investigations to include during postnatal evaluation. Adrenal hemorrhage is the most common cause of an adrenal mass in a newborn and must be differentiated from neuroblastoma; it can be noted on a sonogram as early as the second trimester.6 Extra-lobar subdiaphragmatic pulmonary sequestrations may also have a similar appearance, but these masses will have a systemic arterial branch that connects to the aorta that can be visualized with color flow Doppler during ultrasonography.
Plasma metanephrine levels (Option C) are elevated in patients with pheochromocytoma. However, this tumor is not seen in neonates, and this test has not been validated for the diagnosis of neonatal neuroblastoma.
Paired urine and serum osmolalities (Option B) can help diagnose the etiology of hyponatremia, which may be present with adrenal hemorrhage. However, obtaining these osmolalities would not provide a diagnosis for the suprarenal mass in this case.
Did you know: Congenital neuroblastomas most commonly occur on the right side of the body? A right-sided isoechoic or hypoechoic solid mass that is present after 29 weeks of gestation has a >95% chance of being a neuroblastoma.14
Bonus Question: Some neuroblastomas can present with chronic diarrhea and electrolyte abnormalities in a neonate. What is the mechanism of this unusual paraneoplastic presentation?
To find the answer, please read the following article: Minavoka E, Lang J. Congenital neuroblastoma. Neoreviews. 2020;21(11):e716-727
NeoQuest January 2025 Authors:
Andrew Beverstock, MBChB, Baylor College of Medicine
Allison N. J. Lyle, MD, MA, University of Louisville School of Medicine
References
- Ryan K, Haag M, Kim A, Sohaey R, Fiest C, Dukovny S. Prenatal diagnosis of neuroblastoma. Neoreviews. 2025;26(1);e66-72
- Minakova E, Jordan L. Congenital neuroblastoma. Neoreviews. 2020;21(11):e716-727
- Arendonk KJV, Chung DH. Neuroblastoma: tumor biology and its implications for staging and treatment. Children (Basel). 2019;6(1):12
- Fischer JPH, Tweddle DA. Neonatal neuroblastoma. Semin Fetal Neonatal Med. 2012;17(4):207-215
- Werner H, Dalton P, Davaus T, Araujo Junior E. Fetal neuroblastoma: ultrasonography and magnetic resonance imaging findings in the prenatal and postnatal IV-S stage. Obstet Gynecol Sci. 2016;59(5):407-410
- Nuchtern JG. Perinatal neuroblastoma. Semin Pediatr Surg. 2006;15(1):10–16
- Davidoff AM. Neonatal neuroblastoma. Clin Perinatoll. 2021;48(1):101-115
- Hazard FK, Shimada H. The role of the clinical laboratory in the diagnosis of neuroblastoma. J Appl Lab Med. 2020;5(2):254-256
- Verly IRN, van Kulienburg ABP, Abeling NGGM et al. Catecholamines profiles at diagnosis: increased diagnostic sensitivity and correlation with biological and clinical features in neuroblastoma patients. European Journal of Cancer. 2017;72:235-243.
- Singh H, Mohan C, Mohindroo NK, Sharma DR. Cervical neuroblastoma. Indian J Otolaryngol Head Neck Surg. 2007;59(3):288–290
- Allen-Rhoades W, Whittle SB, Rainusso N. Pediatric solid tumors of infancy: an overview. Pediatr Rev. 2018;39(2):57-67
- Donelan W, Brisbane W, O’Malley P et al. Hyaluronan metabolism in urologic cancers. Advanced Biology. 2023;7(12):e2300168.
- Fernandez K. Solid tumors in the neonatal period. Neoreviews. 2014 Feb;15(2):e56-68
- Rubenstein SC, Benacerraf BR, Retik AB, Mandell J. Fetal suprarenal masses: sonographic appearance and differential diagnosis. Ultrasound Obstet Gynecol. 1995:5(3);164-167