Congenital Neuroblastoma

Neuroblastoma is a cancer which develops from immature nerve cells (neuroblasts) in the sympathetic nervous system and is found in several areas of the body [1]. The term neuro refers to nerves, while blastoma refers to a cancer that starts in immature or developing cells [1].

Neuroblastoma most commonly arise in and around the adrenal gland at the superior aspect of the kidney [1,2], but can arise in any area of the body where groups of nerve cells exist including the abdomen, chest, neck and near the spine [2]. 

74.90 Malignant neoplasm of adrenal gland

Neuroblastoma accounts for 20% of all foetal malignancies and is the most frequent malignant tumour observed in the neonate [2]. The overall incidence is 8/1000 live births. Perinatal neuroblastoma represents one-fifth of all cases [1—3]. Sixteen percent of infant neuroblastomas are diagnosed in the first month following birth, and 40% present during the first 3 months of life [2]. Neuroblastoma is more common in males [2]. 

Neuroblastoma is an embryonal tumour of the sympathetic nervous system [1,4]. 

During embryogenesis, neural crest cells, which originate from the embryonic ectoderm, undergo an epithelial to mesenchymal transition.  This transition permits cells to delaminate, migrate and differentiate into cell types that contribute to different anatomical structures [1,4]. This process is regulated by complex integration of external signalling, activation of transcriptional programs and epigenetic events [2,4]. The dysregulation of the neural crest development alters cell specification and differentiation and causes hyper neoplastic lesions that results in neuroblastoma initiation and progression [4]. Neuroblastoma derives only from the stem cells of the sympathoadrenal lineage, therefore, the events which cause neuroblastoma occurs after these cells have begun differentiating into sympathetic neurons [4]. 

The exact etiology of neuroblastoma is unknown [1—4]. 
The in-utero onset of this condition suggests that pre-conceptional or gestational environmental events may play a role i.e. exposure to drugs, hormones, toxins and viruses [2,5]. In-utero drug exposure to phenytoin and opiates have been shown to confer a higher risk for neuroblastoma development with some studies quoting odds ratios of 3.4, however these associations have not been consistently demonstrated [5]. Similarly, women with gestational diabetes have higher rates of foetal neuroblastoma compared with controls [2].  
Maternal folic acid consumption has been shown to decrease the risk of neuroblastoma by 60%. [1—3]. 
There is emerging data to suggest a genetic etiology for neuroblastoma as the condition primarily arises from aberrant neural crest development and differentiation [1]. Neuroblastoma has been found in conjunction with other neural crest lesions, including Hirschprung’s disease, phaeochromocytoma and neurofibromatosis type I; It is possible that the genes identified in these conditions may play a part in neuroblastoma tumorigenesis [2,5,6]. A higher incidence of neuroblastoma has been seen in neonates with Turner syndrome. 
Genetic studies have shown that single nucleotide polymorphisms at the LMI domain (LMO1) are observed in approximately 12% of patients with neuroblastoma [6]. Some studies have also shown chromosomal deletions localized to chromosomes 1p, 11q and 14q are found in approximately 50% of neuroblastomas [7]; while other data focusing on the role of oncogenic drivers have found that ALK mutations or overexpression of the McyN gene is associated with neuroblastoma development [7-9]. 

Foetal neuroblastoma is usually a third trimester diagnosis with an average gestational age at diagnosis of 33 weeks, although there are case reports of diagnosis as early as 23 weeks [1]. The majority of tumours are located on the right side [1]. Approximately 90% of foetal neuroblastoma are adrenal in location and the remainder either thoracic or cervical. 
There are three basic tumour morphologies noted on ultrasound. Half of the tumours are solid echogenic masses, with typical diameters between 2 and 4 cm [1,9]. The remaining cases are either purely cystic hypoechoic masses, or complex structures containing both cystic fluid and echogenic solid material [9]. Usually no identifiable adrenal gland is seen on the side containing the mass. Colour Doppler imaging reveals that the solid components often have some Doppler flow, and the septa in cystic neuroblastomas may show Doppler flow. Calcifications are sometimes present but are not as common in foetal neuroblastoma as in childhood cases. Rarely there may be placental metastases resulting in a bulky and hydropic placenta. Hydrops and infiltrating hepatic lesions are indicative of metastases.

Neuroblastomas which are complex are typically larger in size, measuring between 3 and 10 cm in their widest dimension [9]. It is common for masses which are primarily solid to increase in size during pregnancy, whereas the cystic and complex masses may grow or regress [9].

The differential diagnoses for neuroblastoma include [1-3, 9-11]:     
Adrenal haemorrhage: 
Adrenal Haemorrhage is the most common cause of an adrenal mass. While most cases of adrenal haemorrhage occurs at birth or in early neonatal period, there are some case reports of cases diagnosed in second or third trimester. The ultrasound appearance of an adrenal haemorrhage varies depending on the age of the haemorrhage. It can be either solid, cystic or contain mixed echogenicity. The size of these lesions usually shrinks during foetal life.
The texture of haemorrhage can gradually change over time, becoming more cystic. On colour Doppler imaging, no feeding vessel from a systemic artery or internal vascularity is noted. Adrenal haemorrhage can occur unilaterally or bilaterally. The right adrenal gland is involved in 75% of cases. Distinguishing these lesions from neuroblastoma can be challenging. Serial ultrasound follow up with changes in the echogenicity overtime is the most distinguishing feature. Prenatal MRI may be useful in differentiating between neuroblastoma and adrenal haemorrhage using high signal on T1W1, 

Extra-lobar pulmonary sequestration:
Extra-lobar pulmonary sequestrations are less common than neuroblastoma. On ultrasound, these lesions usually present as a well-circumscribed homogenous, echogenic mass that grows in proportion to the foetal size. These lesions are more commonly seen in the left suprarenal region and are commonly identified during second trimester. The most distinguishing feature is a single feeding vessel from a systemic artery, commonly the aorta. 
Other possible lesions which may be confused with neuroblastoma include: cystic masses of the kidneys, dysplastic duplex kidney, renal cyst, obstructed upper pole duplication, cystic Wilms tumour, mesoblastic nephroma and enteric duplication cysts
Ultrasound is 60% sensitive in delineating neuroblastoma from other supra-renal lesions including adrenal haemorrhage, extra-pulmonary sequestration and other renal lesions [9].  

Cardiac malformations have been associated with neuroblastoma in 10–20% of cases [1,9], so a careful look at the foetal heart structures is indicated when neuroblastoma are identified. 

The majority of neuroblastoma are sporadic [1—3] and have no increased risk for recurrence in a subsequent pregnancy. In approximately 1-2% of cases there is a family history of neuroblastoma. These cases are thought to result from autosomal dominant inheritance with incomplete penetrance. Inherited cases usually present at an earlier age and many of these patients have bilateral adrenal disease [1—3]. The risk for children of survivors of neuroblastoma is difficult to determine due to the small number of cases and treatment-related infertility [4]. 

Most foetal neuroblastomas are incidental findings identified during third trimester obstetrical ultrasound [9,10]. 
While foetal MRI can be performed in cases of neuroblastoma, it has not been shown to improve the antenatal diagnostic accuracy for neuroblastoma, [9] and may not alter the management of the pregnancy. The primary role of MRI in the antenatal setting is for staging and evaluation of metastatic disease [10]. 

Neuroblastomas detected before birth have a better prognosis than those diagnosed after birth (88% survival versus 64%) [11,12]. Cystic adrenal neuroblastoma shows higher survival rates as compared to non-cystic neuroblastoma (92% survival versus 70%) and are less likely to metastasise [12,13,15]. Metastatic disease involving the liver and placenta, particularly if identified antenatally, carries an extremely poor prognosis [12]. Spontaneous regression of neuroblastoma has also been documented in mass-screening studies in infants [12—15]. 
Direct tumour involvement and occlusion of the umbilical cord has been associated with foetal death in utero [9]. Very large tumours may predispose to foetal hydrops and pre-eclampsia either by direct compression of the foetal vasculature or by high output heart failure through the perfusion demands of the high volume/low resistance tumour vascular bed [1,9,10]. Large tumours can also lead to abdominal  dystocia with foetal  compromise or maternal trauma if not detected prenatally [16]. 
Outcome after surgical treatment of low stage neuroblastoma is excellent [11—15]. Age at diagnosis, tumour stage, and histopathology all reliably correlate with treatment outcomes [11]. Chromosome number (ploidy), and amplification of the N-myc oncogene are also used to stratify risk [13]. 

Ideally, patients with suspected neuroblastoma on ultrasound should be referred to a tertiary centre with expertise in foetal medicine, neonatology, paediatric surgery and oncology. Prenatal consultation with neonatology, paediatric surgery and paediatric oncology may be helpful. 

Once a neuroblastoma is identified, a careful look at the anatomic structures of the remainder of the baby, including the other adrenal gland to ensure that it is normal and the liver for metastatic lesions is suggested. The foetal heart should carefully be scanned to look for structural malformations as heart abnormalities are commonly seen in foetuses with neuroblastoma. The placental appearance and thickness should be noted, as thick or hydropic placentas are associated with metastatic disease and poor prognosis. Middle cerebral artery Dopplers can be performed to look for evidence of foetal anaemia, which might be seen in cases of large neuroblastomas or adrenal haemorrhage. 

The patient should be scanned regularly to assess foetal size, the size and appearance of the neuroblastoma, and to evaluate the foetus for hydrops [9]. Large tumour size requires more frequent foetal and maternal surveillance due to the risk of foetal hydrops. If the foetal abdominal circumference becomes quite large, caesarean delivery may be considered to avoid infant or maternal trauma during delivery [9], however, most patients can be delivered vaginally with caesarean delivery for the usual obstetric reasons. Patients should be watched carefully for preeclampsia and mirror syndrome as it may be a sign that the foetus has developed hydrops. 

Management of neuroblastoma at birth depends on staging and prognostic factors [16]. In most cases the neonates with localised primary tumours undergo surgery to remove the tumour. Partial resection is performed when there is a widespread tumour with high risk of injury to the surrounding organs [16]. Infants with stage 3 or 4 disease receive intense chemotherapy [16]. 

1.    Isaacs H Jr. Fetal and neonatal neuroblastoma: retrospective review of 271 cases. Fetal Pediatr Pathol. 2007 Jul-Aug;26(4):177-84. 

2.    Newman EA, Abdessalam S, Aldrink JH, Austin M, Heaton TE, Bruny J, Ehrlich P, Dasgupta R, Baertschiger RM, Lautz TB, Rhee DS, Langham MR Jr, Malek MM, Meyers RL, Nathan JD, Weil BR, Polites S, Madonna MB; APSA Cancer committee. Update on neuroblastoma. J Pediatr Surg. 2019 Mar; 54(3):383-389.

3.    Chen CP, Chen SH, Chuang CY, Lee HC, Hwu YM, Chang PY, Chen ML, Chen BF. Clinical and perinatal sonographic features of congenital adrenal cystic neuroblastoma: a case report with review of the literature. Ultrasound Obstet Gynecol. 1997 Jul;10(1):68-73.

4.    Buck GM, Michalek AM, Chen CJ, Nasca PC, Baptiste MS. Perinatal factors and risk of neuroblastoma. Paediatr Perinat Epidemiol. 2001 Jan;15(1):47-53.

5.    Nuchtern JG. Perinatal neuroblastoma. Semin Pediatr Surg. 2006 Feb;15(1):10-6.

6.    Hosoda Y, Miyano T, Kimura K, Oya T, Ishimoto K, Tanno M, Takeuchi H. Characteristics and management of patients with fetal neuroblastoma. J Pediatr Surg. 1992 May;27(5):623-5.

7.    Hwang SM, Yoo SY, Kim JH, Jeon TY. Congenital Adrenal Neuroblastoma With and Without Cystic Change: Differentiating Features With an Emphasis on the of Value of Ultrasound. AJR Am J Roentgenol. 2016 Nov;207(5):1105-1111.

8.    Werner H, Daltro P, Davaus T, Araujo Júnior E. Fetal neuroblastoma: ultrasonography and magnetic resonance imaging findings in the prenatal and postnatal IV-S stage. Obstet Gynecol Sci. 2016 Sep;59(5):407-10.

9.    Flanagan SM, Rubesova E, Jaramillo D, Barth RA. Fetal suprarenal masses--assessing the complementary role of magnetic resonance and ultrasound for diagnosis. Pediatr Radiol. 2016 Feb;46(2):246-54. 

10.    Maki E, Oh K, Rogers S, Sohaey R. Imaging and differential diagnosis of suprarenal masses in the fetus. J Ultrasound Med. 2014 May;33(5):895-904. 

11.    Granata C, Fagnani AM, Gambini C, Boglino C, Bagnulo S, Cecchetto G, Federici S, Inserra A, Michelazzi A, Riccipetitoni G, Rizzo A, Tamaro P, Jasonni V, De Bernardi B. Features and outcome of neuroblastoma detected before birth. J Pediatr Surg. 2000 Jan;35(1):88-91. 

12.    Menegaux F, Olshan AF, Reitnauer PJ, Blatt J, Cohn SL. Positive association between congenital anomalies and risk of neuroblastoma. Pediatr Blood Cancer. 2005 Oct 15;45(5):649-55. 

13.    Wang Z, Sun H, Li K, Yao W, Dong K, Ma Y, Zheng S. Prognostic factor analysis of stage 4S neuroblastoma in infant patients: A single center study. J Pediatr Surg. 2019 Dec;54(12):2585-2588.

14.    Rios P, Bailey HD, Orsi L, Lacour B, Valteau-Couanet D, Levy D, Corradini N, Leverger G, Defachelles AS, Gambart M, Sirvent N, Thebaud E, Ducassou S, Clavel J. Risk of neuroblastoma, birth-related characteristics, congenital malformations and perinatal exposures: A pooled analysis of the ESCALE and ESTELLE French studies (SFCE). Int J Cancer. 2016 Nov 1;139(9):1936-48.

15.    Parodi S, Merlo DF, Ranucci A, Miligi L, Benvenuti A, Rondelli R, Magnani C, Haupt R; SETIL Working Group. Risk of neuroblastoma, maternal characteristics and perinatal exposures: the SETIL study. Cancer Epidemiol. 2014 Dec;38(6):686-94.

16.    Birkemeier KL. Imaging of solid congenital abdominal masses: a review of the literature and practical approach to image interpretation. Pediatr Radiol. 2020 Dec;50(13):1907-1920.

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