Cuillier F, MD*, Carasset G, MD**, Lemaire P***, Deshayes M***

* Department of Gynecology ** Gynecologist, Saint Clothil clinic *** Sonogapher, Moufia’street , Hôpital Félix Guyon - Ile de la Réunion, France

Definition: Neuroblastoma is a sarcoma consisting of malignant neuroblasts, usually arising from cells of the autonomic nervous system (1/3) or the adrenal medulla (2/3). Neuroblastoma is the most common malignant tumor in infancy and early childhood (1).

Approximately:

• 70% develop in the abdomen, with about half being in the adrenal gland
• 20% occur in the thoracic cavity
• 10% occur in all the areas where cells of the neural crest can be found.

The most frequent metastases are in the liver, bones, marrow and skeleton.We report one case of fetal adrenal mass detected by routine prenatal ultrasound.

Synonyms: Neuroblastoma in situ ; Adrenoblastoma.

Case report: A 35-year-old primigravid woman had a normal 13 and 22 weeks scan. The nuchal translucency and the triple test were strictly normal. At 34 weeks, the patient underwent a routine ultrasound examination. The scan revealed a heterogeneous, hypoechoic and hyperechoic mass, between the upper pole of the right kidney and the diaphragm, measuring 29 x 30 x 32 mm (Figure N°1-2-3-4). The color Doppler demonstrated that the tumor was arising from the adrenal gland and there was a poor vascularization around the tumor (Figure N°5). Fetal biometry, biophysical profile and Doppler examination were normal (Figure N°6). At 34 weeks, a MRI was performed and confirmed the right heterogeneous mass (Figure N°9-10). A adrenal hemorrhage and a neuroblastoma were suspected. The mother did not demonstrate any adrenergic symptomatology or hypertension. Fetal biometry and morphology were otherwise normal. At 35, 37 and 39 weeks, another scans were performed (Figure N°7-8).

At 40 weeks, the baby was delivered (2800g) vaginally.  The Apgar score was 10/10 at 1/5 minutes, respectively. A small right flank mass was palpable on physical examination. Vanilmandelic acid and catecholamine levels were negative in a 24-hour-urine sample. MRI and ultrasound scans confirmed a right solid adrenal mass. Perfusion scan showed contrast enhancement and calcifications suggestive of neuroblastoma (Figure N°11-12).

Preoperative diagnostic evaluation was otherwise normal and included bone marrow aspirate, bone scan, urinary catecholamines and liver function tests. Concentrations of catecholamines metabolites and vanilmandelic acid were not elevated in the neonatal blood. Adrenal scintigraphy was done and confirmed the neuroblastoma diagnosis. A right tumorectomy was performed on day-25.  Pathological examination showed an encapsulated stage I neuroblastoma with favorable histology. No further treatment was performed. After one month, the baby is healthy.

Figure 1,2,3,4 :Transverse view at 34 weeks showing a hypoechoic suprarenal mass

Figure 5: Transverse view at 34 weeks showing a solid echogenic suprarenal mass
Figure 6: 3D of the fetal face

Figure 7: Parasagital view at 37 weeks showing normal left kidney and right normal kidney

Figure 8: Parasagital view at 39 weeks showing normal left kidney and right normal kidney

Figure 9: MRI at 34 weeks showing a hypoechoic suprarenal mass (right) and the right kidney (left).
Figure 10: MRI at 34 weeks showing the lesion appeared echoic and anechoic with multiple septa

Figure 11: Postnatal MRI view showing right heterogeneous mass located at the superior pole of the kidney
Figure 12: Postnatal coronal MRI showing a sagittal view of neuroblastoma with intracystic septations

History: Prenatal neuroblastoma diagnosis was first reported in 1983 by Fenart et al and after that more than 55 case have been published (2). The localization is essentially on adrenal. All published reports of prenatally diagnosed cases were detected in the third trimester of pregnancy. Recently De Filipi et al reported one case of a thoracic mass seen at 37 weeks. Atkinson et al detected a complex abdominal mass at 32 weeks although a previous ultrasound in the 16 weeks showed no pathology (4). Kesrouani et al (1999) described two cases of antenatal neuroblastoma. Both cases had favorable outcome and surgery was necessary in only one (1).

Prevalence: Neuroblastoma represents 30% of all neonatal tumors and it is the most common malignant tumor (6). The incidence of neuroblatoma ranges from1/10.000 to 1/30.000 in childhood according to Kessouani (1). This discrepancy is caused by a high rate of spontaneous regression that is well documented in infants younger than one year of age without treatment. According to Girschick (2), the incidence of congenital neuroblatoma had been estimated in 10.000-30.000 live births, but in area where screening for neuroblatoma during the first six months of life was introduced, the incidence was found to be two to three times higher than expected. This is consistent with autopsy series, which show that incidental neuroblstamo in situ occur in 1:200 to 1:250 among stillbirths and infants who have died under three months of age. Although neurobastoma is the most common abdominal malignancy diagnosed in neonates and early childhood, it is seen as frequently as 1/40 in autopsy studies (1/259 cases according to Beckwiths). This is 40 times greater than the incidence of clinically manifested (6).

• Neonatal prevalence:  1,9 / 1000
• Prenatal prevalence:  Unknown.
• Neuroblastoma is slightly more frequent in the white population and in males.
• About 2/3 of cases are located in the adrenal gland
• The right side appears to be more frequently affected

Etiology: Most neuroblastomas are sporadic, although a small number may be familiar with complex inheritance patterns (7). Congenital neuroblastoma has also been reported following treatment with phenobarbital and phenytoin (coincidental association?). Adverse biologic features are diploid tumor karyotype (cytometry) and amplify neuroblastoma-myc oncogene. A genetic defect is involved in the etiology, with a loss of critical region in Chr 1 (locus p36). Amplification of the neurobastoma-myc proto-oncogene is also correlated with the aggressiveness of the tumor (1). The S-100b protein may inhibit the development of neuroblastoma in Down' syndrome as the gene coding for this protein os located on chromosome 2 (11).

Pathogenesis: The adrenal gland develops from a mesodermal portion (which form the cortex) and from an ectodermal portion (which forms the medulla) (8). The size of the adrenal gland in the fetus is about 20 times its relative size in the adult, reaching a weight of 2 to 4g at birth. Normal adrenal development goes through a stage that is indistinguishable from in situ neuroblastoma. Thus, the development of clinical neuroblastoma may be a defect in the cellular control of division and attachment, which may be temporary. After birth, 50% of babies have elevated HMA/VMA levels. Most enjoy improved survival due to: lower stage of disease, cystic variety and higher stage IV-S, which has been associated with spontaneous immuno-regression.

Sonographic findings: Fetal adrenal gland can be easily identified by the ultrasound examination. They have a discoid shape on a transverse view and appear as Y- or V-shaped structures at the superior border of the kidney on an axial view. They can be imaged from the end of the first trimester. In the third trimester, the normal ultrasonographic appearance of the adrenal gland consists of a large hypoechoic cortex surrounding a small hyperechoic medulla. This appearance differs from that of the adult adrenal, where the medulla is larger than the cortex (9).

Prenatal diagnosis of neuroblastoma is a rare event. Prenatal diagnosis of a fetal adrenal mass can be difficult and can pose therapeutic dilemma. Neurobastoma is frequently encapsulated and displaces the kidney inferiorly and laterally. Clear separation of theses structures is typical. The sonographic appearance of the tumor can vary: it may be solid, purely cystic (50%) or mixed echo pattern. The key to the diagnosis is the change in appearance over time, usually to a cystic mass of decreasing size (8). Peripherica, rim-like calcification may remain. The sonographic picture is characterized by a cystic, solid complex mass in the region of the adrenal gland, directly above the level of the kidney and under the diaphragm (8). Calcifications can be seen. If arising in a sympathetic ganglion, the tumor may appear in the chest, neck or paravertebral. In 2003, 90 cases of antenatally detected neuroblastoma have been described. Most cases are detected by ultrasound in the third trimester and sonographic appearance varied from solid to purely cystic. Urinary VMA and HVA were increased in 38% of antenatally detected neurobl;astoma whereas abnormally high levels are found in 85% of patients with postnatally diagnosed neuroblastoma. The liver is commonly affected by metastasis, these being observed in 25% of all patients (9). However a suprarenal mass associated with hepatomegaly is very suggestive of neuroblastoma. The findings of a nodule or a cystic mass in the liver or in the retroperitoneal nodes, necessitates evaluation of all neural crest regions and especially.

Implications for target examinations: Most cases of neuroblastoma are diagnosed during the third trimester, even though earlier scans had been performed. So this third sonography confirms its importance. Only one case of neuroblastoma associated with multiple anomalies has been reported in the literature, so associated malformations are unusual.

Differential diagnosis: The sonographic appearance of fetal neuroblastoma varies from cystic to homogeneous echoic and hyperechoic with mixed foci of calcifications. One criterion, which may assist in the differential diagnosis, is the gestational age at diagnosis. Most cases of neuroblastoma are diagnosed in the third trimester even though earlier scans had been performed. So prenatal diagnosis of a fetal adrenal mass can pose a diagnosis dilemma:

• Adrenal hemorrhage: The differentiation essentially from fetal adrenal hemorrhage may be difficult, particularly because some richly vascularized neuroblastoma are associated with intratumoral hemorrhage. Adrenal hemorrhage is not common in neonates and has been classically associated with birth trauma. Adrenal hemorrhage mainly occurs at birth or during the early neonatal period and less frequently in utero, usually during the third trimester. The pathophysiology is not fully understood. As neuroblastoma hemorrhage preferentially affects the right side, this is probably owing to compression of the right adrenal between the liver and the spine. Nevertheless, sonographic appearances of adrenal hemorrhage depend on the various stage of the hematoma visualized. Fresh clot following active bleeding is sonographically visualized as a hyperechogenic irregular mass and the echogenicity persists after clot retraction. Thereafter, internal echoes due to fragmentation of the hemolyzed clot develop, producing multiple interfaces. It product a more heterogeneous sonographic appearance, with mixed echogenicity. Finally, the lesion develops into an echolucent hematoma, as in our case. The causes and natural history of neonatal adrenal hemorrhage are poorly understood. More cases are sporadic. Some factors can be birth trauma, difficult labor or delivery, asphyxia, septicemia, hemorrhagic disorders or hypoprothrombinemia. But spontaneous occurrence can arrive in otherwise normal neonates. The pathogenesis of adrenal hemorrhage in utero is unknown. The pathophysiology is believed to be related to a sudden increase in intravascular pressures, which is perhaps transmitted from the IVC to the adrenal gland. The second hypothesis is that the adrenal gland is susceptible to trauma and hemorrhage because of their relatively large size and vascularization. So the right adrenal gland is also more common involved (75 %), because there is a short vein, which drains directly into the inferior venan cava, while the left adrenal vein empties into the ipsilateral renal vein (7). Hypoxy is another factor to predispose to adrenal hemorrhage. Indeed, in IUGR fetuses, there is an increased diastolic flow to the adrenal gland, resulting in lower adrenal artery pulsatility index and suggesting an « adrenal sparing effect ».

• Adrenal cysts: Exceptional
• Cortical renal cysts or cystic Wilm's tumor
• Splenic cyst: may be confused with a left-sided neuroblastoma
• Mesoblastic nephroma: demonstrates a solid appearance
• Duplications of the uretero-renal system
• Sub-diaphragmatic extra-lobar pulmonary sequestration: The pedicle arising from the thoracic aorta by color Doppler, which aids in the differential diagnosis. With respect to extralobar sequestration versus neuroblastoma, the former is usually left sided solid, and seen in the second trimester at the time of the fetal anatomic survey
• Hepatic, choledochal or enteric cysts
• Ovarian cyst
• Renal vein thrombosis
• Retroperitoneal teratoma

The use of color Doppler imaging allows the correct localization of the adrenal gland. Adrenal hematoma may display, at an early stage, a marked rim-shaped pattern of vascularization around the tumor, a sign that has already been described angiographically in neonates. Doppler imaging has been used in the characterization of neuroblastoma in children and in fetuses. However color Doppler did not help in differentiating benign from malignant adrenal masses in adults. In our case, the mass was located between the inferior pole of the left kidney and could be differentiated from the kidney.

Associated anomalies:

• Hydrops
• Neurofibromatosis
• Hirschprung's disease
• Chromosomal anomalies
• Fetal hydantoin syndrome
• Fetal alcohol syndromes
• Beckwith-Wiedemann syndrome which is frequently associated with adrenal tumors and hemorrhage .

Prognosis: Prognosis depends on the tissue of origin, age at diagnosis, stage of disease, cytogenetic abnormalities and associated congenital malformations. A good prognosis in infants depends on early detection because of the possibility of metastasis. The survival rate is higher in cases detected prenatally than in cases detected in infants. There are two types of neuroblastoma according to Girschick:

Type 1. One subset includes the favorable neuroblastoma diagnosed at an early stage  (<12 month), which are associated with favorable genetic prognostic factors and have an excellent clinical outcome with minimal treatment even in cases with metastases.

Type 2. The second subset includes the unfavorable neuroblastoma diagnosed in older children and associated with unfavorable genetic prognostic factors. This one show a poor clinical outcome, even with aggressive treatment.

Spontaneous regression of the neuroblastoma has been reported. Girschick et al (2003) described one case of adrenal tumor at 23 weeks, which regressed regularly during pregnancy. At the age of four month, the tumor was disappeared (2). It is the regular evolution. Kesrouani described his first case. The neuroblastoma tumor was staged as IV-S. Spontaneous regression was observed and at seven month of age, the infant was clinically normal. Girschick described one case of spontaneous regression of an adrenal mass. The adrenal mass was discovered at 22 weeks and which disappeared at four month of life. These observations suggest that neuroblastoma undergoes regression and especially fetal neuroblastoma .

Unfavorable fetal evolution is also possible. Associated fetal hydrops can be explained by several hypotheses:

• Hepatomegaly with subsequent mechanical obtruction of the umbilical vein or inferior vena cava
• Compromised liver function with subsequent hypoalbuminemia
• Infiltration of the fetal bone marrow, leading to anemia and heart failures
• Arrhythmia followed by heart failure due to excessive catecholamine release and hypersecretion of fetal aldosterone
• Metastases/placental lesions
• Tumors cells may also infiltrate the placenta, leading to the reporting of metastatic foci in the umbilical vessels (1). There are several reports of hydropic placenta. Strauss et al reported two cases of hydropic placenta with placental metastases in two cases and the infants from both of these pregnancies died in the postnatal period. Given these informations, it is possible that tumour cells could pass into the maternal circulation, although no cases of metastases in the mother have been reported.

Managment: Serial follow up of the tumor. Surgery and chemotherapy are necessary according to the tumor classification.

REFERENCES

1- Kesrouani A., Duchatel F., Seilanian M., Muray J.M.- Prenatal diagnosis of adrenal neuroblastoma by ultrasound : a report of twocases and review of the literature. Ultrasound Obstet Gynecol 1999 ; 13 : 446-9.

2- Girschick G., Singer D., Trusen A., Dietl J., Muller T.- Intrauterin regression of an adrenal mass. Ultrasound obstet Gynecol 2003 ; 21 :306-9.

3- Heling K.S., Chaoui R., Bollman R.- Prenatal diagnosis of congenital neuroblastoma : report of five cases and review of the literature.Frontiers in Fetal Health ; 1999 ; 1 : 1-3.

4- Le bouar G., Lassel L., Loeuillet-Olivo L., D’hervé D., Poulain P.- Le neuroblastome métastatique anténatal : critère pronostiques. Apropos d’un cas. J Gynecol Obstet Biol Reprod2003 ; 32 : 740-4.

5- Aslan H., Ozseker B., Gul A.- Prenatal sonographic and MRI diagnosis of cystic neuroblastoma. Ultrasound Obstet Gynecol 2004. 24 : 692-5.

6- Houlihan C., Jampolsky M., Shilad A., Prinicipe D.- Prenatal diagnosis of neuroblastoma with sonography and magnetic resonanceimaging. J Ultrasound Med 2004 ; 23 : 547-50.

7- Schwärzler P., Bernard J.P., Senat M.V., Ville Y.- Differenciation between hemorrhage and solid tumor by color doppler sonography.Ultrasound Obstet Gynecol 1999 ; 13 : 351-5.

8- Tsague Y., Megier P., Lebas P., Laufenburger A., Desroches A.- Diagnostic antenatal d’un cas de tumeur de la surrenale. Propositiond’une conduite à tenir après revue de la literrature. J Gynecol Obstet Biol Reprod 1999 ; 28 : 292-301.

9- Jaffa A.J., Many A., Hartoov J., Kupperminc M.J., Reuben Peyser M.- Prenatal sonographic diagnosis of metastatic neuroblastoma : report of a case and review of the literature. Prenatal Diagn 1993 ; 13 : 73-7.