*Centro de Atendimento Materno-Fetal, Aracatuba Sao Paulo, Brazil; ^&Magdalena Sonora, Mexico, ^#Nashville, TN

Synonyms:   Ganglioneuroblastoma

Definition: Neuroblastoma is an embryonal tumor, derived from the sympathetic nervous system. Neuroblastomas present neuronal characteristics and some of them also demonstrate evidence of extra-adrenal neuroendocrine differentiation in discrete cell layers [1] that are able to produce catecholamines. Most often they are localized in the adrenal glands [2] .

Case report:  This G₁P₀ patient was referred at 34 weeks and 3 days for an abdominal mass on the right side. The ultrasound examination confirmed the presence of a 37 by 36 by 29 mm mass. The mass was heterogeneous, mostly solid. No large vessel feeder was seen. The mass displaced the inferior vena cava anteriorly, revealing its retroperitoneal nature. The rest of the examination was unremarkable and in particular there was no evidence of either adenopathy or metastasis. Because of the intimate contact of this lesion with the upper pole of the right kidneys, the failure to identify the right adrenal gland and the anterior displacement of the vena cava we suspected (as did the referring physician) that this lesion represented a neuroblastoma.

The mass:

The mass in sagittal view

Doppler of the mass:

There are also 3 video-clips of the lesion (1.8 MB, 2.2 MB, 2.3 MB)

The mother did not experience complications; in particular she had no evidence of hypertension. The baby was delivered at term and was followed-up in pediatric oncology. In spite of a rapid confirmation of the prenatal diagnosis and aggressive treatment, the child died at 3 months. This fatal evolution might suggest that in contrary to the commonly held belief that early detection of the neuroblastoma carries a favorable prognosis, it might also be tumors that are detected early are also more aggressive tumors.

Etymology:  Greek: neuron , = (neuron) sinew, nerve, and blastoma from blastoV a germ, a shoot and oma, tumor.

Prevalence: Neuroblastoma is the most common malignant solid tumor in infants less than 1 year old [3] and the second most common malignant tumor of childhood. The diagnosis of this tumor has been made prenatally on several occasions [4] ^{, [5] , [6]} .

Etiology:  Several studies have pointed at a possible deletion of the distal portion of the short arm of chromosome 1 (1p36.1-p36.2 [7] or 1p34-p35 [8] ). Associations with the use of some medications before or during pregnancy have been reported:

• carbamazepine (for bipolar disorder) [9] .
• phenytoin [10]
• sex hormone exposure 3 months prior to or during pregnancy [11] ,
• frequent alcohol consumption11
• maternal use of diuretic drugs11
• use of hair coloring products11

Pathogenesis:  The peak incidence of neuroblastoma during early infancy indicates that prenatal factors may influence in the pathogenesis of this disease. Some researchers suggested that the fetus is susceptible to an in-utero oncogenic initiator or promoter during the last 4 weeks of gestation [12] .

Neuroblastomas arise from the sympathetic nervous system and the gene markers expressed, parallel the evolution of the embryo with earlier stages of the tumor being less differentiated and more aggressive, while later stages are better differentiated and less aggressive. In undifferentiated tumors (mostly adrenal, high stage, and of poor prognosis) gene markers of early fetal ganglionic lineage are expressed. While in highly differentiated neuroblastoma (associated with more favorable outcome, and a mostly extra-adrenal location) the following characteristics were identified:

• loss of expression of gene products associated with normal fetal sympathetic ganglionic differentiation such as Bcl-2, HNK-1, and neuropeptide Y
• Increased extra-adrenal chromaffin marker gene expression (TrkA, TrkC, TH, IGF-2, and neuron-specific enolase expression)
• lack of phenylethanolamine N-methyltransferase expression [13] .

Neuroblastomas express growth-associated protein-43, neuropeptide tyrosine, and Bcl-2 [14] . The amplification of the N-myc gene can establish the aggressiveness of neuroblastoma (oncogenesis). Tumors cells with neuroendocrine features expressed these genes only in the morphologically immature, proliferating stage [15] .

Diagnosis: Ultrasound establishes the size, localization and sonographic features of the tumor and search for metastases. Some have found that color flow mapping and Doppler flow studies may be helpful in assessing the origin of the feeding vessel [16] . MRI can be a complementary in some cases [17] . Other diagnostic procedures include biochemical markers in the fetal blood, such as the determination of catecholamines [18] and neuron-specific enolase. References for neuron-specific enolase are available in cord blood (median concentration = 8.0 micrograms/l, 5^th-95^th percentiles =  4.8-19.4 micrograms/l.) [19] . Elevated amniotic fluid catecholamines can also be present [20] .

Sonographic findings: Neuroblastomas can have a solid, purely cystic or complex sonographic appearance [21] . About one-half of neuroblastomas are cystic neuroblastomas [22] . Neuroblastomas can be found in the neck, chest or in a paravertebral intra-abdominal location. The detection is typically performed in the third trimester of gestation [23] . A very characteristic finding is the anterior displacement of the vena cava, which divulges their retroperitoneal origin.

Clinical staging of a neuroblastoma 14

• Stage I: Tumor confined to the organ or structure of origin
• Stage II: Tumor extending in continuity beyond the organ or structure of origin but not crossing the midline. Regional lymph nodes on the ipsilateral side may be involved. For tumors arising in midlines structures, e.g. the organ of Zuckerkandl, penetration beyond the capsule and lymph node involvement are to be stage II. Bilateral extensions of any sort are considered to be stage III.
• Stage III: Tumor extending in continuity beyond the midline. Regional lymph nodes may be involved bilaterally.
• Stage IV: Remote disease involving the skeleton, organs, soft tissue or distant lymph nodes.
• Stage IV-S: Patients who would otherwise be stage I or II, but who have remote disease confined to the liver, skin or bone marrow, and who have no radiographic evidence of bone metastases on complete skeletal survey.

Differential diagnosis

• cystic adenomatoid malformation [35] ,
• pulmonary sequestration35 ,
• nephroblastoma (Wilm’s tumor) [36] ,
• lymphangioma [37] ,
• bronchial atresia37
• angioma37 ,
• myofibromatosis [38] ,
• bronchogenic cystic [39] ,
• cystic/dysplastic kidney3 ,
• enteric duplication cyst3 .

Most of adrenal and juxtarenal masses are premalignant or malignant lesions, but some may be benign (adrenal hemorrhage, pulmonary sequestration). The prenatal diagnosis of neuroblastoma has increased and the benign behavior of many neonatal neuroblastomas has stimulated debate to establish adequate treatment for neonatal adrenal masses [40] .

Subdiaphragmatic extralobar pulmonary sequestrations are 2.5 times more common then neuroblastoma. Neuroblastoma is most frequently cystic, right-sided and identified in the third trimester [41] . On the other hand, subdiaphragmatic extralobar pulmonary sequestration is most often echogenic, left-sided and can be identified in the second trimester.

Associated anomalies: Neuroblastoma, Hirschsprung"s disease, and central hypoventilation (Ondine"s curse) are abnormalities of neural crest cell growth, migration, or differentiation, and are considered neurocristopathy [42] . In a case of 46,XY/ 47,XY,+ 17p+ mosaicism the fetus had Dandy-Walker malformation, bilateral choroid plexus cysts, post-axial polydactyly and neuroblastoma-in-situ affecting both adrenals [43] . Congenital neuroblastoma can be associated with nonimmunologic hydrops fetalis [44] . Some authors feel that these associations are so rare that that no true link can be made.

Maternal complications: Neuroblastoma can produce catecholamines, leading to maternal hypertension and maternal symptoms could raise the possibility of fetal neuroblastoma25 .

Autopsy: In a case of large placenta with hemorrhagic and necrotic areas, cells showed immunoreactivity for NSE, NB 84, chromogranin, synaptophysin and neurofilaments, while desmin, MIC 2, and protein S-100 were negative.

Prognosis: The prognosis of children with neuroblastoma depends on:

• the patient"s age at diagnosis,
• the location of the primary tumor, and
• histologic tumor cell differentiation [45] .

Early diagnosis permits appropriate treatment and a better postnatal outcome [46] ,49 . The outcome for patients with Stage I neuroblastoma treated with surgery alone is excellent, although event-free survival and survival rates were significantly worse for patients with MYCN-amplified tumors (gene associated with neuroblastoma) a subset achieved long-term remission after surgery alone [47] .

Management: The surgical indications for suprarenal masses detected prenatally are not well defined [48] . The benign behavior of some neonatal neuroblastomas has stimulated debate to establish appropriate treatment for neonatal adrenal masses [49] . In contrast with our current case, the majority of infants with antenatally detected neuroblastoma present with excellent outcome [50] . These authors suggested that aggressive treatment may always not be necessary and chemotherapy not indicated unless substantial progression of disease occurs. Infants with antenatally detected neuroblastoma with unfavorable features should undergo early surgical excision, whereas patients with favorable features could be observed awaiting spontaneous regression of the mass, reserving delayed surgery for tumors that increase in size or do not regress.

Reviewer: Ahmed Al-Sinan, MD

References

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