Neuroblastoma (NB) is the most common extra cranial solid neoplasm of infancy; it is believed to constitute 8% to 10% of all childhood cancers [1]. NB usually arises in the adrenal glands or the retroperitoneal paravertebral ganglia, and less frequently in the posterior mediastinal ganglia [1-2]. Up to 20% of all NB arise in the thorax [3]. The prognosis of mediastinal NB is better than tumors at other sites [4]. In the current study, we have reviewed our experience treating patients with mediastinal NB for a 3-year period.

We conducted a retrospective analysis of patients diagnosed with a mediastinal NB at the Habib Bourguiba’s Hospital of Sfax over a period of 3 years (from January 2018 to December 2020). All the clinical details including demographic profile, histologic variants, treatment results and disease outcomes were investigated. Patients were staged according to International Neuroblastoma Risk Group Staging System (INRGS). Risk group classification criteria were based on the Children’s Oncology Group. Shimada’s classification was used to determine histologic grade. Overall survival was defined as the interval from the day of diagnosis to the death or the date of last follow-up. Kaplan-Meier method was used to determine survival. The analysis was conducted with a data cut-off in July 2021.

Patients Characteristics

Six patients were identified with thoracic NB between 2018 and 2020. The median age at first diagnosis was 41, 3 months (range 3 to 156). Half of the children were under 1-year-old at diagnosis. Only one patient reported family history of malignancy. The average delay in diagnosis was of 1, 8 months. Clinical findings are summarized in (Table 1)

Table 1: Patients’ clinical characteristics and histologic subtypes.

• International Neuroblastoma Risk Group Staging System
• Female
• Ganglioneuroblastoma
• Neuroblastoma
• Male

Imaging Findings

In all cases, CT scan showed a posterior mediastinal mass with a mean tumor size of 45,5 mm. Calcification was found in 4 cases while tumor necrosis was present only in 1 child. Thoracic MR imaging was realized in 2 patients. Tumor extension was assessed by abdominal CT scan or ultrasound in all children, bone scan in 5 cases, metaiodobenzylguanidine scintigraphy in 2 patients and bone marrow aspiration and biopsy in 4 cases. In patient B, imaging revealed a large mass involving nearly all the posterior mediastinum and compressing the spinal cord leading to paraplegia (Figure 1).

Figure 1: Axial T2 wheighted MRI images of the thoracic spinal cord showing an intra-dural, extra medullary postero-lateral intermediate hyper T2 tissular lesion with right foraminal extension and onset of spinal cord compression.

Metastases were reported in all children over 1-year-old. They are summarized in table 1. Bilateral Hutchinson syndrome was seen in the 2 children with orbital metastases. For these 2 patients, we identified tumor thrombus within the superior sagittal sinus. In all cases, the tumor was unresectable at diagnosis with image-defined risk factors (IDRFs) (Table 2).

Table 2: Image defined risk factors in our study.

Thirty-three percent of children had 2 or more IDRF.

Histologic and Molecular Findings

A biopsy of the mediastinal mass was performed in 3 cases. The diagnosis was confirmed by a biopsy of a metastatic site in 2 cases. Histologic findings are summarized in (Table 1). For one patient with INRG stage L2 (patient D), the biopsy of the mediastinal mass was not feasible and we started chemotherapy before confirming histologic diagnosis and determining MYCN status by delayed surgery. Molecular studies evidenced a MYCN gene amplification in 33, 3 % of patients. Four children (66, 7 %) had a high risk of recurrence according to Children's Oncology Group.

Treatment Strategies and Outcome

Chemotherapy was administered according to the age, stage and MYCN status. All children with localized unresectable NB under 1-year-old were treated with chemotherapy followed by surgery (Table 3). For patient D, despite MYCN amplification after delayed surgery, low dose chemotherapy was maintained. For patient A and F without MYCN amplification, chemotherapy was administered according to INES 99.1 trial [5]. All IDRFs disappeared after prior chemotherapy.For children older than 1 year with metastatic disease; treatment was based on chemotherapy with six courses alternating Carboplatin-Etoposide, Vincristine-Cyclophosphamide- Doxorubicin and Cisplatin-Etoposide (Table 3).

Table 3: Treatment strategies and outcome in our study.

• Cyclophosphamide + Vincristine
• VP16 + carboplatin
• Cyclophosphamide + Adriamycin + Vincristine
• Cisplatin + VP16
• Alive in complete remission

The (Figure 2)Figure 2: Axial non contrast CT brain scan showing a multiples metastasis of a neuroblastoma (intra orbital, sub arachnoidal and sub cutaneous) with a heavy subarachnoid hemoragee.

Reveals the subarachnoid hemorrhage and the tumor progression following the first cycle of chemotherapy and leading to patient E’s death. None of the 6 patients received intensive therapy followed by megatherapy with autologous stem cell rescue. Only one patient (patient B) underwent radiation therapy for spinal cord compression without any benefit.

Survival

The survival curve is shown in (Figure 3).

Figure 3: Overall survival in our study.

The thorax is an uncommon primary site of NB accounting for 20 % of all cases [3]. However, thoracic NB is the most common mediastinal mass in children under 2 years old [6]. It is known to be less aggressive than NB occurring in other sites [4]. Adams et al demonstrated in their study that young age and localized disease are favorable prognostic factors for mediastinal NB [7].Many studies reported that mediastinal NB is more common in females [8-9]. In our study, the female to male ratio was 2. In several series, the median age at onset ranged from 10 to 24 months [6-9], while in the present study, the median age was higher (41,3 months). This may be due to the onset at 13 years old in one of the patients. In tow series, children were under 1 year of age in about 52 % [7-8] which was approximately the same reported in our study. Many authors reported an asymptomatic presentation in 48 to 60% of patients [7-8], while in our study, all children were symptomatic. The most common signs reported at first diagnosis were respiratory symptoms occurring in 37 to 63 % of all cases [7-9]. In our study, half of the patients presented with respiratory distress which is similar to the literature. In the study of Demir et al, bone was the most common site of metastases accounting for 70 % of all stage M thoracic NB [9]. However, in our study, all patients with stage M mediastinal NB developed bones metastases. The incidence of ganglioneuroblastoma ranges from 20 to 38 % of all thoracic NB [7-10]. Witch was parallel to our study (33 %). Suita et al reported a favorable histology according to Shimada's classification in all cases of thoracic NB (8). In another study, Adams et al noted that 88 % of the patients belonged to the low risk or favorable histology group [7]. However, our data showed a lower percentage.Häberle et al [6] reported MYCN amplification in 9 % of thoracic NB (24 % of stage 4 and 2,5% of localized stages). Whereas in the study of Suita et al, N-copy number was less than 10 in all cases of mediastinal NB [8].About 50 to 70 % of mediastinal NB are diagnosed at early stages [6-8]. These rates are similar to those found in our study (50%). Since most thoracic NB appear as localized disease, surgery is the main treatment for these tumors. However, radical surgery is not the first priority [6]. After chemotherapy, complete resection should be achieved whenever is possible without risking severe complications [6-9]. Two series reported surgical complications in 20 % of patients with mediastinal NB [6-7] which is similar to the percentage found in our study (33%). Horner’s syndrome and pulmonary disorders are the most frequent complications [3-6].Monclair et al showed that 42 % of thoracic NB had 1 or more IDRFs (11), which is lower compared to our data (100%). As demonstrated by a recent study, neoadjuvant chemotherapy reduced the number of IDRFs in NB [12].Different treatment regimens were reported in the literature. In the study of Suita et al, low- dose chemotherapy of cyclophosphamide and vincristine was administered in localized disease without MYCN amplification. Whereas patients with advanced stage or MYCN amplification were treated with high dose chemotherapy [8]. In our study, all patients with localized disease received low dose chemotherapy regardless MYCN status. Seventy four percent of non-surviving patients with thoracic NB died of progressive disease [6]. While in our study, all deaths resulted of disease progression. Many series reported that 5- year overall survival ranged from 77 to 98 % [6-8, 11, 13]. In the present study, further follow up is necessary to compare survival rates.

Patients over 1-year-old with metastatic disease and MYCN amplification or unfavorable histology have a poorer prognosis. Disease progression is the main cause of death. For children under 1-year-old, localized mediastinal NB can be considered as a curable disease even when the tumor is unresectable at diagnosis. Prior chemotherapy reduces the number of IDRFs. Delayed surgery offers a survival benefit to these patients in spite of incomplete resection.

The authors have no acknowledgments to declare.

All authors declare that they have no conflict of interest. No funds, grants, or other support was received.

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