Neuroblastomas are the most frequently identified extracranial tumors that affect children under the age of 4 years old, with an incidence of approximately 1 to 3 in 100,000 cases.[1,2] These account for approximately 6% to 10% of all pediatric tumors and 15% of tumor-related deaths in children. Neuroblastomas are neuroendocrine tumors that can originate anywhere in the sympathetic nervous system, although these are most commonly found in one of the adrenal glands. The clinical symptoms and signs of neuroblastomas are commonly atypical, depending on the location of the primary tumor and metastases. Although metastasis to the orbits has been well-documented for neuroblastomas presenting with various symptoms, such as periorbital ecchymoses (raccoon eyes) and proptosis, neuroblastoma cases with initial symptoms of orbital involvement are rare, accounting for approximately 8% of all neuroblastomas. In the present study, we report a specific case of a 3-year-old girl with neuroblastoma, who presented with initial signs of periorbital ecchymoses (raccoon eyes) and proptosis. In addition, the clinical, radiological, and histopathological studies of orbital neuroblastoma metastasis reported in the literature were summarized.
2 Case presentation
The present study was approved by the Ethics Committee of the Central Hospital of Wuhan, Tongji Medical College of Huazhong University of Science and Technology. All procedures performed in studies that involved human participants were in accordance with the ethical standards of the institutional and national research committee, and the 1964 Helsinki declaration and its later amendments, or comparable ethical standards. A written informed consent was obtained from the patient's legal guardian.
A 3-year-old girl was admitted to our hospital presenting with periorbital ecchymoses and proptosis for 40 days. On examination, multiple hard masses were palpated on both the face and head. Bilateral subconjunctival hemorrhages, periorbital ecchymoses (raccoon eyes), and proptosis were identified (Fig. 1A). Fundus fluorescein angiography (FFA) and macular optical coherence tomography (OCT) revealed no abnormality on the fundus. The systemic evaluations, which included routine blood and urine tests, hepatic and renal function examinations, and the serum glucose test, revealed unremarkable findings, with the exception of anemia. The electrocardiogram and chest roentgenogram results were also unremarkable. However, an abdominal mass was palpated by a pediatrician.
The computed tomography (CT) scan highlighted multiple soft tissue masses in the skull and both orbits, with evident erosion into the adjacent bones (Fig. 1B). The magnetic resonance imaging (MRI) also revealed multiple masses in the head-face area, and a large mass in the left suprarenal gland (Fig. 1C and D). The abdominal sonography examination revealed a heterogeneous hypoechoic mass in the left adrenal gland (Fig. 1E).
The mass on the right face was surgically removed. The tumor was cardinal red, with an irregular surface (Fig. 1F). The hematoxylin-eosin (H&E) staining revealed small uniform round cells with a scanty cytoplasm and darkly stained nuclei. Furthermore, nodules and Homer-Wright pseudorosettes were occasionally found, with no ganglionic differentiation (Fig. 1G). The tumor was immunopositive for synaptophysin and neuron-specific enolase, but immunonegative for S-100 and leukocyte common antigens. According to the clinical, radiological, and histopathological findings, the patient was diagnosed with stage IV neuroblastoma. The patient was transferred to the Department of Pediatric Oncology for the treatment of the tumor. However, the patient refused the recommended chemotherapy, which included cisplatin, doxorubicin, etoposide, and ifosfamide. Hence, the patient was discharged without any therapeutic regimen. The patient presented no deteriorative signs at the 6-month follow-up.
3 Discussion and conclusion
Orbital tumors in children can rapidly develop and lead to vision loss, and are associated with significant risk of mortality and morbidity. Neuroblastoma is an undifferentiated malignant tumor that commonly occurs in children, which can rapidly metastasize and widely spread, resulting in a variety of clinical manifestations, such as proptosis, periorbital ecchymosis, abdominal pain, anemia, pancytopenia, bone pain, and paralysis. In the present study, we present a case of a 3-year-old girl with stage IV neuroblastoma, who presented with periorbital ecchymoses and proptosis as initial symptoms. The diagnosis of neuroblastoma was confirmed by radiological analysis of the orbital tumors and an abdominal mass in the adrenal gland, as well as the characteristic histological findings of neuroblastoma. Since clinical manifestations and imaging features are not specific or defined for neuroblastoma, it remains difficult to differentiate neuroblastoma with orbital involvement from other metastatic orbital tumors, such as malignant lymphoma, rhabdomyosarcoma, granulocytic sarcoma, and Wilms tumors. Relevant literature was reviewed, and 10 cases of neuroblastoma with orbital involvement were found by searching PUBMED for published articles between 2000 and 2017 (Table 1). The clinical manifestations, radiological findings, and histological features of these cases, as well as the present case, were summarized (Table 1), which are integral to the clinical diagnosis and differential diagnosis of neuroblastoma with orbital involvement.
Periorbital ecchymoses and proptosis have been reported to be classic signs of pediatric neuroblastoma.[4,8] Consistent with these symptoms, it was found that the most common clinical manifestation of neuroblastoma with orbital involvement reported in the literature was periorbital ecchymoses (8/11, 72.7%), followed by proptosis (6/11, 54.5%; Table 1). The emergence of periorbital ecchymoses is probably due to tumor obstruction of the blood vessels in and around the orbits. Less common ophthalmic manifestations include periorbital swelling/edema (5/11, 45.4%), subconjunctival hemorrhage (2/11, 18.2%), vision loss (2/11, 18.2%), and decreased ocular mobility (1/11, 9.1%). Other uncommon clinical associations include pancytopenia, anemia, abdominal pain, fever, vomiting, and hepatosplenomegaly, which may be associated with the metastasis of the tumor to the bone or other organs.
Since orbital neuroblastoma metastasis presents with non-specific clinical manifestations, it is often misdiagnosed as child abuse, orbital fracture, or other tumors such as rhabdomyosarcoma. CT and MRI can provide valuable diagnostic information for neuroblastoma identification, especially for pin pointing the primary site of the tumor. A giant hypoechoic mass with hyperechoic areas is the most common abdominal sonographic finding, which was observed in the present case. With the exception of case 11, abdominal CT and/or MRI scans were performed in all of the cases reviewed, and abdominal masses in the adrenal gland were often discovered. The radiographic findings in the orbits usually included thickened bones, periosteal reactions (speculated bones), and lytic defects. In the MRI scans, neuroblastomas usually present with heterogeneous low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.
The histopathological analyses of biopsied orbital masses were often performed to confirm the diagnosis of orbital neuroblastoma metastasis. The histological staining of the biopsied tissues revealed small round cells with a scanty cytoplasm and darkly stained nuclei.[9,12] Moreover, neural markers, such as neuron-specific enolase, TH, and synaptophysin, were often immunopositive in the tumor tissues, while S100 and leukocyte common antigens were immunonegative (Table 1).
The present patient refused any therapeutic regimen. At present, the primary treatment for neuroblastoma is chemotherapy. Multiple protocols with various agents, including carboplatin, vincristine, etoposide, cisplatin, doxorubicin, cyclophosphamide, and ifosfamide, are presently available. Other combined therapeutic strategies include 13-cis-retinoic acid, local radiation, resection of the periorbital tumor, and autologous hematopoietic stem cell transplantation. However, in case of more aggressive tumors, drug resistance should be resolved in the future. Targeting techniques by infusion of meta-iodobenzylguanidine conjugated to 131I and 125I are also promising for future developments.
The prognosis for children with neuroblastoma is dependent on many factors, such as age at diagnosis, disease stage, and histological grade. Orbital neuroblastoma metastases are commonly associated with poor prognosis. Among the 11 cases with orbital neuroblastoma metastases, systemic chemotherapy was initiated in 6 cases. Although the symptoms improved by follow up after 4 months to 2 years in 4 patients, 2 children died after chemotherapy. Furthermore, although the survival chances for children diagnosed with neuroblastoma have markedly improved over the last 30 years with the advance of multiple treatment modalities, such as chemotherapy, surgery, stem cell transplantation, and immunotherapy, the survival rate for patients with neuroblastoma with orbital metastasis remains low.
Conceptualization: Wan-Ju Yang, Yuan-Yuan Zhou, Shuang Li, Yi Xiang.
Data curation: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao, Zhong-Ming Mei, Shuang Li, Yi Xiang.
Investigation: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao, Zhong-Ming Mei, Shuang Li, Yi Xiang.
Project administration: Wan-Ju Yang, Yuan-Yuan Zhou, Shuang Li, Yi Xiang.
Resources: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao, Zhong-Ming Mei, Shuang Li, Yi Xiang.
Supervision: Wan-Ju Yang, Yuan-Yuan Zhou, Shuang Li, Yi Xiang.
Validation: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao, Zhong-Ming Mei, Shuang Li, Yi Xiang.
Visualization: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao, Zhong-Ming Mei, Shuang Li, Yi Xiang.
Writing – original draft: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao.
Writing – review & editing: Wan-Ju Yang, Yuan-Yuan Zhou, Fang Zhao, Zhong-Ming Mei, Shuang Li, Yi Xiang.
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