Neuroblastoma (NB) is one of the most common malignancies in children. Metastasis in NB is not uncommon. However, nasal metastases are rare. Here, we reported two pediatric cases of nasal metastases.

Case 1 was a 3-year-old boy without a history of NB. Case 2 was a 10-year-old girl who had a history of NB for 6 years. Both of them presented with symptoms of nasal and sinus masses such as epistaxis or discharge from the nose. The radiologic imaging results revealed masses in the nasal cavity or nasopharynx in both cases and a mass in the right adrenal gland of case 1. The pathologic examination of biopsy samples of their nasal masses revealed “small round blue-cell tumor” along with abundant vascular fibrous septa. The tumor cells expressed synaptophysin, cluster of differentiation 56, chromogranin A, paired like homeobox protein 2B and a very high Ki67 index in both case but were negative for vimentin, desmin, leucocyte common antigen and cytokeratin. Myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification was detected in both cases. Finally, the two cases were diagnosed as nasal metastases from NB based on the clinical and pathologic findings. The two patients affected by NB were > 18 mo old, the primary tumor location was adrenal gland, and they presented with multiple metastases.

It is difficult to differentiate between metastatic NB in the nose and olfactory neuroblastoma in the absence of a history of NB. Paired like homeobox protein 2B can play an important role in the diagnosis and differential diagnosis of this disease.

Neuroblastoma (NB) is one of the most common malignancies in children[1], and its incidence is approximately 9.1-10.0 per million children (< 18 years) per year in some Western countries[1-3]. In some studies, approximately 53%-58% of patients have metastasis upon diagnosis[2-4]. However, nasal metastases are rare, and only one case has been reported to date[4,5]. Given that the low incidence and the morphological characteristics and immunohistochemical results of NB overlap with those of other nasal primary tumors such as olfactory neuroblastoma[1,6,7], nasal metastases from NB is prone to be misdiagnosed, particularly when this disease initially presents with a nasal mass without a history of NB. Two cases of nasal metastases from NB were retrospectively analyzed to raise awareness of this disease.

Case 1: The tumor was initially considered as olfactory neuroblastoma, but the final diagnosis was corrected as nasal metastases from NB after abdominal B-ultrasound revealed a big mass in the right adrenal gland and multiple nodules in the liver (Figure 4).

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Figure 4 A schematic diagram of diagnosis procedure. SYN: Synaptophysin; CGA: Chromogranin A; CD56: Cluster of differentiation 56; S100: S-100 protein; CK: Cytokeratin; DES: Desmin; SMA: Smooth muscle actin; LCA: Leucocyte common antigen; CD99: Cluster of differentiation 99; NB: Neuroblastoma.

Case 2: A diagnosis of nasal metastases from NB was quickly pronounced based on the pathologic results and her NB history (Figure 4).

Case 1: The patient underwent a biopsy of the nasal masses. However, after the diagnosis of NB with multiple metastases including nasal metastases was pronounced, the patient refused to receive any treatment because of economic factors.

Case 2: The patient underwent a biopsy of the nasal masses. She received high-dose chemotherapy (temozolomide + irinotecan) in November and December 2017 and radiotherapy (DT39.6Gy/22Fx) in February 2018 after the diagnosis of nasal metastases from NB.

Case 1: The patient died 1 mo after the diagnosis.

Case 2: The patient died 12 mo after the diagnosis.

NB is one of the most common malignancies in children[1], and “the second-most common solid tumor of children”[6]. This tumor seems to occur in any location of the sympathetic nervous system[8]. Therefore, it often presents as a mass in the abdomen, retroperitoneum, pleural cavity or neck causing various symptoms, such as hypertension, abdominal pain or constipation. Among them, the adrenal gland is the most common location because of the abundant sympathetic nerves in the adrenal medulla[8]. Although the imaging and lab exam such as a mass in one adrenal grand, an increase in catecholamine in the urine of patients and metaiodobenzylguanidine uptake on scintigraphy provide some useful data[9], definite diagnosis of NB is mainly dependent on pathological findings[1,6]. The biological behavior of NB is heterogeneous, which presents with spontaneous regression, maturation or aggressive progression[1,6]. According to prognosis and relapse risk, the International Neuroblastoma Staging System classifies NB into the following stages: stage I, stage IIA, stage IIB, stage III, stage IV and stage IV-S. The high-risk group includes patients with stage IV and stage IV-S disease[10].

The high-risk group not only shows a low rate of cure but also has distant metastasis and/or MYCN amplification[10]. The cancer in these patients metastasizes rapidly and spreads extensively. The metastatic locations include lymph nodes, bone marrow, bone, liver, skin/subcutaneous tissue and other locations[1,4]. Among them, the nose is rare[4,5]. Only one case has been reported so far[4,5]. The patients of the case together with our two cases were all > 18 mo old at the initial diagnosis, and the primary tumor location in each case was the adrenal gland (Table 1). The previous case report of nasal metastases from NB did not report immunohistochemical and molecular detection results[5]. However, the two patients in our report displayed MYCN amplification. These characteristics were the same as some of the high-risk factors of NB patients with a poor prognosis, which include age at diagnosis > 18 mo, adrenal gland as the primary location, molecular changes (MYCN amplification, segmental chromosomal alteration and diploidy) and increased lactate dehydrogenase blood levels[10]. Indeed, all three patients died within 2 years after the diagnosis of nasal metastases. Therefore, nasal metastases might be a clinical presentation at the late stage of NB and an indicator of poor prognosis.

With NB history, metastatic NB in the nose is not difficult to be diagnosed. However, if a nasal mass is the first symptom, the diagnosis becomes challenging. Clinical presentations such as nasal congestion and epistaxis are similar to those of nasal primary tumors, such as NK/T cell lymphoma, embryonic rhabdomyosarcoma and olfactory neuroblastoma. In our report, case 1 presented with frequent epistaxis from the right nose and a lymphoma or hemangioma diagnosis was considered in clinics. In general, pathological findings can favor the diagnosis; however, the morphological characteristics and immunohistochemical results of olfactory NB overlap with those of NB[1,7], so differentiating between them in a biopsy sample is difficult if only based on pathological findings. Both of them could form nests and rosette structures with a fibrovascular septa[1,7]. The tumor cells of NB are round and oval with dispersed chromatin, and the nucleoli are not obvious, resembling those of olfactory neuroblastoma[1,7]. Ganglion cells could even be detected in the two tumors[1,7]. In addition, specific immunohistochemical markers for them are lacking. The immunohistochemical results of NB revealed cluster of differentiation 56, synaptophysin and chromogranin A expression, which was also positive in olfactory neuroblastoma. Case 1 in our report was considered as olfactory neuroblastoma before a big mass was detected in the right adrenal gland.

Recently, it was found that paired like homeobox protein 2B (PHOX2B) was a relatively specific immunohistochemical marker of NB[11]. The wild-type PHOX2B gene is an important neurodevelopmental gene[11], and the PHOX2B protein participates in the development of the peripheral nervous system[11]. As a neural crest-derived marker, its expression in the tumors of the autonomic nervous system origin (NB, pheochromocytoma and paraganglioma) has relatively high sensitivity and specificity[12-14]. In NB, PHOX2B has high specificity in primary (96%–98% positive rate) and treated (94% positive rate) NB[9] and can be used to identify small residual and bone marrow metastatic NB lesions (87% positive rate)[9,15]. In our practice, most cases of NB express PHOX2B, whereas olfactory neuroblastoma does not. PHOX2B analysis was performed on the two cases of our report, which was not in the NB immunohistochemistry panel during diagnosis. Both of them were positive for PHOX2B (Figure 5). Therefore, the immunohistochemistry of PHOX2B can help differentiate NB from olfactory neuroblastoma.

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Figure 5 Immunohistochemistry assay of paired like homeobox protein 2B. A: Case 1; B: Case 2. The tumor cells were positive for paired like homeobox protein 2B in both cases. (× 400 magnification).

Nasal metastases from NB are rare. This condition may be a clinical presentation at the late stage of NB. Differentiating it from olfactory neuroblastoma in a biopsy sample is difficult if only based on pathological findings. PHOX2B, a new immunohistochemical marker, is very helpful for accurate diagnosis.