https://doi.org/10.1007/s12105-020-01277-2 CASE REPORTS
Metastatic Neuroblastoma to the Mandible of Children: Report of Two Cases and Critical Review of the Literature
Gleyson Kleber do Amaral‑Silva1
· Amanda Almeida Leite1
· Bruno Augusto Linhares Almeida Mariz1
Fernanda dos Santos Moreira1
· Márcio Ajudarte Lopes1
· Ana Carolina Prado Ribeiro2
· Alan Roger Santos‑Silva1
· André Caroli Rocha3
· Pablo Agustin Vargas1
Received: 24 November 2020 / Accepted: 14 December 2020 / Published online: 4 January 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021
Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the head and neck region is rare. Here, we present two cases of metastatic neuroblastoma of childhood, in which a mandibular swelling was the first sign of disseminated disease. Case 1 describes a 4-year-old boy with a 2-week history of painful swelling in the left mandibular region, body soreness and weakness. Pano- ramic radiography and computed tomography showed a destructive lesion in the left mandibular ramus. Case 2 describes a 3-year-old boy with a 1-month history of swelling in the right mandibular area. Panoramic radiograph and cone-beam computed tomography showed a destructive lesion in the right body and ramus of the mandible, displacing tooth germs, with the destruction of vestibular and lingual bone cortices. In both cases, microscopic analyses revealed a diffuse proliferation of small, round, and blue cells with hyperchromatic nuclei and scant cytoplasm. While Case 1 was more undifferentiated, Case 2 presented eosinophilic areas suggestive of neuropil. A large immunohistochemical panel was performed, showing expression of neural markers such as CD56, neuron-specific enolase (in Case 2), chromogranin, and synaptophysin. Both lesions presented a high proliferation index (Ki67 > 70% and 80%, respectively). Positron emission tomography-computed tomography revealed ipsilateral adrenal primary lesions in both cases, with multiple bone metastatic lesions. Besides the mandible, multiple sites of the axial and appendicular skeleton were affected. Treatment consisted of induction chemotherapy, adrenalectomy, consolidation chemoradiotherapy, and post-consolidation therapy.
Keywords Neuroblastoma · Neoplasm metastasis · Mandible · Pediatrics · Oral diagnosis · Case reports
Neuroblastoma (NB) is a complex heterogeneous neoplasm arising from the sympathetic nervous system, represent- ing 97% of all neuroblastic tumours, including gangli- oneuroblastoma and ganglioneuroma. It is the most com- mon extracranial solid tumour found in children, with an
early onset and high metastatic rates. It is estimated that 700 cases of neuroblastoma are diagnosed every year in the United States alone, normally affecting children less than 5 years old with a mean age at diagnosis of 19 months. NB is responsible for approximately 15% of all pediatric cancer fatalities. This neuroblastic tumour originates from neural crest cell derivates in the sympathetic nervous system. Usu- ally, the primary sites comprise the adrenal gland (46% of cases), extra-adrenal abdominal area (18%), posterior medi- astinum/thorax (14%), pelvis, and other sites (22% together) [1, 2]. Advanced disease usually shows metastases, and bone marrow, cortical bone, liver, and lymph nodes are the sites most often involved . Hence, we report two cases of meta- static neuroblastoma, in which a mandibular swelling was the primary signal, and a critical review of the literature.
* Pablo Agustin Vargas firstname.lastname@example.org
1 Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901, Piracicaba, São Paulo CEP: 13414-903, Brazil
2 Dental Oncology Service, Instituto do Câncer do Estado de São Paulo, ICESP-FMUSP, São Paulo, Brazil
3 Medical School, Clinics Hospital, University of São Paulo, São Paulo, Brazil
A 4-year-old boy was referred from his treating dentist due to a painful swelling in the mandible, with a 2-week history of body soreness and weakness. On extra-oral examination, the patient presented a significant swelling on the left side of the face. Intra-oral evaluation was impaired because of the trismus, but an expansive lesion covered by normal mucosa could be observed in the left retromolar trigone area (Fig. 1a, b). Medical history was otherwise noncontributory.
Panoramic radiography showed a diffuse radiolucent image in the left mandibular ramus extending to the coro- noid process (Fig. 1c). Computed tomography (CT) dis- played the destruction of mandibular cortices associated with hyperdense images, similar to the “sun-ray” pattern (Fig. 1d). With these aspects, the main diagnostic hypoth- eses included osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma, lymphoma, and Langerhans cells histiocytosis.
An incisional biopsy was performed under general anaes- thesia in the left retromolar mucosa. The macroscopic aspect presented a gelatinous compound in the deep conjunctive tissue (Fig. 2a). Microscopic analyses revealed a solid pro- liferation of undifferentiated small round blue cells, with
hyperchromatic nuclei and scant cytoplasm, presenting considerable pleomorphism. An alveolar pattern could be seen in some areas. Necrotic areas were absent (Fig. 2b, c).
Immunohistochemical analysis showed diffuse expression of synaptophysin and chromogranin and a proliferation index of more than 80% of cells positive for Ki67 (Fig. 2d–f). A large immunohistochemical panel was performed to exclude other malignant lesions, as shown in Table 1. These data strongly suggested the diagnosis of neuroblastoma, and the patient was referred to a pediatric oncology centre.
A positron emission tomography–computed tomography (PET-CT) scan revealed an 18-fluorodeoxyglucose-avid left adrenal mass, the presumable primary tumour site, and multiple metastatic sites in the axial and appendicular skel- eton. Additionally, 131-iodine metaiodobenzylguanidine (MIBG) scintigraphy showed MIBG-positive areas in the ilium (Fig. 3a–d), where punch biopsies confirmed neuro- blastoma involvement. Then, the patient was diagnosed with Stage M neuroblastoma (High risk) .
The treatment course consisted of three phases: induc- tion, consolidation and post-consolidation. The induction phase was initiated using six cycles of high-dose chemo- therapy (cisplatin, cyclophosphamide, doxorubicin, dexra- zoxane, etoposide, ondansetron, and vincristine). After the
Fig. 1 Clinical features of metastatic neuroblastoma (Case 1). a Extra-oral presentation with facial asymmetry due to a left mandibu- lar enlargement. b Intra-oral presentation displaying slight mucosal discolouration near the left retromolar trigone. c Panoramic radio-
graphic presenting radiolucent image in the left mandibular ramus.
d Computed tomography evidencing a “sun-ray” pattern in left man- dibular ramus. e 3D tomography reconstruction illustrating the bone destruction in the left mandibular ramus
second chemotherapy cycle, the patient showed a partial response and was submitted to a left adrenalectomy with regional lymphadenectomy. Adrenal tissue showed about 20% of residual poorly differentiated neuroblastoma, with dystrophic calcifications and fibrotic areas. The consolida- tion phase was started with a higher-dose chemotherapy cycle (cyclophosphamide 1407 mg), a myeloablative regi- men using BuMel (busulfan plus melphalan), an autogenous bone marrow transplantation, and 3D radiotherapy in the primary tumour site (20 Gy in 10 cycles of 200 cGy each) and for the residual lesion in the left mandible (30 Gy in 15 cycles of 200 cGy each). At the end of consolidation therapy, no signs of active disease were seen on MIBG or PET-CT. Then, the post-consolidation phase was initiated using 13-cis-retinoic acid therapy (160 mg/m2
/day, 14 days/
month, for 6 months). During the treatment phases, acyclo- vir, fluconazole, and Bactrim®
were used prophylactically.
Almost 2 years after treatment, the patient is in continu- ous follow-up by oncology and oral medicine services, with no evidence of recurrence.
A 3-year-old boy was referred to our oral diagnosis clinic, with a recent history of rapid swelling in the right mandible area, present for about 1 month. Medical history was other- wise unremarkable. Extraoral examination revealed facial asymmetry due to extensive swelling in the right mandibular body region, extending below the inferior border of the man- dible (Fig. 4a). Intraoral examination showed a prominent vestibular swelling in the right mandibular region, firm to palpation, with a slightly reddish colouration around the cus- pid of an unerupted permanent molar (Fig. 4b). Panoramic radiograph showed a poorly defined radiolucency affecting the right body and ramus of the mandible, displacing the tooth germs of the first and second permanent lower right
Fig. 2 Macroscopic and micro- scopic features of metastatic neuroblastoma (Case 1). a Macroscopic view after the incisional biopsy, showing a submucous lesion present- ing a pale gelatinous aspect.
b Mucosal fragment lined by squamous epithelium, present- ing a solid proliferation of hyperchromatic cells in the deep connective tissue (HE, orig.
mag.: 4×). c Diffuse prolifera- tion of pleomorphic small round blue cells (HE, orig. mag.:
200×). d Strong and diffuse immunohistochemical positivity for chromogranin (DAB, orig.
mag.: 200×). e Focal immuno- histochemical positivity for syn- aptophysin (DAB, orig. mag.:
200×). f Ki67 positivity in more than 80% of the neoplastic cells (DAB, orig. mag.: 200×)
molars (Fig. 4c). Cone-beam computed tomography (CBCT) revealed a hypodense image in the same mandibular area, with the destruction of vestibular and lingual bone cortices (Fig. 4d, e).
An intraoral incisional biopsy was performed under gen- eral anaesthesia, which revealed a diffuse proliferation of small round blue hyperchromatic cells, separated by fibrous septa. Groups of pleomorphic neoplastic cells in a loosely eosinophilic material (neuropil) were characteristic. Mitotic figures and necrotic areas were frequent (Fig. 5a–c). Immu- nohistochemical analysis showed diffuse expression of CD56
(NCAM), NSE, and with less intensity, chromogranin and synaptophysin, and a proliferation index of more than 70%
of cells positive for Ki67 (Fig. 5d, f and Table 1). A diag- nosis of neuroblastoma (probably metastatic) was rendered, and the patient was referred to a pediatric oncology service.
PET-CT showed an anomalous concentration of [18F]- fluorodeoxyglucose (FDG) in the following areas: right cer- vical region (multiple lymphadenopathies, some coalescent), abdominal region (primary lesion in the right adrenal gland), and osseous system (expansive lesion in the right mandible, and multiple medullar lesions in the axial and appendicular
Table 1 Immunohistochemical reactions performed in the current two cases of metastatic neuroblastoma
LCA leukocyte common antigen, NCAM neural cell adhesion molecule, NP not performed, NSE neuron- specific enolase, TdT terminal deoxynucleotidyl transferase
Antibody Clone Manufacturer Dilution Result
Case 1 Case 2
Ki67 Mouse monoclonal MIB-1 DAKO 1:100 > 80% > 70%
CD56 (NCAM) Mouse monoclonal 1B6 Novocastra 1:50 Positive Positive
NSE Mouse monoclonal BBS/NC/VI-H14 DAKO 1:800 Positive Positive
Chromogranin Mouse monoclonal DAK-A3 DAKO 1:800 Positive Positive
Synaptophysin Mouse monoclonal SY38 DAKO 1:100 Positive Positive
S100 Mouse polyclonal DAKO 1:10,000 Negative Negative
AE1AE3 Mouse monoclonal AE1/AE3 DAKO 1:300 Negative Negative
Desmin Mouse monoclonal D33 DAKO 1:500 Negative Negative
Myogenin Mouse monoclonal F5D DAKO 1:800 NP Negative
Myo-D1 Mouse monoclonal 5.8 A DAKO 1:300 Negative NP
CD45 (LCA) Mouse monoclonal 2B11+PD7/26 DAKO 1:200 Negative Negative
CD20 Mouse monoclonal L 26(1,2) DAKO 1:300 Negative Negative
CD3 Mouse polyclonal DAKO 1:300 Negative Negative
CD10 Mouse monoclonal 56C6 DAKO 1:100 NP Negative
TdT Rabbit polyclonal DAKO 1:50 NP Negative
CD99 Mouse monoclonal 12E7 DAKO 1:100 Negative Negative
Fli1 Rabbit polyclonal Santa Cruz 1:100 Negative Negative
Fig. 3 Positron emission tomography-computed tomography (PET- CT) aspects of metastatic neuroblastoma (Case 1). a PET-CT using 18-fluorodeoxyglucose shows multiple bone metastases in multi- ple sites (black arrowheads). b, c Neuroblastoma primary lesion is
located in the left adrenal gland (yellow arrowheads), along with sev- eral metastatic lesions in the vertebral column (C). d Bilateral man- dibular metastatic lesions
skeleton), as shown in Fig. 6a–h. A punch biopsy in the left iliac crest confirmed neuroblastoma involvement. Then, the patient was diagnosed with Stage M neuroblastoma (High risk) . In this case, the patient did not submit to any surgi- cal procedure but received a similar chemotherapy protocol as was used with the Case 1 patient. After 6 months of treat- ment, the mandibular lesion presented significant improve- ment, with bone formation and maintenance of teeth germs (Fig. 7).
About 65% of the neuroblastomas occur in the abdo- men, typically showing an abdominal mass that may be palpable and painful. However, the symptoms depend on the primary tumour size and metastatic sites, which can cause compression and invasion of vital structures. Weight loss, fever, and fatigue usually indicate advanced disease and bone marrow involvement [1, 2]. Metastases to the head and neck are rare, showing in less than 1% of all cancers that affect this site in pediatric patients , and the mandible-maxilla ratio corresponds to 6.25:1. When
the mandible is affected, the tumour presents as a rapidly enlarging mass with bone destruction, tooth mobility or displacement, and colour alteration of the oral mucosa .
Additionally, radiographic images present a poorly defined and destructive radiolucent lesion, sometimes demonstrat- ing the “sun-ray” pattern that mimics osteosarcoma fea- tures . Only 17 cases of metastatic neuroblastoma to the mandible were described in the English language in the PubMed database in the last 39 years (Table 2). Of these cases, 12 were male (mean age 37.5 months, rang- ing from 8 to 84 months) and five females (mean age 83.2 months, ranging from 20 to 180 months) [5–21]. Usually, the adrenal glands represented the primary tumour site [5, 8–10, 12, 14–16, 21]. Moreover, two cases of abdominal neuroblastoma with metastatic component differentiated in ganglioneuroblastoma to the mandible were reported [22, 23] (not included in the Table 2).
The neuroblastoma diagnosis confirmation is made under the histological analysis of the incisional biopsy, the vanil- lylmandelic and homovanillic acids levels in the serum and urine (not specific to the diagnosis, although 75% of neuro- blastoma cases show high levels; these tests were not per- formed in these cases), bone marrow aspirate biopsies (to
Fig. 4 Clinical features of metastatic neuroblastoma (Case 2). a Extra-oral presentation showing facial asymmetry with a right man- dibular swelling. b Intra-oral presentation showing prominent ves- tibular swelling in the right mandibular region. c Panoramic radio- graphic showing a poorly-defined radiolucency affecting the right
body and ramus of the mandible, displacing the tooth germs of the first and second permanent lower right molars. d, e Cone beam com- puted tomography revealed a hypodense image in the right mandibu- lar body, with the destruction of vestibular and lingual bone cortices
assess the marrow involvement) , and image exams like 18-fluorodeoxyglucose PET/CT and MIBG scintigraphy (the exam with high specificity) .
The International Neuroblastoma Risk Group staging sys- tem (INRGSS, 2005) is the newest risk classification system that uses pretreatment criteria and is superior to the Inter- national Neuroblastoma staging system (INSS, 1986) .
In the INRGSS, neuroblastoma is classified into four stages (L1, L2, M, or MS) combined with four pretreatment risk groups (Very Low, Low, Intermediate, or High), totalling 16 classification subsets. The INRGSS classification takes into account the metastatic disease occurrence, patient age, image-defined risk factors (IDRF, Table 3), histologic cat- egory, tumour differentiation grade, MYCN amplification,
presence/absence of 11q aberrations, and tumour cell ploidy.
Because both patients described above presented distant metastatic disease and were older than 18 months, they were automatically diagnosed as Stage M neuroblastoma (High risk), according to INRGSS (Table 4) [3, 26]. At least 13 of the 17 cases (76.5%) reported in Table 2 could also be clas- sified similarly to our cases, while 4 of the 17 cases (23.5%) represent Stage MS neuroblastoma (Very Low or High risk, depending on the existence of an MYCN amplification or an 11q aberration), according to the INRGSS classification.
The neuroblastoma treatment and prognosis are variable, depending on the risk classification and tumour features.
Some specific cases can show spontaneous disease regres- sion, permitting expectant observation during a 90-week
Fig. 5 Microscopic features of metastatic neuroblastoma (Case 2). a Lobular prolifera- tion of hyperchromatic cells, separated by hyalinized fibrous stroma (HE, orig. mag.: 25×). b Uniform small round blue cells with scant cytoplasm present- ing in some areas as single-line cords (HE, orig. mag.: 200×).
c Clusters of neuroblasts in a background of eosinophilic neuropil (HE, orig. mag.:
400×). d Strong and diffuse immunohistochemical positivity for CD56 (DAB, orig. mag.:
200×) and (e) neuron-specific enolase (DAB, orig. mag.:
200×). f Ki67 positivity in more than 70% of the neoplastic cells (DAB, orig. mag.: 200×)
interval. On the other hand, patients with non-High-risk tumours, Stage L1, or Stage MS show a favourable prog- nosis, needing minimal therapy (surgery with or without
chemotherapy). The remaining High-risk tumour patients (Stage L2 and M), as the two current patients, have a poor prognosis, with 5-year overall survival below 50%. For these cases, current treatment regimens include induction chemotherapy, surgery, radiotherapy, consolidation therapy with myeloablative chemotherapy, and autologous stem cell rescue [2, 27].
In summary, we have reported two additional challenging cases of metastatic neuroblastoma, in which the mandibu- lar lesion led to the diagnosis of advanced disease. In both cases, a rapid and effective interaction between oral medi- cine, oral pathology, and oncology services was paramount to managing these patients and boosting their chance of survival.
Fig. 6 Positron emission tomography-computed tomography (PET- CT) aspects of metastatic neuroblastoma (Case 1). a PET-CT using 18-fluorodeoxyglucose shows multiple areas affected by neuroblas- toma (white arrows). b–d Multiple coalescent lymphadenopathies in
the right cervical region, with an expansive lesion in the right mandi- ble (C). e Neuroblastoma primary lesion is located in the right adre- nal gland. f–h Multiple bone metastases were found in the upper and lower limbs
Fig. 7 Panoramic radiographic (Case 2) after 6 months of treatment, showing bone formation and maintenance of tooth germs in the right mandibular area
Table 2 Cases of neuroblastoma presenting with metastasis to the mandible CaseCase reportSexAgeSigns and symptomsPrimary tumour siteTreatmentFollow-Up 1Reich et al., Female13 yearsRecurrence of neuroblastoma with right mandibular paraes- thesia
Left adrenal glandChemotherapy and radiotherapyDied after 1 month 2Borler et al., Male02 yearsLeft mandibular swelling–Chemotherapy and radiotherapyDied after 3 weeks 3Chan et al., Female02 yearsPain associated with a left man- dibular swelling–Chemotherapy and radiotherapy18 months in remission 4Ogunsalu and Smith Male02 yearsLeft mandibular swellingLeft adrenal glandChemotherapy and radiotherapyDied after 43 weeks 5Pellegrino and Berardi Male06 yearsLeft mandibular swellingLeft adrenal glandAdrenalectomy, chemotherapy and local radiotherapy2 years in remission 6Otmani and Khattab Male03 yearsGeneralized bone pain and swelling of the left mandibleLeft adrenal glandPalliative chemotherapyDied after 4 weeks 7Baber et al., Female15 yearsLeft preauricular swelling and pain–Chemotherapy– 8Parker et al., Male08 monthsMandible mass, intraoral bruising, tooth loosening, and progressive weight loss
Right adrenal glandChemotherapy and adrenalec- tomy2 years in remission 9Kürklü et al., Male01 yearsIrritability and abdominal massRight adrenal glandChemotherapyDied after 43 weeks 10Udall and Cho, 2011 Male10 monthsMass in the right mandibular ramus–Chemotherapy– 11Manor et al., Male07 yearsMass in the left mandible and tooth loosening and displace- ment
Left adrenal glandChemotherapy and adrenalec- tomy– 12Dwojak et al., Male03 yearsFacial swelling and ear and jaw pain––– 13Eley et al., Male02 yearsSwelling in the right mandible and right retromolar region–Chemotherapy, autologous hematopoietic stem cell transplantation and surgical resection of the right hemi- mandible
9 months in remission 14Piccardo et al., Male06 yearsRecurrence of neuroblastoma in the right mandibular branch–Radioiodine therapy– 15Mittal et al., Female03 yearsSwelling in the right mandible and loosening of teeth, fever, anorexia and weight loss
Right adrenal glandChemotherapyDied after 6 weeks 16Wade et al., Male11 monthsMass in the ramus of the right mandibleLeft adrenal glandChemotherapy6 months in remission 17Waldron et al., Female20 monthsSwelling in the right mandible, discomfort and changes in gait and a palpable mass in the abdomen
Left adrenal glandChemotherapy, radiotherapy and immunotherapy with monoclonal antibodies
6 months in remission
Table 2 (continued) CaseCase reportSexAgeSigns and symptomsPrimary tumour siteTreatmentFollow-Up 18 and 19Current cases reportsMale4 years
(Case 1) 3 years (Case 2)
Painful swelling in the left mandibular region, soreness, and weakness (Case 1) Swelling in the right mandibu- lar region with tooth germ displacement (Case 2)
Left adrenal gland (Case 1). Right adrenal gland (Case 2)Chemotherapy, autologous hematopoietic stem cell transplantation, adrenalec- tomy (except Case 2), and radiotherapy
18 months in remission (Case 1) Under treatment (Case 2)
Table 3 Image-defined risk factors (IDRF) in neuroblastic tumours 
Ipsilateral tumour extension within two body compartments Neck-chest
Chest-abdomen Abdomen-pelvis Neck
Tumour encasing carotid and/or vertebral artery and/or internal jugular vein Tumour extending to the base of the skull
Tumour compressing the trachea Cervico-thoracic junction
Tumour encasing brachial plexus roots
Tumour encasing subclavian vessels and/or vertebral and/or carotid artery Tumour compressing the trachea
Tumour encasing the aorta and/or major branches Tumour compressing the trachea and/or principal bronchi
Lower mediastinal tumour, infiltrating the costovertebral junction between T9 and T12 Thoraco-abdominal
Tumour encasing the aorta and/or vena cava Abdomen/pelvis
Tumour infiltrating the porta hepatis and/or the hepatoduodenal ligament Tumour encasing branches of the superior mesenteric artery at the mesenteric root Tumour encasing the origin of the coeliac axis and/or of the superior mesenteric artery Tumour invading one or both renal pedicles
Tumour encasing the aorta and/or vena cava Tumour encasing the iliac vessels
Pelvic tumour crossing the sciatic notch
Intraspinal tumour extension whatever the location provided
More than one-third of the spinal canal in the axial plane is invaded, and/or the perimedullary leptome- ningeal spaces are not visible, and/or the spinal cord signal is abnormal
Infiltration of adjacent organs/structures
Pericardium, diaphragm, kidney, liver, duodenum-pancreatic block, and mesentery Conditions to be recorded, but not considered IDRFs
Multifocal primary tumours
Pleural effusion, with or without malignant cells Ascites, with or without malignant cells
Funding This work was supported in part by the Coordenação de Aper- feiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001, and Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/08995-2).
Compliance with ethical standards
Conflict of interest The author declares that hey have no conflict of interest to disclose.
1. Swift CC, Eklund MJ, Kraveka JM, Alazraki AL. Updates in diag- nosis, management, and treatment of neuroblastoma. Radiograph- ics. 2018;38:566–80.
2. Newman EA, Abdessalam S, Aldrink JH, Austin M, Heaton TE, Bruny J, et al. Update on neuroblastoma. J Pediatr Surg . Elsevier Inc; 2019;54:383–9.
3. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, et al. The international neuroblastoma risk group (INRG) staging system: an inrg task force report. J Clin Oncol.
4. Arboleda LPA, Hoffmann IL, Cardinalli IA, Santos-Silva AR, de Mendonça RMH. Demographic and clinicopathologic distribution of head and neck malignant tumors in pediatric patients from a Brazilian population: a retrospective study. J Oral Pathol Med.
5. Manor E, Kapelushnik J, Joshua B-Z, Bodner L. Metastatic neu- roblastoma of the mandible: a cytogenetic and molecular genetic study. Eur Arch Otorhinolaryngol. 2012;269:1967–71.
6. Eley KA, Wheeler K, Tiam RN, Watt-Smith SR. An unusual man- dibular mass in a child. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:386–91.
7. Baber MA, Abubaker O, Laskin DM. Metastatic neuroblastoma in the mandibular condyle: report of a case. J Oral Maxillofac Surg.
8. Otmani N, Khattab M. Metastatic neuroblastoma to the mandible in a 3-year-old boy: a case report. Med Oral Patol Oral Cir Bucal.
9. Pellegrino SV, Berardi TR. Expansile mandibular lesion in a child. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
10. Ogunsalu C, Smith NJ. Metastatic neuroblastoma of the mandible mimicking osteogenic sarcoma radiologically. Case report Aust Dent J. 1999;44:207–10.
Table 4 International neuroblastoma risk group staging system (INRGSS) classification for neuroblastic diseases stage and risk group [3, 26]
GNm ganglioneuroma maturing, GNBint ganglioneuroblastoma intermixed, GNBnod ganglioneuroblastoma nodular, NB neuroblastoma, diff. dif- ferentiated, Undiff. undifferentiated
L1 Localized tumour not involving vital structures as defined by the list of IDRFs and confined to one body compartment L2 Locoregional tumour with the presence of one or more IDRFs
M Distant metastatic disease (except Stage MS)
MS Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow Stage Age (months) Histologic category Grade of tumour dif-
11q aberration Ploidy Pretreatment risk group
L1/L2 Any GNm and GNBint Any Any Any Any Very low
L1 Any Any, except GNm or
GNBint Any No Any Any Very low
Yes Any Any High
L2 < 18 Any, except GNm or
GNBint Any No No Any Low
Yes Any Intermediate
≥ 18 GNBnod and NB Differentiating No No Any Low
Yes Any Intermediate
Poorly diff. or Undiff. No Any Any
Any Yes Any Any High
M < 18 Any Any No Any Hyperdiploid Low
< 12 Any Any No Any Diploid Intermediate
12 to < 18 Any Any No Any Diploid Intermediate
<18 Any Any Yes Any Any High
≥ 18 Any Any Any Any Any High
MS < 18 Any Any No No Any Very low
Yes Any High
Yes Any Any High
11. Chan AR, Johnston DH, Stoneman D. Disseminated neuroblas- toma with initial presentation as an intraoral mass: case report.
Pediatr Dent. 1994;16:310–3.
12. Reich DR, Croll TP, Serota FT, Powers J. Neuroblastoma with mandibular metastasis: a case report. Pediatr Dent.
13. Borle RM, Hazare VK, Bhowate RR, Borle SR. Neuroblas- toma metastatic to the mandible. J Oral Maxillofac Surg.
14. Waldron MA, Halpern SL, Sikorskyj T, Mazzola CA. Stage IV neuroblastoma with metastatic spread to the mandible in a young child: case report and review of the literature. World Neurosurg.
15. Wade G, Revels J, Hartman L, Brown W. Pediatric mandibular metastasis: a rare finding of neuroblastoma. Radiol case Rep.
16. Mittal D, Mandelia A, Bajpai M, Agarwala S. Adrenal neuroblas- toma with metastatic mandibular mass: an unusual presentation. J Cancer Res Ther. 2015;11:645.
17. Piccardo A, Lopci E, Conte M, Cabria M, Cistaro A, Garaventa A, et al. Bone and lymph node metastases from neuroblastoma detected by 18F-DOPA-PET/CT and confirmed by posttherapy 131I-MIBG but negative on diagnostic 123I-MIBG scan. Clin Nucl Med. 2014;39:e80-3.
18. Dwojak SM, Hunt JL, Cunningham MJ. Pathology quiz case 3.
Neuroblastoma with cervical metastases. Arch Otolaryngol Head Neck Surg. 2012;138:99–101.
19. Udall D, Cho SY. Congenital agenesis of right parotid gland con- founds MIBG scan interpretation in craniocervical neuroblastoma.
Clin Nucl Med. 2011;36:e162-4.
20. Kürklü E, Emiroğlu HH, Kebudi R, Ozdaş DO, Ayan I, Görgün O, et al. Metastatic mandibular neuroblastoma: a rare cause of tooth mobility. J Clin Pediatr Dent. 2011;36:203–6.
21. Parker CA, Liess BD, Gov-Ari E, Sramek BW. Metastatic neuro- blastoma to the mandible: an unusual presentation. Am J Otolar- yngol. 2011;32:438–40.
22. Bhattacharyya I, Williamson A, Cohen DM, Bever JL. Metastatic neuroblastoma with ganglioneuromatous differentiation and man- dibular involvement. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol. 1999;88:586–92.
23. Patterson AR, Barker CS, Loukota RA, Spencer J. Ganglioneu- roma of the mandible resulting from metastasis of neuroblastoma.
Int J Oral Maxillofac Surg. 2009;38:196–8.
24. Xia J, Zhang H, Hu Q, You LS, Qing ZL, Zhang A, et al. Compari- son of diagnosing and staging accuracy of PET (CT) and MIBG on patients with neuroblastoma: Systemic review and meta-anal- ysis. J Huazhong Univ Sci Technol Med Sci. 2017;37:649–60.
25. Sokol E, Desai A. The evolution of risk classification for neuro- blastoma. Children. 2019;6:27.
26. Cohn SL, Pearson ADJ, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The international neuroblastoma risk group (INRG) classification system: an INRG task force report. J Clin Oncol. 2009;27:289–97.
27. Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high- risk neuroblastoma (HR-NBL1/SIOPEN): an international, ran- domised, multi-arm, open-label, phase 3 trial. Lancet Oncol.
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.