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医療専門家向け Childhood Esthesioneuroblastoma Treatment (PDQ®)

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood esthesioneuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Incidence

Esthesioneuroblastoma (also termed olfactory neuroblastoma) is a small round cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[ 1 ][ 2 ][ 3 ][ 4 ] In children, esthesioneuroblastoma is a very rare malignancy, with an estimated incidence of 0.1 cases per 100,000 per year in children younger than 15 years.[ 5 ]

Despite its rarity, esthesioneuroblastoma is the most common cancer of the nasal cavity in pediatric patients, accounting for 28% of cases in a Surveillance, Epidemiology, and End Results (SEER) study.[ 6 ] In a series of 511 patients from the SEER database, there was a slight male predominance, the mean age at presentation was 53 years, and only 8% of cases were younger than 25 years.[ 7 ] Most patients were white (81%) and the most common tumor sites were the nasal cavity (72%) and ethmoid sinus (13%).[ 7 ] In a retrospective, multi-institutional review of 24 pediatric patients with esthesioneuroblastoma, the median age at presentation was 14 years and 75% of patients were female.[ 8 ]

参考文献
  1. Kumar M, Fallon RJ, Hill JS, et al.: Esthesioneuroblastoma in children. J Pediatr Hematol Oncol 24 (6): 482-7, 2002 Aug-Sep.[PUBMED Abstract]
  2. Theilgaard SA, Buchwald C, Ingeholm P, et al.: Esthesioneuroblastoma: a Danish demographic study of 40 patients registered between 1978 and 2000. Acta Otolaryngol 123 (3): 433-9, 2003.[PUBMED Abstract]
  3. Dias FL, Sa GM, Lima RA, et al.: Patterns of failure and outcome in esthesioneuroblastoma. Arch Otolaryngol Head Neck Surg 129 (11): 1186-92, 2003.[PUBMED Abstract]
  4. Nakao K, Watanabe K, Fujishiro Y, et al.: Olfactory neuroblastoma: long-term clinical outcome at a single institute between 1979 and 2003. Acta Otolaryngol Suppl (559): 113-7, 2007.[PUBMED Abstract]
  5. Bisogno G, Soloni P, Conte M, et al.: Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees. BMC Cancer 12: 117, 2012.[PUBMED Abstract]
  6. Benoit MM, Bhattacharyya N, Faquin W, et al.: Cancer of the nasal cavity in the pediatric population. Pediatrics 121 (1): e141-5, 2008.[PUBMED Abstract]
  7. Soler ZM, Smith TL: Endoscopic versus open craniofacial resection of esthesioneuroblastoma: what is the evidence? Laryngoscope 122 (2): 244-5, 2012.[PUBMED Abstract]
  8. Venkatramani R, Pan H, Furman WL, et al.: Multimodality Treatment of Pediatric Esthesioneuroblastoma. Pediatr Blood Cancer 63 (3): 465-70, 2016.[PUBMED Abstract]
Histology and Molecular Features

Esthesioneuroblastoma can be histologically confused with other small round cell tumors of the nasal cavity, including sinonasal undifferentiated carcinoma, small cell carcinoma, melanoma, and rhabdomyosarcoma. Esthesioneuroblastoma typically shows diffuse staining with neuron-specific enolase, synaptophysin, and chromogranins, with variable cytokeratin expression.[ 1 ]

Sixty-six samples of olfactory neuroblastoma and tumor samples from other cancers, including alveolar rhabdomyosarcoma and sinonasal adenocarcinoma, were obtained from nine medical centers and analyzed by genome-wide DNA methylation profiling, copy number analysis, immunohistochemistry, and next-generation panel sequencing. Unsupervised hierarchal clustering analysis of DNA methylation data identified the following four distinct clusters:[ 2 ]

Using this information, the authors developed an algorithm that incorporates methylation analysis to improve the diagnostic accuracy of this entity.[ 2 ]

参考文献
  1. Su SY, Bell D, Hanna EY: Esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma: differentiation in diagnosis and treatment. Int Arch Otorhinolaryngol 18 (Suppl 2): S149-56, 2014.[PUBMED Abstract]
  2. Capper D, Engel NW, Stichel D, et al.: DNA methylation-based reclassification of olfactory neuroblastoma. Acta Neuropathol 136 (2): 255-271, 2018.[PUBMED Abstract]
Clinical Presentation

Most children present in the second decade of life with symptoms that include the following:

Prognostic Factors

Review of multiple case series of mainly adult patients indicate that the following may correlate with adverse prognosis:[ 1 ][ 2 ][ 3 ]

参考文献
  1. Dulguerov P, Allal AS, Calcaterra TC: Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol 2 (11): 683-90, 2001.[PUBMED Abstract]
  2. Patel SG, Singh B, Stambuk HE, et al.: Craniofacial surgery for esthesioneuroblastoma: report of an international collaborative study. J Neurol Surg B Skull Base 73 (3): 208-20, 2012.[PUBMED Abstract]
  3. Herr MW, Sethi RK, Meier JC, et al.: Esthesioneuroblastoma: an update on the massachusetts eye and ear infirmary and massachusetts general hospital experience with craniofacial resection, proton beam radiation, and chemotherapy. J Neurol Surg B Skull Base 75 (1): 58-64, 2014.[PUBMED Abstract]
Stage Information for Childhood Esthesioneuroblastoma

Tumors are staged according to the Kadish system (refer to Table 1). Correlated with Kadish stage, survival ranges from 90% (stage A) to less than 40% (stage D). Most patients present with locally advanced–stage disease (Kadish stages B and C) and almost one-third of patients have tumors at distant sites (Kadish stage D).[ 1 ][ 2 ][ 3 ]

Recent reports suggest that positron emission tomography–computed tomography (PET-CT) may aid in staging the disease.[ 4 ]

Table 1. Kadish Staging System
Stage Description
A Tumor confined to the nasal cavity.
B Tumor extending to the nasal sinuses.
C Tumor extending to the nasal sinuses and beyond.
D Tumor metastases present.
参考文献
  1. Bisogno G, Soloni P, Conte M, et al.: Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees. BMC Cancer 12: 117, 2012.[PUBMED Abstract]
  2. Benoit MM, Bhattacharyya N, Faquin W, et al.: Cancer of the nasal cavity in the pediatric population. Pediatrics 121 (1): e141-5, 2008.[PUBMED Abstract]
  3. Venkatramani R, Pan H, Furman WL, et al.: Multimodality Treatment of Pediatric Esthesioneuroblastoma. Pediatr Blood Cancer 63 (3): 465-70, 2016.[PUBMED Abstract]
  4. Broski SM, Hunt CH, Johnson GB, et al.: The added value of 18F-FDG PET/CT for evaluation of patients with esthesioneuroblastoma. J Nucl Med 53 (8): 1200-6, 2012.[PUBMED Abstract]
Treatment and Outcome of Childhood Esthesioneuroblastoma

The use of multimodal therapy optimizes the chances for survival, with more than 70% of children expected to survive 5 or more years after initial diagnosis.[ 1 ][ 2 ][ 3 ] A multi-institutional review of 24 patients younger than 21 years at diagnosis found a 5-year disease-free survival and overall survival of 73% to 74%.[ 4 ][Level of evidence: 3iiiA] The French very rare tumors group registry identified 18 patients younger than 18 years with esthesioneuroblastoma from 1990 to 2015. After a median follow-up of survivors of 7.6 years (range, 3.8–17.9 years), ten patients developed neuromeningeal progression, whereas no cervical nodal relapses occurred. Only eight patients survived.[ 5 ][Level of evidence: 3iA]

Treatment options according to Kadish stage include the following:[ 6 ]

  1. Kadish stage A: Surgery alone with clear margins. Adjuvant radiation therapy is indicated in patients with close and positive margins or with residual disease.
  2. Kadish stage B: Surgery followed by adjuvant radiation therapy. The role of adjuvant chemotherapy is controversial.
  3. Kadish stage C: Neoadjuvant approach with chemotherapy, radiation therapy, or concurrent chemotherapy-radiation therapy followed by surgery.
  4. Kadish stage D: Systemic chemotherapy and radiation therapy to local and metastatic sites.

The mainstay of treatment is surgery and radiation.[ 7 ] Newer techniques such as endoscopic sinus surgery may offer similar short-term outcomes to open craniofacial resection.[ 8 ]; [ 9 ][Level of evidence: 3iiiDii] Other techniques such as stereotactic radiosurgery and proton-beam therapy (charged-particle radiation therapy) may also play a role in the management of this tumor.[ 3 ][ 10 ]

Nodal metastases are seen in about 5% of patients. Routine neck dissection and nodal exploration are not indicated in the absence of clinical or radiological evidence of disease.[ 11 ] Management of cervical lymph node metastases has been addressed in a review article.[ 11 ]

Reports indicate promising results with the increased use of resection and neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease.[ 2 ][ 4 ][ 12 ][ 13 ][ 14 ]; [ 15 ][Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include cisplatin and etoposide with or without ifosfamide;[ 6 ][ 16 ] vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin; ifosfamide and etoposide; cisplatin plus etoposide or doxorubicin;[ 2 ] vincristine, doxorubicin, and cyclophosphamide;[ 17 ] and irinotecan plus docetaxel.[ 18 ][Level of evidence: 3iiA]

参考文献
  1. Bisogno G, Soloni P, Conte M, et al.: Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees. BMC Cancer 12: 117, 2012.[PUBMED Abstract]
  2. Eich HT, Müller RP, Micke O, et al.: Esthesioneuroblastoma in childhood and adolescence. Better prognosis with multimodal treatment? Strahlenther Onkol 181 (6): 378-84, 2005.[PUBMED Abstract]
  3. Lucas JT, Ladra MM, MacDonald SM, et al.: Proton therapy for pediatric and adolescent esthesioneuroblastoma. Pediatr Blood Cancer 62 (9): 1523-8, 2015.[PUBMED Abstract]
  4. Venkatramani R, Pan H, Furman WL, et al.: Multimodality Treatment of Pediatric Esthesioneuroblastoma. Pediatr Blood Cancer 63 (3): 465-70, 2016.[PUBMED Abstract]
  5. Dumont B, Fresneau B, Claude L, et al.: Pattern of loco-regional relapses and treatment in pediatric esthesioneuroblastoma: The French very rare tumors group (Fracture) contribution. Pediatr Blood Cancer 67 (4): e28154, 2020.[PUBMED Abstract]
  6. Kumar R: Esthesioneuroblastoma: Multimodal management and review of literature. World J Clin Cases 3 (9): 774-8, 2015.[PUBMED Abstract]
  7. Ozsahin M, Gruber G, Olszyk O, et al.: Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study. Int J Radiat Oncol Biol Phys 78 (4): 992-7, 2010.[PUBMED Abstract]
  8. Soler ZM, Smith TL: Endoscopic versus open craniofacial resection of esthesioneuroblastoma: what is the evidence? Laryngoscope 122 (2): 244-5, 2012.[PUBMED Abstract]
  9. Gallia GL, Reh DD, Lane AP, et al.: Endoscopic resection of esthesioneuroblastoma. J Clin Neurosci 19 (11): 1478-82, 2012.[PUBMED Abstract]
  10. Unger F, Haselsberger K, Walch C, et al.: Combined endoscopic surgery and radiosurgery as treatment modality for olfactory neuroblastoma (esthesioneuroblastoma). Acta Neurochir (Wien) 147 (6): 595-601; discussion 601-2, 2005.[PUBMED Abstract]
  11. Zanation AM, Ferlito A, Rinaldo A, et al.: When, how and why to treat the neck in patients with esthesioneuroblastoma: a review. Eur Arch Otorhinolaryngol 267 (11): 1667-71, 2010.[PUBMED Abstract]
  12. Kumar M, Fallon RJ, Hill JS, et al.: Esthesioneuroblastoma in children. J Pediatr Hematol Oncol 24 (6): 482-7, 2002 Aug-Sep.[PUBMED Abstract]
  13. Loy AH, Reibel JF, Read PW, et al.: Esthesioneuroblastoma: continued follow-up of a single institution's experience. Arch Otolaryngol Head Neck Surg 132 (2): 134-8, 2006.[PUBMED Abstract]
  14. Porter AB, Bernold DM, Giannini C, et al.: Retrospective review of adjuvant chemotherapy for esthesioneuroblastoma. J Neurooncol 90 (2): 201-4, 2008.[PUBMED Abstract]
  15. Benfari G, Fusconi M, Ciofalo A, et al.: Radiotherapy alone for local tumour control in esthesioneuroblastoma. Acta Otorhinolaryngol Ital 28 (6): 292-7, 2008.[PUBMED Abstract]
  16. Kim DW, Jo YH, Kim JH, et al.: Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Cancer 101 (10): 2257-60, 2004.[PUBMED Abstract]
  17. El Kababri M, Habrand JL, Valteau-Couanet D, et al.: Esthesioneuroblastoma in children and adolescent: experience on 11 cases with literature review. J Pediatr Hematol Oncol 36 (2): 91-5, 2014.[PUBMED Abstract]
  18. Kiyota N, Tahara M, Fujii S, et al.: Nonplatinum-based chemotherapy with irinotecan plus docetaxel for advanced or metastatic olfactory neuroblastoma: a retrospective analysis of 12 cases. Cancer 112 (4): 885-91, 2008.[PUBMED Abstract]
Treatment Options Under Clinical Evaluation for Childhood Esthesioneuroblastoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[ 1 ] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[ 2 ] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[ 3 ] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[ 4 ] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. Adult rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people, and they are estimated to account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[ 5 ][ 6 ] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

These rare cancers are extremely challenging to study because of the low incidence of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.

参考文献
  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.[PUBMED Abstract]
  2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.[PUBMED Abstract]
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.[PUBMED Abstract]
  4. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.[PUBMED Abstract]
  5. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.[PUBMED Abstract]
  6. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.[PUBMED Abstract]
  7. Ferrari A, Bisogno G, De Salvo GL, et al.: The challenge of very rare tumours in childhood: the Italian TREP project. Eur J Cancer 43 (4): 654-9, 2007.[PUBMED Abstract]
  8. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.[PUBMED Abstract]
  9. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. Bethesda, Md: National Cancer Institute, 2015. Also available online. Last accessed February 20, 2020.[PUBMED Abstract]
Changes to This Summary (06/08/2020)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment and Outcome of Childhood Esthesioneuroblastoma

Added text to state that the French very rare tumors group registry identified 18 patients younger than 18 years with esthesioneuroblastoma from 1990 to 2015. After a median follow-up of survivors of 7.6 years, ten patients developed neuromeningeal progression, whereas no cervical nodal relapses occurred. Only eight patients survived (cited Dumont et al. as reference 5 and level of evidence 3iA).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood esthesioneuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Esthesioneuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/child/esthesioneuroblastoma-treatment-pdq. Accessed <MM/DD/YYYY>.

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