In this clinical quandary, investigators determine how to best treat patients with opsoclonus-myoclonus–associated neuroblastoma with bone marrow metastases.
A 1.9-year-old girl was presented to the hospital with dancing eye movements, ataxia, and behavioral disorders. The MRI showed a retroperitoneal tumor (transversal size: 3.9 x 2.5 cm, craniocaudal size: 4.6 cm) extending from T12 to L3 vertebral bodies (Figure), which was suspicious for neuroblastoma. Afterwards, biopsy of the lesion and bone marrow was performed. The initial pathological evaluation (CD56+, PHOX2B+, NKX2-, Ki67 50%-55%, NSE+, CD99-) of the tumor and bone marrow confirmed the diagnosis of poorly differentiated, high-risk neuroblastoma.
What would be the best choice for further management of this patient?
The “dancing eye syndrome,” or opsoclonus-myoclonus syndrome (OMS), is a rare disorder that affects the nervous system. OMS is characterized by rapid, multidirectional eye movements (opsoclonus), quick, involuntary muscle jerks, sleep disturbance, cognitive dysfunction, and behavioral changes.1 OMS typically occurs in association with tumors, usually with neuroblastoma (NB). Approximately half of pediatric OMS is related to NB. The incidence of OMS is rare; one of the prospective studies in the United Kingdom estimated 0.18 cases per million per year.2
The literature states that OMS is caused by an autoimmune process for which it is recommended to provide early immunosuppressive treatment.3 In addition to corticosteroids, intravenous immunoglobulin (IVIG), cyclophosphamide, or rituximab can be also used. However, there is no standard combination or duration of immunomodulatory therapy.4
Patients with cancer with paraneoplastic OMS tend to have higher survival than those without paraneoplastic OMS.5
An earlier study showed that the typical characteristics of neuroblastoma differ among OMS children. Notably, the frequency of OMS associated with NB is the lowest among children aged 6 month or younger.6
NB is the most common extracranial solid tumor in childhood. It can be categorized into different prognostic groups based on age, histological subtype, tumor grade, stage, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy. In addition, according to revised classification, segmental chromosome aberrations (loss or gain of a portion of a chromosome arm) also play a role in the classification system and are associated with unfavorable prognosis. Accurate staging plays a crucial role in treatment planning, as it is provided according to assigned risk groups.7
There is a wide range of treatment approaches for patients with NB: observation, chemotherapy, myeloablative consolidation therapy (single or tandem), surgery, radiation therapy, immunotherapy. Surgical resection of the tumor is an essential part of the treatment of NB, however, in some cases, induction chemotherapy is needed in order to make the tumor amenable for surgical resection.8 Hence, initial surgical resection with negative margins and without any loss of neurological function is not always feasible. Performing surgery in patients with a disseminated disease does not assure achieving gross total resection of the primary tumor. In addition, in case of upfront surgical treatment, because the radiation volume is set at the resection, the radiation field is much bigger. Despite that, some recent studies suggest better treatment outcomes for complete resection. Surgery alone is a preferable option for most patients with low-risk disease. However, based on several studies, resection should be conducted after several courses of induction chemotherapy when the tumor becomes smaller in size and less invasive. Therefore, initial surgical treatment would lead to a number of complications and would not improve survival for this patient, making answer B (surgical resection of the primary tumor) a poor choice.9
Despite the fact that OMS is associated with better outcome and low-risk disease, in this particular case the patient had disseminated disease and unfavorable histological type according to Shimada classification. Patients older than 18 months and those having disease dissemination or localized disease with unfavorable markers, such as MYCN amplification, are at the highest risk for disease progression and mortality. Therefore, answer C (observation) is not the preferred path for management for this patient since observation only would lead to disease progression.10
Radiation therapy is another option for local control, along with surgical resection, and is a necessary part of the treatment of high-risk neuroblastoma. However, it has greater benefit in case of administration after surgical resection as part of further therapy. Moreover, radiation therapy at this young age would lead to a number of adverse effects and complications. Therefore, answer D (radiation therapy) is not the preferred option for this child.11
Standard approach for high-risk neuroblastoma includes initial chemotherapy with further surgical treatment and aHSCT. These patients typically present with unresectable diseases.12 Thus, it is critical to provide induction chemotherapy to reduce tumor burden and continue with local control. In order to reduce the recurrence of the disease and reduce the symptoms of the nervous system, children with OMS NB should be treated with the combined modality therapy, including surgery, chemotherapy, aHSCT, and/or radiotherapy. The current treatment approaches for OMS include immunomodulatory therapies, including steroids, IVIG, cyclophosphamide, and more recently, rituximab.13 Given this information, answer A (chemotherapy with further treatment including surgery and aHSCT) is the best treatment option for this patient.
The child received 6 cycles of chemotherapy according to NB2004 protocol, after which complete surgical resection of the tumor was possible. After the first cycle of chemotherapy, symptoms of OMS were resolved; hence, no steroids or immunoglobulins were added to the treatment. Pathological examination of resected tumor showed histological differentiation (ganglioneuroma-, CD56+, NSE+, Ki67 1%-2%). Afterwards, aHSCT was performed. Now the child is disease-free and has no neurological abnormalities due to OMS. n
Author Affiliations: 1Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center after Prof. R.H. Yeolyan, Yerevan, Armenia; 2Yerevan State Medical University, Yerevan, Armenia; 3Department of Pediatric Oncology and Hematology, Yerevan State Medical University, Yerevan, Armenia; 4Institute of Cancer and Crisis, Yerevan, Armenia; 5Pediatric Oncology Clinic, Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center after Prof. R.H. Yeolyan, Yerevan, Armenia; 6Musculoskeletal tumors working group, Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center after Prof. R.H. Yeolyan, Yerevan, Armenia.
CONFLICT OF INTEREST: All authors disclosed no conflict of interest.
About the SERIES EDITORS:
Maria T. Bourlon, MD is associate professor, Head Urologic Oncology Clinic; national researcher, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. She is also a member of ASCO’s IDEA Working Group.
E. David Crawford, MD, is chairman, Prostate Conditions Education Council; editor in chief, Grand Rounds in Urology; and professor of Urology, University of California San Diego, La Jolla, CA.
1. Digre KB. Opsoclonus in adults. Report of three cases and review of the literature. Arch Neurol. 1986;43(11):1165-1175. doi:10.1001/archneur.1986.00520110055016
2. Bhatia P, Heim J, Cornejo P, Kane L, Santiago J, Kruer MC. Opsoclonus–myoclonus–ataxia syndrome in children. J Neurol. Published online March 29, 2021. doi:10.1007/s00415-021-10536-3
3. Connolly AM, Pestronk A, Mehta S, Pranzatelli MR III, Noetzel MJ. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. J Pediatr. 1997;130(6):878-884. doi:10.1016/s0022-3476(97)70272-5
4. Wilbur C, Yea C, Licht C, Irwin MS, Yeh EA. An upfront immunomodulatory therapy protocol for pediatric opsoclonus-myoclonus syndrome. Pediatr Blood Cancer. 2019;66(8):e27776. doi: 10.1002/pbc.27776
5. Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol. 1997;28(4):284-288. doi:10.1002/(sici)1096-911x(199704)28:4<284::aid-mpo7>3.0.co;2-e
6. Pranzatelli MR, Tate ED, McGee NR. Demographic, clinical, and immunologic features of 389 children with opsoclonus-myoclonus syndrome: a cross-sectional study. Front Neurol. 2017;8:468. doi:10.3389/fneur.2017.00468
7. Irwin MS, Naranjo A, Zhang FF, et al. Revised neuroblastoma risk classification system: a report from the Children’s Oncology Group. J Clin Oncol. Published online July 28, 2021. doi: 10.1200/JCO.21.00278
8. Tolbert VP, Matthay KK. Neuroblastoma: clinical and biological approach to risk stratification and treatment. Cell Tissue Res. 2018;372(2):195-209. doi:10.1007/s00441-018-2821-2
9. Ryan AL, Akinkuotu A, Pierro A, Morgenstern DA, Irwin MS. The role of surgery in high-risk neuroblastoma. J Pediatr Hematol Oncol. 2020;42(1):1-7. doi:10.1097/MPH.0000000000001607
10. Pang KK, de Sousa C, Lang B, Pike MG. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom. Eur J Paediatr Neurol. 2010;14(2):156-161. doi:10.1016/j.ejpn.2009.03.002
11. Jo JH, Ahn SD, Koh M, et al. Patterns of recurrence after radiation therapy for high-risk neuroblastoma. Radiat Oncol J. 2019;37(3):224-231. doi:10.3857/roj.2019.00353
12. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341(16):1165-1173. doi:10.1056/NEJM199910143411601
13. Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol. 2010;14(5):400-409. doi:10.1016/j.ejpn.2009.12.005