The neurocristopathy syndrome occurs because of a germline mutation of the paired-like homeobox 2b (PHOX2B) gene at 4p12, a neurogenesis regulator gene. The result is abnormal neural crest cell development resulting in congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma (NB), which is often multifocal and disseminated in its presentation. Previously, such widespread disease was regarded as highly aggressive and treated either with palliative intent or, conversely, with very intense, high-dose chemotherapy. We now present a patient who had neurocristopathy syndrome who had multifocal NB associated with an underlying germline PHOX2B mutation. He was treated conservatively with surgery and low-dose chemotherapy. After treatment he had extensive residual disease that has continued to mature despite no further treatment. A literature review identified 26 similar patients presenting with multifocal NB as part of the neurocristopathy syndrome. In all cases the NB behaved in an indolent manner with no deaths from tumor reported when patients received appropriate treatment. These provocative findings suggest for the first time that children who have neurocristopathy-associated NB should be treated conservatively, despite the aggressive appearance of their disease.
- multifocal neuroblastoma
- bilateral neuroblastoma
- familial neuroblastoma
- neurocristopathy syndrome
- ALK —
- anaplastic lymphoma kinase
- MIBG —
- 123I metaiodobenzylguanidine
- NB —
- PHOX2B —
- paired-like homeobox 2B gene
Neuroblastoma (NB) is a neuroendocrine tumor arising from the neural crest of the sympathetic nervous system and is the most common cancer of infancy. It may occur as part of the “neurocristopathy syndrome,” a poorly characterized genetic syndrome associated with multifocal NB.1 The neurocristopathy syndrome is caused by a germline mutation of the paired-like homeobox 2b (PHOX2B) gene at 4p12 (a neurogenesis regulator gene), resulting in abnormal neural crest cell development and the clinical triad of NB, congenital central hypoventilation syndrome, and Hirschsprung disease.2
Treatment strategies for NB vary from observant to aggressive multimodal therapy. Although localized disease can often be managed with surgery alone, treatment of children who have widely disseminated disease can pose a clinical challenge. Standard therapy for those who have high-risk disease usually comprises intensive chemotherapy, surgery, radiation therapy, and myeloablative chemotherapy with autologous stem cell transplant as well as retinoic acid, and now immunotherapy.3 However, even with this aggressive approach, overall survival is as low as 40% for children who have high-risk metastatic disease.4 Historically, the treatment approach for NB associated with neurocristopathy syndrome is largely palliative owing to concerns about the perceived aggressive nature of such widespread, disseminated disease, and the low tolerability of intensive treatment in children who have other comorbidities. However, recent case reports have suggested that favorable long-term outcomes may be possible when such patients are treated with surgery and conventional chemotherapy.5 There has been no study to date evaluating the clinical outcomes associated with neurocristopathy or PHOX2B-associated NB.
A 10-month-old boy presented to the emergency department with a 3-day history of coryzal symptoms. His past medical history included lower bowel resection for Hirschsprung disease in the neonatal period. He was otherwise well, with normal achievement of developmental milestones. On examination his vital signs were within normal limits. Cardiorespiratory and neurologic examination was unremarkable. His abdomen was tense and distended, with reduced bowel sounds.
Investigations revealed mild anemia with microcytic red blood cells with low ferritin. Renal and liver function tests were all within normal limits. Abdominal ultrasound revealed bilateral suprarenal masses that were heterogeneous in echotexture with lobulated margins, exhibiting minimal vascularity. Further imaging with CT revealed extensive bilateral paravertebral masses in the thoracic (T2–T11), lumbar, and presacral areas as well as large suprarenal masses. There was a large (4.5 cm × 4.5 cm × 5.6 cm) soft-tissue density mass replacing the right adrenal gland containing internal calcifications displacing the liver and underlying kidney, and a large (5.6 cm × 3.4 cm × 4.5 cm) multilobulated mass in the location of the left adrenal gland. There were also 2 large masses in the presacral region, and extensive soft-tissue masses in the para-aortic regions bilaterally and the left retrocrural region with extension into the spinal cord at L2/L3. The masses were all of soft-tissue density, with foci of calcification.
These findings were confirmed with MRI (Fig 1), which showed extension of the masses into the epidural spaces at T3, T8, and L2–L3; and 123I metaiodobenzylguanidine (MIBG) scanning showed increased uptake in all of the lesions in the thorax and abdomen (Fig 2). A bone scan also showed increased tracer uptake in the known masses as well as uptake in a single vertebral body that was not seen on MIBG imaging. Urinary catecholamines were elevated (Table 1). A biopsy specimen of the retroperitoneal masses revealed poorly differentiated NB arising from the adrenals, with marked nuclear pleomorphism and high mitosis-karyorrhexis index, which was consistent with unfavorable histology by Shimada classification. N-MYC was not amplified; DNA index 1.96. Bone marrow aspirate and trephine were normal. Given his previous history of Hirschsprung disease, genetic analyses were undertaken that revealed the presence of a germline de novo frameshift mutation in the PHOX2B gene (c.691–698dup, p.Gly234AlafsX78). However, subsequent sleep studies did not reveal evidence of central hypoventilation.
Despite the widespread, multifocal appearance of his stage IV NB, owing to favorable biological features he was treated as per the “intermediate-risk” Children’s Oncology Group A3961 protocol, with 8 cycles of chemotherapy containing carboplatin, etoposide, doxorubicin, and cyclophosphamide.6 He had a partial response to chemotherapy with a reduction in size of many of his lesions by ∼50%. Surgical debulking of residual paravertebral and adrenal lesions was undertaken after completion of the sixth cycle of chemotherapy. Postoperatively he was found to have suffered a complete infarct of his left kidney and a partial infarction of his right kidney. His kidneys remained in situ and caused mild renal impairment and necessitated treatment of mild hypertension. The subsequent 2 cycles of chemotherapy were modified to avoid nephrotoxic agents.
Repeat investigations after the completion of therapy showed that overall he had a very good partial response to chemotherapy and surgery, with >90% reduction in size of all his lesions; however, all of the residual lesions were still MIBG avid. He was subsequently observed and 1 year after completing treatment, surveillance scans revealed a subtle increase in size in his residual lesions by 1 to 2 mm each, prompting treatment with retinoic acid for 6 months, followed by observation only. It is now 4.5 years since his initial diagnosis and MRI surveillance scans have shown persistent paravertebral, para-aortic, presacral, and suprarenal masses that continue to show subtle increase in size of 1 to 2 mm per year, yet progressively diminished MIBG uptake, suggesting disease maturation and differentiation. His most recent MIBG scan shows only minimal activity in a single lesion (Fig 3). He is thriving, and his renal function and blood pressure have normalized.
This case demonstrates the potential indolent behavior of multifocal NB associated with the neurocristopathy syndrome. Although the aggressive appearance of his disease may have prompted treatment with intensive high-dose therapy, he was instead treated as an “intermediate risk patient,” achieving a favorable outcome with conservative therapy. NB patients are stratified by assessing multiple risk factors, including age, Shimada classification of histopathology, tumor stage, and genetic factors including the presence of N-MYC amplification, DNA ploidy, and loss of heterozygosity at 1p or 11q. Recent studies have shown that aggressive treatment of tumors with favorable biological features is unwarranted and that there may be greater morbidity and mortality associated with treatment complications, rather than the underlying disease.7
However, there is no reliable data on whether the presence of multifocal disease or a germline PHOX2B mutation affects prognosis and should direct therapy. To ascertain the prognosis of patients presenting with multifocal NB associated with PHOX2B mutation or the neurocristopathy syndrome, we conducted a literature review that identified 25 more cases (Table 2). The results show that, in contrast to the historical perception, the associated extensive disease is not indicative of an aggressive tumor. Of the 26 patients, 50% (n = 13) survived (including 2 with residual disease) and most importantly there were no deaths attributable to NB itself, despite its disseminated presentation. Two patients (15%) died from complications of their aggressive management, and almost all survivors were treated with conservative therapy: the majority (62%, n = 8) with surgery alone, and those who did receive chemotherapy avoided high-dose therapy. Among the 13 children who died, the cause of death in almost half of these patients (6/13) was attributable to complications associated with congenital central hypoventilation syndrome; whereas 2 died from complications associated with Hirschsprung disease, 2 died from postoperative or high-dose chemotherapy complications and a further 3 had all treatment withheld.
This highlights 2 important points: first, the indolent course that appears to be associated with neurocristopathy or PHOX2B-associated NB (despite its typically aggressive appearance), and second, the importance of a more conservative approach to the treatment of such children. Of note, our patient developed bilateral renal infarctions as a consequence of his surgery, and his disease has proven to be indolent. This evidence suggests that multifocal NB associated with neurocristopathy syndrome should be classified for treatment purposes using the same prognostic criteria as unifocal tumors, and that the multifocal and widespread nature of their disease, or the presence of an underlying PHOX2B germline mutation, does not warrant an escalation of treatment. Neurocristopathy syndrome should not be a reason to withhold treatment, and when comorbid conditions are well managed these children may have a favorable outcome.
As more tumors are categorized according to their genetic characteristics, the challenge lies in translating this new genetic knowledge into definitive risk stratification and identifying possible therapeutic targets to advance the management of NB.8 One target for such therapeutic intervention is the recently discovered high incidence of both somatic and inherited germline anaplastic lymphoma kinase (ALK) mutations. ALK is a receptor tyrosine kinase frequently mutated in NB and, like PHOX2B, may be associated with familial cases of NB. In contrast to the data shown here for PHOX2B cases, ALK mutations can be associated with NB with a wide variety of biological features, often including cases with N-MYC amplification (conferring a very poor prognosis).2,9–11 Notably, N-MYC amplification was not found in any of the neurocristopathy-associated tumors in which it was specifically tested (Table 2). This suggests that, unlike tumors with an ALK mutation, the presence of a PHOX2B mutation or the neurocristopathy syndrome may be associated with favorable biological characteristics that should be validated in prospective studies. Meanwhile, our results suggest that a conservative approach with adequate treatment rather than a palliative approach is warranted.
Despite the treatment challenge that PHOX2B or neurocristopathy-associated multifocal NB may appear to present with its disseminated presentation and medical comorbidities, a very good outcome may be achievable with relatively conservative management. If favorable biological profiles are evident, such cases may be safely managed with a conservative approach with the potential that the tumors may undergo maturation and differentiation.
- Accepted January 9, 2014.
- Address correspondence to David Ziegler, MBBS, BSc (Med), FRACP, MD, Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, NSW, 2031, Australia. E-mail:
Dr Williams conceptualized and designed the study and drafted the initial manuscript; Dr Ziegler conceptualized the study question and population for investigation and critically reviewed the manuscript; Dr Wegner provided expertise (and images) on the nuclear imaging studies conducted on the case report; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Haupt R,
- Garaventa A,
- Gambini C,
- et al
- ↵The National Cancer Institute. Combination chemotherapy in treating children with neuroblastoma. In: 20th November 2012. National Institutes of Health; 2012
- ↵Wylie L, Philpott A. Neuroblastoma progress on many fronts: the Neuroblastoma Research Symposium. Paediatr Blood Cancer. 2012;2012(58):4
- McDermott U,
- Iafrate AJ,
- Gray NS,
- et al
- Levard G, Boige N, Vitoux C, et al. Neurocristopathy: Hirschsprung's disease associated with ganglioneuroblastoma and autonomic nervous system impairment in 2 children. Arch Fr Pediatr. 1989;46:595–597
- Commare M, Francois B, Estournet G, Barois A. Odine's curse: a discussion of five cases. Neuropaediatrics. 1993;24(313–318)
- Bower RJ,
- Adkins JC
- Latchaw RE,
- L’Heureux PR,
- Young G,
- Priest JR
- Copyright © 2014 by the American Academy of Pediatrics