Statistics from Altmetric.com
We read with interest the recent report by Cascon et al1 of three families with a germline SDHB deletion. In particular, we noted that in one family an SDHB deletion carrier was diagnosed with an adrenal neuroblastoma (with metastasis in five homolateral ganglia) at the age of 5 years. Cascon et al1 also reported that both phaeochromocytomas and the neuroblastoma from people with the SDHB deletion showed 1p36 allele loss. This finding suggested a possible association between SDHB mutations and neuroblastoma susceptibility. However, germline or somatic SDHB mutations have not been described previously in neuroblastoma.2 3
Recently we detected an SDHB deletion in a 13-year-old girl with a composite paraganglioma/neuroblastoma. The girl had consulted her general practitioner for dysmenorrhoea, and during the examination had been found to have high blood pressure. A paraganglioma (extra-adrenal phaeochromocytoma) was diagnosed by analysis of 24-hour urine collection, MRI and 123I labelled meta-iodobenzylguanidine scintigraphy. Clinical examination and review of the patient’s family history failed to find an underlying syndromic cause. Elective surgery was performed to excise a large left paravertebral lesion closely related to the kidney and neighbouring vasculature. Complete macroscopic excision of tumour was achieved, but renal ischaemia demonstrated on post-operative Doppler and dimercaptosuccinic acid (DMSA) scan kidney studies required later left nephrectomy to ensure long-term blood-pressure control.
Initial histological evaluation of the tumour showed characteristic features of a paraganglioma, with nests of large polygonal cells surrounded by a capillary-rich framework, resulting in the characteristic Zellballen appearance. Immunohistochemistry showed that the tumour cells were positive for chromogranin and vimentin. S100 staining highlighted the sustentacular cells at the periphery of the nests. Further in-depth analysis revealed an area with morphology suggestive of a differentiating neuroblastoma (fig 1). There were sheets of small round cells in a neurofibrillary background. Ganglionic differentiation was also evident. Immunohistochemistry showed positive staining for neurofilament proteins, neuron-specific enolase and CD56. Based on the presence of two distinct morphologies and the immunophenotype, a diagnosis of composite paraganglioma/neuroblastoma was made.
In view of the early age at diagnosis, molecular genetic testing was performed and a heterozygous complete SDHB gene deletion detected by multiplex ligation-dependent probe amplification (MLPA) analysis (SALSA MLPA Kit P226; MRC-Holland, Amsterdam, The Netherlands; details of methods available on request) (fig 2). This was subsequently found to have been inherited from the girl’s asymptomatic father and further family studies have been started.
The term “composite” is used to describe complex tumours containing foci of phaeochromocytoma/paraganglioma, and also neuroblastoma, ganglioneuroblastoma, ganglioneuroma or malignant peripheral nerve sheath tumour.
Common embryogenesis from the neural crest may help explain these unusual tumours. The possibility of differentiation along more than one cell line has been supported by studies that have shown that normal and neoplastic chromaffin cells are capable of differentiation into ganglion cells under the influence of nerve growth factor.4 Furthermore, SDHB has been implicated in a developmental apoptotic pathway, and germline mutations in a downstream target of this pathway, KIF1Bbeta, have been reported in patients with neuroblastoma and or phaeochromocytoma.5
Relatively few patients with SDHB deletions have been reported, and previous studies of SDHB in patients with neuroblastoma have used methods that would not detect germline deletions. Therefore it will interesting to determine if germline SDHB deletions are present in some patients with neuroblastoma and whether composite paraganglioma/neuroblastoma tumours are found in further patients with SDHB deletions or other mutations.
Competing interests: none declared.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.