Where to next with extracranial rhabdoid tumours in children

Abstract

Rhabdoid tumours are rare, highly aggressive and frequently lethal tumours of childhood. Renal rhabdoid tumour was first recognised as a separate pathological entity in the early 1980s [1]. Atypical teratoid/rhabdoid tumour (AT/RT) of the central nervous system (CNS) is well defined [2] and rhabdoid tumours have been reported widely at many other anatomical sites [3,4]. Although there are many reports describing their lethal outcome [4,5] there are few published series describing their management in a consistent manner on national or international protocols [5,3]. This is mainly due to their rarity. Data from the National Registry of Childhood Tumours (NRCT) for 1987—1999 give annual incidence rates in the United Kingdom (UK) of 0.24 per million children under 15 years for renal and 0.15 per million for extracranial extrarenal rhabdoid tumours. Incidence of AT/RT was 0.11 per million, but this may well be an underestimate [2]. Recently, there have been reports of survivors, even when there has been metastatic disease, with the use of more intensive chemotherapy regimes including doxorubicin [6,7]. There has been considerable debate over whether extrarenal rhabdoid tumour represents the same entity as rhabdoid tumour of the kidney. However, recent progress in analysis of their molecular biology has shown that they share a common genetic defect, namely deletion or mutation of the hSNF5/INI1 gene on chromosome 22q [8]. In two subsequent studies of substantial numbers of tumours, mutation of the hSNF15/ INI1 gene was found in 25 of 29 extrarenal rhabdoid tumours and in 51 of 76 renal rhabdoid tumours [9,10]. It is less clear whether all non-CNS extrarenal malignant rhabdoid tumours have the same histogenetic origin as their renal counterparts [11,12,13], as some of these tumours may be considered to be undifferentiated sarcomas or carcinomas with ‘‘rhabdoid features’’. In these cases, documention of a hSNF5/INI1 mutation may be helpful in diagnosing the true malignant rhabdoid tumours. Underlying hSNF/INI1 gene mutations may also explain the association of renal rhabdoid tumours with brain tumours. These brain tumours are usually located in the midline cerebellum and may be of diverse histological composition, not always conforming to the definition of AT/RT. However, again most of these CNS rhabdoids, whether they occur in association with extracranial primary tumours or not, carry mutations in hSNF5/INI1 (46 of 61 cases in two recent studies) [9,10]. There is some suggestion of a genotypephenotype correlation, with exon 9 mutations reported almost exclusively in CNS rhabdoids in one study [9] and homozygous deletions being commoner in extracranial rhabdoid tumours in the other [10]. Germline predisposing mutations in hSNF5/INI1 are found in children with rhabdoid tumours, particularly those with combined CNS and extracranial rhabdoid tumours [9]. Mutation of the hSNF5/INI1 gene appears to be confined to rhabdoid tumours, particularly when in extracranial sites. Analysis of other non-CNS embryonal tumours types, even those that demonstrate allele loss for the chromosome 22q region spanning the hSNF/