Discussion
Composite tumors in children are very rare and usually have no definitive etiology. Many of them have been linked to TP53, a gene that controls many cell cycle regulation pathways and thus is susceptible to many germline mutations that have been identified. ACT in particular is noted as closely related tumor to the TP53 gene mutation.4 Very little evidence links NB to LFS.
Cases of LFS with multiple malignancies are numerous but are rarely simultaneous.5 A handful of cases have reported homozygous TP53 mutations with associated with ACT and NB, most of which presented with unique presentations and TP53 gene variations.6–9 One case did report a simultaneous ACT and NB in an eight-month-old infant, but its germline p53 mutation was not present in this patient.10 The variation in this case is different from any previously cited in the literature. To discern understanding links between ACT and NB in the context of TP53, more cases are warranted.
The patient’s particular mutation, c.818G>A, pArg273His, is one that has only been cited twice, both due to different malignant etiologies. One case report indicated a child with LFS with two separate germline mutations, c.818G>A and c.814G>A, leading to three separate malignancies presenting as early as four months.11–13 Although none of the three malignancies were either ACT or NB, it is notable that the c.818G>A mutation is present in both cases. The mutation c.818G>A is within the DNA binding domain of TP53 and prevents wild-type transcriptional activity. This can inactivate the second allele, granting gain-of-function properties that show a more aggressive phenotype than mutations resulting in loss of TP53 expression.14 This may explain the early onset of the compound tumor in this patient and literature reveals a near decade earlier mean age of onset of primary cancer in LFS due to TP53 gene missense mutations compared to TP53 deletions15. The other article indicated its pathogenicity, among many other mutations, in cases of adult gastric type mucinous carcinoma.16It is noteworthy that c.818G>A, pArg273His has now been seen in tumors in both pediatric and adult patients. Additional links between the mutation and its various linked pathologies across the lifespan are warranted but are out of the scope of this paper.
It is speculated that this germline mutation may be a factor in the pathogenesis of this composite tumor and in composite adrenal malignancies in general. Family cancer history also plays an important clue for TP53 gene mutation screening due to LFS’s autosomal dominant inheritance, such analysis maybe indicated for the first-degree relatives of this patient, and close monitoring is warranted for subsequent LFS-related tumors in the patient.
We report a composite NB and ACT in an infant associated with a heterozygous TP53 c.818G>A, pArg273His mutation, the first of its kind. The mutation is pathogenic and may predispose carriers to malignancies across the lifespan.