Discussion:
As leiomyosarcoma is exceedingly rare in pediatric age group, treatment is extrapolated from experience with other non-rhabdomyosarcoma soft tissue sarcomas. Since, our patient had low grade disease measuring< 5cm in diameter with no metastatic disease, we decided to closely observe her with serial imaging rather than radiation therapy to avoid the long-term consequences of radiation. The presence of residual disease placed our patient at risk for local recurrence. The risk of recurrence in low risk tumors with positive margins was 18%, with 80% EFS. Out of the patients who recurred, all were local recurrence only and salvaged with surgery, with or without radiation. Only one patient died of metastatic disease following salvage therapy with radiation. Furthermore, delaying the administration of radiotherapy in young children until the time of local recurrence (which may years after tumor resection) may diminish the late toxicity of this treatment modality [5-7].
With the recent success of targeted therapies such as BRAF, EGFR and TKI in the management of cancers, many groups have taken advantage of the availability of genomic sequencing to understand the biology of these tumors and develop a personalized therapeutic option. NGS, showed a chromosomal re-arrangement involving FGFR1-TACC1 as well as copy number loss of MTAP, CDKN2A, and CDKN2B on array cGH.
FGFR fusion genes were first discovered in Glioblastoma Multiforme (GBM) and have since been found in many other solid tumors like breast, prostate, gastric, NSCLC, adenocarcinoma and colorectal carcinomas [8-10], however, to date, none has been described in pediatric leiomyosarcoma.
In our patient, the genomic breakpoints map to exon 18 of FGFR1 at the 5’ end and intron 1 of TACC1 at the 3’ end, both located on chromosome 8. Figure 1C shows the chromosomal rearrangement seen in the patient as well as the breakpoint locations. The fusion was observed at the DNA level, where part of FGFR1 gene, 5’ of the exon 18 breakpoint is duplicated and inverted at the 3’ breakpoint position within TACC1.
Fusion genes generally result in constitutive activation of the 3’ partner gene. It is possible the duplicated and reinserted FGFR1 may be transcribed resulting in increased activity of FGFR1 tyrosine kinase. Preclinical studies show that FGFR–TACC fusion proteins allow FGFR to dimerize, leading to autophosphorylation and constitutive FGFR tyrosine kinase activation. The distinctive feature of TACC proteins is a coiled-coil domain at the C terminus, known as the TACC domain, which mediates localization to the mitotic spindle. Together, aberrant FGFR and TACC signaling results in increased cell proliferation and cancer progression [9,10]. Perhaps the most convincing data on the importance of this gene fusion comes from in vitro studies showing the FGFR-TACC fusion predicts for sensitivity to FGFR inhibitors [10-12]. As such it is logical that the use of these inhibitors may benefit this subset of patients. In lieu of the newly FDA approved FGFR inhibitor, Erdafitinib, in the event of recurrence the use of this TKI in combination with chemotherapy and radiation remains a therapeutic option for this patient. Among other copy number losses reported in this patient, only loss of CDKN2A has been reported previously in leiomyosarcomas.
The paucity of pediatric leiomyosarcomas and differences in the biology compared to adult tumors, justifies molecular analysis of such tumors. For our patient, oncological transformation may be explained partially by chromosomal arrangements. It also provides a therapeutic option in case of disease progression.
Funding Source: No funding was secured for this study
Acknowledgements: We would like to acknowledge the team at “Tempus ” for assistance in analysis of the FGFR1-TACC1 gene rearrangement.
Financial Disclosure: The authors have no financial relationships relevant to this article to disclose
Conflict of Interest : The authors have no conflicts of interest to disclose