Abstract
Purpose
To report a case of aggressive infantile orbital embryonal rhabdomyosarcoma harboring germline ATM mutation and 2 somatic mutations as revealed by next-generation sequencing and the potential application for personalized therapy.
Observations
A 7-month-old male developed a rapidly progressive left proptosis over 6 weeks due to a large medial orbital mass. Biopsy revealed embryonal rhabdomyosarcoma. After the first cycle of chemotherapy, re-imaging showed interval tumor enlargement with intracranial extension. Craniotomy, combined with orbital exenteration, was performed. Tumor specimens and blood samples were sent for 596 gene DNA sequencing panels with RNA-sequencing focused on actionable mutations as well as gene fusion detection. Sequencing revealed 3 clinically relevant mutations: a germline ATM loss-of-function (LOF) mutation, a somatic PIK3CA gain-of-function mutation, and a somatic BCOR LOF mutation. No chromosomal translocation was detected. Workup for metastasis was positive for bone marrow involvement. Despite standard high-dose adjuvant chemotherapy in combination with radiation therapy, the patient died 10 months later with metastatic diseases.
Conclusions and importance
This case highlights an aggressive form of embryonal rhabdomyosarcoma in an infantile orbit. The presence of germline mutation may explain the increased chemo-resistance and adverse prognosis, and may be used as the target for genomic-directed therapy.
1
Introduction
Rhabdomyosarcoma (RMS) is a malignant neoplasm consisting of cells with histopathologic features of striated muscle. RMS is divided into two major histologic subtypes, including embryonal (ERMS) and alveolar (ARMS). Orbital RMS remains the most common primary orbital malignancy in children, and its incidence exceeds all other sarcomas combined. , The majority of orbital RMS is an embryonal subtype, which portends a good prognosis. However, it is rarely found in infants less than 1-year-old. Although the orbital site is proved to have a favorable prognosis for RMS, local invasion and tumor metastasis may occur, resulting in a poor outcome. Despite a significant improvement in failure-free survival for children with RMS over the past decade, the same improvement in outcome has not been seen for infants. , It is still unclear why RMS biology and response to therapy in infants differ from those of older children or adults. The authors report a case of a rapidly growing embryonal rhabdomyosarcoma of the infantile orbit that failed conventional therapy. In this case, next-generation sequencing revealed a germline ATM mutation, which could play a role as a cancer predisposing mutation conferring cancer susceptibility, chemo-resistance, and unfavorable prognosis. This study was adherent to the tenets of the Declaration of Helsinki.
2
Case report
A 7-month-old male infant, previously healthy, presented with progressive left proptosis over six weeks ( Fig. 1 A). Orbital imaging revealed a large, well-circumscribed mass at the medial aspect of left orbit without intracranial lesion ( Fig. 1 B). Anterior orbitotomy via a transcaruncular approach for incisional biopsy of the mass was performed. Pathology and immunohistochemistry results showed round cell neoplasm diffusely marked with myogenin, MyoD1, and desmin ( Fig. 2 ), and stained with PAS with diastase lability, consistent with embryonal RMS. According to the Intergroup Rhabdomyosarcoma Study Group (IRSG), he was classified as a low-risk group (Group IIIa, Stage 1). Hence, systemic chemotherapy following ThaiPOG-RMS-13LR protocol, which consists of vincristine, actinomycin D, and cyclophosphamide (VAC regimen), was inducted.
Two weeks after the first cycle of chemotherapy, he developed rapid tumor progression with exposure keratopathy resulting in severe corneal ulcer and impending globe perforation ( Fig. 1 C). The repeat computed tomography (CT) imaging revealed an interval increase in tumor size with the newly detected intracranial extension via orbital apex ( Fig. 1 D). He underwent cranio-orbitotomy combined with orbital exenteration for tumor resection. The bony defect at the orbital apex was reconstructed with temporoparietal pericranial flap. Pathology reported a presence of residual tumor at the inferoposterior margin where it invaded into the anterior cavernous sinus. Further workups for distant metastasis, including bone marrow biopsy, CT of chest, and bone scan, were performed. Bone marrow metastasis was detected. According to the IRSG, the patient was reclassified as a high-risk group (Group IV, Stage 4) for more intensive treatment. He received chemotherapy with ifosfamide, etoposide, carboplatin, and VAC regimen as per ThaiPOG-RMS-13HR protocol in combination with radiation therapy (1.8 Gy x 28 fractions; total 50.4 Gy). During chemotherapy course, patient developed febrile neutropenia and had to postpone his treatment a few times.
After receiving 3 cycles of chemotherapy and completed course of radiotherapy ( Fig. 3 A), a repeat CT scan revealed progression of the residual tumor at the orbital apex ( Fig. 3 B) with a new metastatic brain lesion at the right frontal cortex. Eight months after diagnosis, he developed multiple brain, lung, and spine metastases. His treatment plan was changed to palliative care at this stage. The patient died at the age of 17 months, approximately 10 months after the initial diagnosis.
