Results
A 16-year-old male presented with worsening of hematuria and urinary retention over two weeks. He was initially treated with antibiotics for possible cystitis. He had a history of PPB type II without metastasis at 3 years of age and local recurrences at 4 and 6 years of age, which were treated with complete resection and chemotherapy, including high-dose chemotherapy with hematopoietic cell rescue. During PPB diagnosis, whole-exome sequencing (WES) was performed using tumor tissue and blood samples, which led to the sporadic PPB diagnosis. A somatic p.D1810Y (c.5428G>T) hotspot mutation in DICER1 was detected in the primary and recurrent PPB, whereas no pathogenic variant was identified in the germline.5 Although the patient’s mother had thyroid nodules, his other family members do not have any history of DICER1 -associated disorders (Fig. 1A). A computed tomography scan detected enhanced masses in the bladder and prostate obstructing the urethra (Figs. 1B-C). Further imaging tests revealed multiple nodules in the thyroid gland, which were considered incidentally found benign nodules. No local recurrence of PPB in the lungs or other metastases was observed. The patient underwent a needle biopsy of the prostate lesion. The pathological findings suggested a distant recurrence of PPB or ERMS (Figs. 1D-G). Chemotherapy (topotecan 0.75 mg/m2 for 5 days plus cyclophosphamide 250 mg/m2 for 5 days) was started on the patient, and he showed a partial response after four cycles.
DNA panel testing performed using the biopsied sample detected p.E1813D (c.5439G>T) instead of p.D1810Y, which had been found in the first PPB. Although no additional pathogenic variant was detected in the panel testing, the DICER1 hotspot mutation in the present lesion, the multinodular goiter, and the history of PPB were highly suggestive of DICER1 syndrome. Therefore, complementary DNA (cDNA) analysis was performed using blood samples, which detected a frameshift pathogenic p.I813Ffs*24 with a 14-base insertion. Subsequent Sanger sequencing revealed an intronic c.2437-15T>G (Fig. 2). Accordingly, the patient was diagnosed with DICER1 syndrome, and the tumor was diagnosed as ERMS, a second tumor that developed in the context of DICER1 syndrome. Through cascade testing, the same pathogenic variant was detected in the patient’s mother. The patient’s other family members do not have any history of DICER1 -associated disorders.
Based on the ERMS diagnosis, the treatment was switched to VAC (4 cycles of vincristine 2 mg, actinomycin D 0.045 mg/kg, and cyclophosphamide 2200 mg/m2), radiotherapy, and tumor resection, based on standard therapy for intermediate ERMS. At the time of writing, 15 months after treatment completion, the patient remains alive without evidence of ERMS. The thyroid nodules showed no remarkable changes in size since diagnosis.