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.