A comparison of adult rhabdomyosarcoma and high-grade neuroendocrine carcinoma of the urinary bladder reveals novel PPP1R12A fusions in rhabdomyosarcoma

Hum Pathol. 2019 Jun:88:48-59. doi: 10.1016/j.humpath.2019.03.007. Epub 2019 Apr 1.


Some rhabdomyosarcomas and sarcomatoid carcinomas with heterologous rhabdomyosarcomatous elements resemble high-grade neuroendocrine carcinoma, creating a diagnostic difficulty. The purpose of this study was to characterize the overlap of adult genitourinary rhabdomyosarcomas, excluding those occurring at paratesticular sites, with high-grade neuroendocrine carcinoma and identify features helpful in their separation. Seventeen cases of rhabdomyosarcoma (11 from the urinary bladder and 3 each from kidney and prostate) were compared to 10 cases of high-grade neuroendocrine carcinoma from the urinary bladder. These tumors were analyzed by immunohistochemistry for desmin, MyoD1, myogenin, chromogranin, synaptophysin, CD56, TTF1, and ASCL1, and RNA sequencing was performed on 4 cases of bladder rhabdomyosarcoma (2 rhabdomyosarcomas and 2 sarcomatoid-rhabdomyosarcoma) and 10 cases of bladder high-grade neuroendocrine carcinoma. This was compared to public data from 414 typical urothelial carcinomas from The Cancer Genome Atlas dataset. Morphologic and immunophenotypic overlap with high-grade neuroendocrine carcinoma was seen in half of the bladder tumors, which included 4 rhabdomyosarcomas and 2 sarcomatoid rhabdomyosarcomas. RNA sequencing confirmed expression of neuroendocrine markers in these cases (2 rhabdomyosarcomas and 2 sarcomatoid rhabdomyosarcomas). Differential neuroendocrine differentiation was highlighted by ASCL1 protein expression only in high-grade neuroendocrine carcinoma. Moreover, both a pure alveolar rhabdomyosarcoma and sarcomatoid rhabdomyosarcoma of the urinary bladder demonstrated a fusion involving PPP1R12A. In summary, adult rhabdomyosarcomas of the urinary bladder are molecularly distinct from high-grade neuroendocrine carcinomas based on specific patterns of expression of myogenic and epithelial to mesenchymal transition-related transcription factors as well as the presence of a novel PPP1R12A fusion which is seen in a subset of cases.

Keywords: ASCL1; Genitourinary; High-grade neuroendocrine carcinoma; PPP1R12A; Rhabdomyosarcoma; Sarcomatoid carcinoma; Urinary bladder.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Biomarkers, Tumor / analysis
  • Carcinoma, Neuroendocrine / genetics*
  • Diagnosis, Differential
  • Female
  • Gene Expression
  • Gene Fusion / genetics*
  • Humans
  • Kidney Neoplasms / genetics
  • Male
  • Middle Aged
  • Muscle Development / genetics
  • Myosin-Light-Chain Phosphatase / genetics*
  • Prostatic Neoplasms / genetics
  • Rhabdomyosarcoma / genetics*
  • Urinary Bladder Neoplasms / genetics*


  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Myosin-Light-Chain Phosphatase
  • PPP1R12A protein, human