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

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

Sounak Gupta  1 , Carlos P Sosa  2 , Farhad Kosari  3 , Andrew Folpe  4 , Kaustubh N Bhinge  5 , Lin Yang  6 , Alireza Agahi  7 , Sarah H Johnson  8 , Igor Frank  9 , Stephen A Boorjian  10 , Donna E Hansel  11 , Hikmat A Al-Ahmadie  12 , Victor E Reuter  13 , George Vasmatzis  14 , Rafael E Jimenez  15 , Loren Herrera-Hernandez  16 , John C Cheville  17
Affiliations
Comparative Study

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

Sounak Gupta et al. Hum Pathol. 2019 Jun.

Abstract

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.

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Figures

Figure1:
Figure1:. Adult Genitourinary Rhabdomyosarcoma: Histopathology.
Representative H&E stained images of pure rhabdomyosarcomas of the urinary bladder (A, B; 400X magnification) and a sarcomatoid carcinoma with heterologous rhabdomyosarcomatous elements showing morphologic overlap with small cell carcinoma (C; 400x magnification).
Figure2:
Figure2:. Adult Genitourinary Rhabdomyosarcoma: Immunohistochemistry.
Representative images detailing the immunophenotype of rhabdomyosarcomas of the urinary bladder, which demonstrate morphologic overlap with small cell carcinoma (Case1: A-H, Case2: I-P, 200 X magnification). H&E stained images (A, I), immunohistochemistry for Desmin (B, J), Myogenin (C, K), MyoD1 (D, L), Synaptophysin (E, M), Chromogranin (F, N), CD56 (G, O), and TTF1 (H, P) is shown.
Figure3:
Figure3:. Adult Genitourinary Rhabdomyosarcoma: Neuroendocrine Gene Expression.
Relative gene expression (log2) for urothelial carcinoma (n=414), high-grade neuroendocrine carcinomas (n=10), sarcomatoid carcinoma with rhabdomyosarcomatous elements (n=2) and pure rhabdomyosarcomas (n=2) for PCSK1 (A), SCG2 (B), NCAM1 (C), CHGB (D), CHGA (E), SYP (F), ASCL1 (G), and INSM1 (H) is shown.
Figure4:
Figure4:. Gene Expression of Transcriptional Regulators of Myogenesis.
Relative gene expression (log2) for urothelial carcinoma (n=414), high-grade neuroendocrine carcinomas (n=10), carcinoma with rhabdomyosarcomatous elements (n=2) and pure rhabdomyosarcomas (n=2) for MYOD1 (A) and Myogenin (B), FOXO1 (C), PAX7 (D), PAX3 (E) and BCOR (F) is shown.
Figure5:
Figure5:. Gene Expression of Transcriptional Regulators of Epithelial to Mesenchymal Transition.
Relative gene expression (log2) for urothelial carcinoma (n=414), high-grade neuroendocrine carcinomas (n=10), carcinoma with rhabdomyosarcomatous elements (n=2) and pure rhabdomyosarcomas (n=2) for ZEB1 (A) and ZEB2 (B), SNAI2 (C) and TWIST1 (D) is shown.
Figure6:
Figure6:. Adult Genitourinary Rhabdomyosarcoma: Immunohistochemistry, ASCL1.
Representative H&E stained images and corresponding ASCL1 expression in a typical urothelial carcinoma (A, B, 200 X magnification), high-grade neuroendocrine carcinoma (C, D, 200 X magnification) and a pure rhabdomyosarcoma (E, F, 200 X magnification) is shown.
Figure7:
Figure7:. Confirmation of PPP1R12A Gene Fusion in Pure Rhabdomyosarcomas of the Bladder.
A schematic representation of the PPP1R12A-LIN7A and PPP1R12A-PTPRQ structural variants has been depicted in A. Pyrosequencing traces demonstrate the breakpoint between exon 2 of PPP1R12A and exon 2 of LIN7A on forward (B) and reverse (C) traces. Similarly, the breakpoint between exon 10 of PPP1R12A and exon 4 of PTPRQ has been shown on both forward (D) and reverse (E) traces.
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