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

Sounak Gupta; Carlos P. Sosa; Farhad Kosari; Andrew Folpe; Kaustubh N. Bhinge; Lin Yang; Alireza Agahi; Sarah H. Johnson; Igor Frank; Stephen A. Boorjian; Donna E. Hansel; Hikmat A. Al-Ahmadie; Victor E. Reuter; George Vasmatzis; Rafael E. Jimenez; Loren Herrera-Hernandez; John C. Cheville

doi:10.1016/j.humpath.2019.03.007

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

Sounak Gupta, Carlos P. Sosa, Farhad Kosari, Andrew Folpe, Kaustubh N. Bhinge, Lin Yang, Alireza Agahi, Sarah H. Johnson, Igor Frank, Stephen A. Boorjian, Donna E. Hansel, Hikmat A. Al-Ahmadie, Victor E. Reuter, George Vasmatzis, Rafael E. Jimenez, Loren Herrera-Hernandez, John C. Cheville

Pathology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	48-59
Number of pages	12
Journal	Human Pathology
Volume	88
DOIs	https://doi.org/10.1016/j.humpath.2019.03.007
State	Published - Jun 2019

Keywords

ASCL1
Genitourinary
High-grade neuroendocrine carcinoma
PPP1R12A
Rhabdomyosarcoma
Sarcomatoid carcinoma
Urinary bladder

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.1016/j.humpath.2019.03.007

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Gupta, S., Sosa, C. P., Kosari, F., Folpe, A., Bhinge, K. N., Yang, L., Agahi, A., Johnson, S. H., Frank, I., Boorjian, S. A., Hansel, D. E., Al-Ahmadie, H. A., Reuter, V. E., Vasmatzis, G., Jimenez, R. E., Herrera-Hernandez, L., & Cheville, J. C. (2019). A comparison of adult rhabdomyosarcoma and high-grade neuroendocrine carcinoma of the urinary bladder reveals novel PPP1R12A fusions in rhabdomyosarcoma. Human Pathology, 88, 48-59. https://doi.org/10.1016/j.humpath.2019.03.007

Gupta, S, Sosa, CP, Kosari, F, Folpe, A, Bhinge, KN, Yang, L, Agahi, A, Johnson, SH, Frank, I, Boorjian, SA, Hansel, DE, Al-Ahmadie, HA, Reuter, VE, Vasmatzis, G, Jimenez, RE, Herrera-Hernandez, L & Cheville, JC 2019, 'A comparison of adult rhabdomyosarcoma and high-grade neuroendocrine carcinoma of the urinary bladder reveals novel PPP1R12A fusions in rhabdomyosarcoma', Human Pathology, vol. 88, pp. 48-59. https://doi.org/10.1016/j.humpath.2019.03.007

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

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",

author = "Sounak Gupta and Sosa, {Carlos P.} and Farhad Kosari and Andrew Folpe and Bhinge, {Kaustubh N.} and Lin Yang and Alireza Agahi and Johnson, {Sarah H.} and Igor Frank and Boorjian, {Stephen A.} and Hansel, {Donna E.} and Al-Ahmadie, {Hikmat A.} and Reuter, {Victor E.} and George Vasmatzis and Jimenez, {Rafael E.} and Loren Herrera-Hernandez and Cheville, {John C.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

doi = "10.1016/j.humpath.2019.03.007",

language = "English (US)",

volume = "88",

pages = "48--59",

journal = "Human Pathology",

issn = "0046-8177",

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T1 - A comparison of adult rhabdomyosarcoma and high-grade neuroendocrine carcinoma of the urinary bladder reveals novel PPP1R12A fusions in rhabdomyosarcoma

AU - Gupta, Sounak

AU - Sosa, Carlos P.

AU - Kosari, Farhad

AU - Folpe, Andrew

AU - Bhinge, Kaustubh N.

AU - Yang, Lin

AU - Agahi, Alireza

AU - Johnson, Sarah H.

AU - Frank, Igor

AU - Boorjian, Stephen A.

AU - Hansel, Donna E.

AU - Al-Ahmadie, Hikmat A.

AU - Reuter, Victor E.

AU - Vasmatzis, George

AU - Jimenez, Rafael E.

AU - Herrera-Hernandez, Loren

AU - Cheville, John C.

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

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KW - High-grade neuroendocrine carcinoma

KW - PPP1R12A

KW - Rhabdomyosarcoma

KW - Sarcomatoid carcinoma

KW - Urinary bladder

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

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Keywords

ASJC Scopus subject areas

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