title: ERG-TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal origin.
abstract: Prostatic carcinoma is a heterogeneous disease with frequent multifocality and variability in morphology. Particularly, prostatic small cell carcinoma is a rare variant with aggressive behavior. Distinction between small cell carcinoma of the prostate and urinary bladder may be challenging, especially in small biopsy specimens without associated prostatic adenocarcinoma or urothelial carcinoma. Recently, gene fusions between ETS genes, particularly ETS-related gene (ERG), and transmembrane protease, serine 2 (TMPRSS2) have been identified as a frequent event in prostate cancer. Thus, molecular methods may be helpful in determining the primary site of small cell carcinoma. Thirty cases of prostatic small cell carcinoma from the authors' archives were studied, among which 13 had concurrent prostatic adenocarcinoma. Tricolor fluorescence in situ hybridization (FISH) was performed on formalin-fixed paraffin-embedded tissue sections with a probe cocktail for 3'/5' ERG and TMPRSS2. Cases of small cell carcinoma of the bladder and conventional prostatic adenocarcinoma (25 each) were also tested as controls. ERG gene alterations were found only in prostate malignancies and not in benign prostatic tissue or bladder small cell carcinoma. TMPRSS2-ERG gene fusion was found in 47% (14/30) of prostatic small cell carcinoma. Of cases with concurrent prostatic adenocarcinoma, 85% (11/13) had identical findings in both components. In 20% of rearranged cases, the ERG abnormality was associated with 5' ERG deletion. In 17% (5/30) of cases, gain of the 21q22 locus was present. Two cases showed discordant aberrations in the small cell carcinoma and adenocarcinoma, one with deletion of 5' ERG and one with gain of chromosome 21q, both in only the adenocarcinoma component. Small cell carcinoma of the prostate demonstrates TMPRSS2-ERG rearrangement with comparable frequency to prostatic adenocarcinoma. In cases with concurrent adenocarcinoma and small cell carcinoma, the majority showed identical abnormalities in both components, indicating a likely common clonal origin. Discordant alterations were present in rare cases, suggesting that acquisition of additional genetic changes in multifocal tumors may be responsible for disease progression to a more aggressive phenotype. TMPRSS2-ERG fusion is absent in bladder small cell carcinoma, supporting the utility of FISH in distinguishing prostate from bladder primary tumors and identifying metastatic small cell carcinoma of unknown origin.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Williamson
authors.forename: Shaobo
authors.initials: S
authors.lastname: Zhang
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Yao
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Beltran
authors.forename: Steven
authors.initials: S
authors.lastname: Shen
authors.forename: Adeboye O
authors.initials: AO
authors.lastname: Osunkoya
authors.forename: Gregory T
authors.initials: GT
authors.lastname: MacLennan
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Montironi
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human