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- W2154676564 abstract "Sir: Sarcomatoid carcinomas (SC) are a rare histological variant of prostate cancer associated with progression in the absence of PSA elevation1 and, overall, a poor prognosis.2 These tumours commonly present alongside conventional adenocarcinoma and can show immunohistochemical (IHC) evidence of prostatic origin.3 However, loss of expression of the androgen receptor (AR) and AR-regulated proteins (including PSA and ERG in ERG gene-fusion positive cancers) in SC could introduce a diagnostic dilemma as to whether a second primary has occurred. Moreover, IHC is unable to establish conclusively whether SC has the same origin as co-occurring adenocarcinomas. We aimed to use fluorescence in-situ hybridization (FISH) to establish whether SC and adenocarcinoma shared a common and clonal genomic aberration that would confirm their common origin. Gene fusions involving transcription factors of the ETS family, most commonly ERG but also ETV1 and ETV4, and a hormone-driven promoter occur in up to 70% of prostate adenocarcinomas.4 Although rearrangements involving ERG can occur in other cancers, concurrent deletion of the 5′ region of ERG is specific to prostate cancer and has not been observed in studies of large numbers of tumours from a wide range of histological subtypes, including four types of sarcomas (i.e. liposarcomas, leiomyosarcomas, malignant fibrous histiocytomas and Kaposi's sarcomas), evaluated using a break-apart ERG FISH assay.5 Here we present three cases of SC arising in patients with a concomitant or previous diagnosis of prostate acinar adenocarcinoma. Two patients recurred with an SC mass and low PSA levels while receiving adjuvant androgen deprivation therapy after radical radiotherapy for a localized adenocarcinoma (Figure 1: short dashes rectangle). In the third case, a focal area of SC was detected adjacent to adenocarcinoma in a radical prostatectomy specimen and accounting for <0.5% of total tumour volume (Figure 1: solid rectangle). In all three cases, the acinar adenocarcinoma components were Gleason ≥8 (Figure 1A–C) and showed IHC positivity for AR (clone AR441; Dako, Carpinteria, CA, USA), PSA and ERG (Figure 1D–F) (clone EPR3864; Abcam, Cambridge, UK). Two of the adenocarcinomas showed diffuse NKX3.1 (clone EPR14970; Abcam) positivity and one was negative. In all three cases, SC presented as a high-grade, pleomorphic malignancy with marked anisokaryosis and karyomegaly (Figure 1G–I) and one case showed focal chondroid differentiation. All the SC areas were negative for AR, PSA, ERG (Figure 1J–L) and NKX3.1, and negative or equivocal for the epithelial markers AE1/AE3, MNF116, CAM5.2, CK7, CK20 and CK5/6, and other commonly used prostate markers, PSAP and AMACR. A panel of stromal markers including desmin, myogenin, SMA, caldesmon, CD117 and CD34 were also negative, excluding the diagnosis of a prostate stroma sarcoma. In the relapsed cases, it was therefore unclear whether the SC was a second primary, potentially radiation-induced, or had evolved from the same epithelial origin as the acinar adenocarcinoma. We performed ERG break-apart FISH, as described previously6 (Figure 2A). Briefly, probes mapping to ERG or the region immediately 5′ were labelled and hybridized onto tissue sections that were then scanned using an Ariol SL-50 microscope (Applied Imaging, San Jose, CA, USA). A minimum of 100 nuclei per case were evaluated. In keeping with the finding of positive ERG IHC, the adenocarcinoma showed an ERG rearrangement. In all three cases this occurred secondary to deletion of the 5′ region and was associated with normal copy number (Class Edel: Figure 2B). Adjacent normal cells invariably showed normal paired probes. Critically, the three SCs also showed an ERG rearrangement secondary to deletion (Figure 1M–O). Although studies of ERG IHC on hormone-naive adenocarcinomas have reported a 99% correlation for ERG-fusion positivity defined by FISH,7 our study demonstrates that loss of AR expression due to a change to a sarcomatoid phenotype in prostate cancer harbouring an ERG gene fusion is associated with negative ERG IHC. Similarly, we recently reported a case of adenocarcinoma in liver metastases progressing on the androgen-synthesis inhibitor, abiraterone acetate, that showed loss of AR expression and consequently negativity for PSA and ERG.8 Additionally, two SC cases showed more than 10 copies of gene-fusion sequences and wild-type alleles in >80% of nuclei, indicating gross aneuploidy associated with the SC phenotype (Figure 1M,O). To the best of our knowledge, this is the first study to use a genomic assay to confirm the epithelial origin of prostate SC and exclude the diagnosis of a secondary cancer. Critically, this was possible due to an ERG gene fusion secondary to a deletion being specific to prostate cancer, and our ERG FISH assay would not have been conclusive for other molecular types. Larger series of prostate SC could be interrogated similarly to confirm that this observation is broadly applicable. Next-generation sequencing studies were beyond the scope of our study, but could allow further dissection of the shared and private genomic aberrations that occur following phenotypic change, in this case to SC, of prostate epithelial adenocarcinoma. The ICR authors were supported by the Prostate Cancer Foundation (Santa Monica, CA, USA), Prostate Cancer UK, Stand Up to Cancer and Cancer Research UK." @default.
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- W2154676564 date "2014-11-10" @default.
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- W2154676564 title "Sarcomatoid carcinoma of the prostate: <i><scp>ERG</scp></i> fluorescence <i>in‐situ</i> hybridization confirms epithelial origin" @default.
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- W2154676564 doi "https://doi.org/10.1111/his.12493" @default.
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