De novo neuroendocrine transdifferentiation in primary prostate cancer–a phenotype associated with advanced clinico-pathologic features and aggressive outcome

Abdulfatah, Eman; Reichert, Zachery R.; Davenport, Matthew S.; Chinnaiyan, Arul M.; Dadhania, Vipulkumar; Wang, Xiaoming; Mannan, Rahul; Kunju, Lakshmi P.; Hollenbeck, Brent K.; Montgomery, Jeffrey S.; Kaffenberger, Samuel D.; Morgan, Todd M.; Alva, Ajjai; Palapattu, Ganesh S.; Vaishampayan, Ulka N.; Alumkal, Joshi J.; Spratt, Daniel E.; Udager, Aaron M.; Mehra, Rohit

doi:10.1007/s12032-021-01473-2

Cited by 20 publications

(26 citation statements)

References 27 publications

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“…While a small number of presumed de novo cases of PCa with diffuse neuroendocrine marker positivity/differentiation have recently been described, 32,33 all 15 such cases in the current cohort were metastatic lesions; 12 were posttherapy, 11 of which received ADT. Possibly reflecting the dual marker positive nature of these lesions, metastases were noted in both sites common for PCa (lymph nodes, bone), as well as in visceral sites (liver, lung) in which NE manifestations are more typically seen 4 .…”

Section: Discussionmentioning

confidence: 81%

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series

et al. 2022

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Aim Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined. Methods and results We reviewed institutional databases for in‐house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post‐ androgen–deprivation therapy (ADT), and 33 post‐RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small‐cell/high‐grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high‐grade PCa and small‐cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet‐like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single‐cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with ‘Paneth cell‐like’ change: all primary. Conclusions In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small‐cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high‐grade PCa + small‐cell/HGNEC and ‘Paneth cell‐like’ change occur in primary disease.

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Section: Discussionmentioning

confidence: 81%

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series

et al. 2022

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“…In contrast, Tsai et al reported the loss of CCND1 expression to be indicative of small cell-like PCa in patient tissue, as 88% of samples classified as small cell carcinoma have been observed to be CCND1-negative compared to less than 10% of the adenocarcinomas [ 49 ]. Additionally, a recent study in de novo NEPC identified loss of CCND1 expression in patient tissue [ 133 ]. Possibly, CCND1 loss is predominantly involved in de novo-emergence of NEPC.…”

Section: Mechanisms Of T-nepc Developmentmentioning

confidence: 99%

Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

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et al. 2022

J Exp Clin Cancer Res

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Prostate cancer is a hormone-driven disease and its tumor cell growth highly relies on increased androgen receptor (AR) signaling. Therefore, targeted therapy directed against androgen synthesis or AR activation is broadly used and continually improved. However, a subset of patients eventually progresses to castration-resistant disease. To date, various mechanisms of resistance have been identified including the development of AR-independent aggressive variant prostate cancer based on neuroendocrine transdifferentiation (NED). Here, we review the highly complex processes contributing to NED. Genetic, epigenetic, transcriptional aberrations and posttranscriptional modifications are highlighted and the potential interplay of the different factors is discussed.BackgroundAggressive variant prostate cancer (AVPC) with traits of neuroendocrine differentiation emerges in a rising number of patients in recent years. Among others, advanced therapies targeting the androgen receptor axis have been considered causative for this development. Cell growth of AVPC often occurs completely independent of the androgen receptor signal transduction pathway and cells have mostly lost the typical cellular features of prostate adenocarcinoma. This complicates both diagnosis and treatment of this very aggressive disease. We believe that a deeper understanding of the complex molecular pathological mechanisms contributing to transdifferentiation will help to improve diagnostic procedures and develop effective treatment strategies. Indeed, in recent years, many scientists have made important contributions to unravel possible causes and mechanisms in the context of neuroendocrine transdifferentiation. However, the complexity of the diverse molecular pathways has not been captured completely, yet. This narrative review comprehensively highlights the individual steps of neuroendocrine transdifferentiation and makes an important contribution in bringing together the results found so far.

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“…However, we now appreciate that lineage plasticity-most commonly exemplified by loss of AR signaling and a switch from a luminal to an alternate differentiation program-is a resistance mechanism that appears to be increasing in the era of more widespread use of ARSIs 19 . The emergence of tumors with features of lineage plasticity may occur through diverse mechanisms: selection of a pre-existing clone that has already undergone differentiation change, acquisition of new genetic alterations that promote differentiation change, or transdifferentiation of tumor cells through epigenetic mechanisms 17,[20][21][22] .…”

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confidence: 99%

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

et al. 2022

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The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

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De novo neuroendocrine transdifferentiation in primary prostate cancer–a phenotype associated with advanced clinico-pathologic features and aggressive outcome

Cited by 20 publications

References 27 publications

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series

Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

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