Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT)
While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neo...
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| Veröffentlicht in: | Histopathology 2023-10, Vol.83 (4), p.546-558 |
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| creator | Neyaz, Azfar Crotty, Rory Rickelt, Steffen Pankaj, Amaya Stojanova, Marija Michelakos, Theodoros P Sekigami, Yurie Kontos, Filippos Parrack, Paige H Patil, Deepa T Heaphy, Christopher M Ferrone, Cristina R Deshpande, Vikram |
| description | While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1-positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere-specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence.
Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases.
ARX reactivity correlated with worse disease-free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT-positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P |
| doi_str_mv | 10.1111/his.14996 |
| format | Article |
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Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases.
ARX reactivity correlated with worse disease-free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT-positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT-negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX-positive tumours and 7.5% (5/67) of ARX-negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX-positive tumours recurred compared to 0 of 33 ARX-negative tumours and 33.3% (3/9) ALT-positive tumours showed recurrence versus 4.4% (2/45) ALT-negative tumours.
Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low-grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention.</description><identifier>ISSN: 0309-0167</identifier><identifier>EISSN: 1365-2559</identifier><identifier>DOI: 10.1111/his.14996</identifier><identifier>PMID: 37455385</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Beta cells ; Fluorescence in situ hybridization ; Immunohistochemistry ; Neuroendocrine tumors ; Pancreas ; Telomeres ; Transcriptomes</subject><ispartof>Histopathology, 2023-10, Vol.83 (4), p.546-558</ispartof><rights>2023 John Wiley & Sons Ltd.</rights><rights>Copyright © 2023 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c313t-716e20bb5b10a4a898bd1174d52d42171dffdd0b0f4b6de20fab14af25d1011e3</citedby><cites>FETCH-LOGICAL-c313t-716e20bb5b10a4a898bd1174d52d42171dffdd0b0f4b6de20fab14af25d1011e3</cites><orcidid>0000-0002-4047-0926 ; 0000-0003-0174-2754 ; 0000-0002-5224-7764 ; 0000-0001-7837-1299 ; 0000-0001-5321-190X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37455385$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Neyaz, Azfar</creatorcontrib><creatorcontrib>Crotty, Rory</creatorcontrib><creatorcontrib>Rickelt, Steffen</creatorcontrib><creatorcontrib>Pankaj, Amaya</creatorcontrib><creatorcontrib>Stojanova, Marija</creatorcontrib><creatorcontrib>Michelakos, Theodoros P</creatorcontrib><creatorcontrib>Sekigami, Yurie</creatorcontrib><creatorcontrib>Kontos, Filippos</creatorcontrib><creatorcontrib>Parrack, Paige H</creatorcontrib><creatorcontrib>Patil, Deepa T</creatorcontrib><creatorcontrib>Heaphy, Christopher M</creatorcontrib><creatorcontrib>Ferrone, Cristina R</creatorcontrib><creatorcontrib>Deshpande, Vikram</creatorcontrib><title>Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT)</title><title>Histopathology</title><addtitle>Histopathology</addtitle><description>While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1-positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere-specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence.
Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases.
ARX reactivity correlated with worse disease-free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT-positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT-negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX-positive tumours and 7.5% (5/67) of ARX-negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX-positive tumours recurred compared to 0 of 33 ARX-negative tumours and 33.3% (3/9) ALT-positive tumours showed recurrence versus 4.4% (2/45) ALT-negative tumours.
Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low-grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention.</description><subject>Beta cells</subject><subject>Fluorescence in situ hybridization</subject><subject>Immunohistochemistry</subject><subject>Neuroendocrine tumors</subject><subject>Pancreas</subject><subject>Telomeres</subject><subject>Transcriptomes</subject><issn>0309-0167</issn><issn>1365-2559</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpd0ctKxDAUBuAgio6jC19AAm5mFtWcJunF3TB4gwFFFNyVNDnVSpuMSSv49kYdXZhNNl9-Ts5PyBGwU4jn7KUNpyDKMtsiE-CZTFIpy20yYZyVCYMs3yP7IbwyBjlP012yx3MhJS_khLzfeTStHlr7TD3q0Xu0Gmlr6VpZ7VENraYWR-_QGqd9a5EOY-9GH86pdx1S19DF_RNV1lDVDehtfPKOtEP7PLyg_QqOZMDO9egx0Nli9TA_IDuN6gIebu4peby8eFheJ6vbq5vlYpVoDnxIcsgwZXUta2BKqKIsagOQCyNTI1LIwTSNMaxmjagzE2mjahCqSaUBBoB8SmY_uWvv3kYMQ9W3QWPXKYtuDFVa8CITEqCI9OQffY2_tHG6qDKes7IQIqr5j9LeheCxqda-7ZX_qIBVX2VUsYzqu4xojzeJY92j-ZO_2-efPeiFnQ</recordid><startdate>20231001</startdate><enddate>20231001</enddate><creator>Neyaz, Azfar</creator><creator>Crotty, Rory</creator><creator>Rickelt, Steffen</creator><creator>Pankaj, Amaya</creator><creator>Stojanova, Marija</creator><creator>Michelakos, Theodoros P</creator><creator>Sekigami, Yurie</creator><creator>Kontos, Filippos</creator><creator>Parrack, Paige H</creator><creator>Patil, Deepa T</creator><creator>Heaphy, Christopher M</creator><creator>Ferrone, Cristina R</creator><creator>Deshpande, Vikram</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4047-0926</orcidid><orcidid>https://orcid.org/0000-0003-0174-2754</orcidid><orcidid>https://orcid.org/0000-0002-5224-7764</orcidid><orcidid>https://orcid.org/0000-0001-7837-1299</orcidid><orcidid>https://orcid.org/0000-0001-5321-190X</orcidid></search><sort><creationdate>20231001</creationdate><title>Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT)</title><author>Neyaz, Azfar ; Crotty, Rory ; Rickelt, Steffen ; Pankaj, Amaya ; Stojanova, Marija ; Michelakos, Theodoros P ; Sekigami, Yurie ; Kontos, Filippos ; Parrack, Paige H ; Patil, Deepa T ; Heaphy, Christopher M ; Ferrone, Cristina R ; Deshpande, Vikram</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c313t-716e20bb5b10a4a898bd1174d52d42171dffdd0b0f4b6de20fab14af25d1011e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Beta cells</topic><topic>Fluorescence in situ hybridization</topic><topic>Immunohistochemistry</topic><topic>Neuroendocrine tumors</topic><topic>Pancreas</topic><topic>Telomeres</topic><topic>Transcriptomes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Neyaz, Azfar</creatorcontrib><creatorcontrib>Crotty, Rory</creatorcontrib><creatorcontrib>Rickelt, Steffen</creatorcontrib><creatorcontrib>Pankaj, Amaya</creatorcontrib><creatorcontrib>Stojanova, Marija</creatorcontrib><creatorcontrib>Michelakos, Theodoros P</creatorcontrib><creatorcontrib>Sekigami, Yurie</creatorcontrib><creatorcontrib>Kontos, Filippos</creatorcontrib><creatorcontrib>Parrack, Paige H</creatorcontrib><creatorcontrib>Patil, Deepa T</creatorcontrib><creatorcontrib>Heaphy, Christopher M</creatorcontrib><creatorcontrib>Ferrone, Cristina R</creatorcontrib><creatorcontrib>Deshpande, Vikram</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Histopathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Neyaz, Azfar</au><au>Crotty, Rory</au><au>Rickelt, Steffen</au><au>Pankaj, Amaya</au><au>Stojanova, Marija</au><au>Michelakos, Theodoros P</au><au>Sekigami, Yurie</au><au>Kontos, Filippos</au><au>Parrack, Paige H</au><au>Patil, Deepa T</au><au>Heaphy, Christopher M</au><au>Ferrone, Cristina R</au><au>Deshpande, Vikram</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT)</atitle><jtitle>Histopathology</jtitle><addtitle>Histopathology</addtitle><date>2023-10-01</date><risdate>2023</risdate><volume>83</volume><issue>4</issue><spage>546</spage><epage>558</epage><pages>546-558</pages><issn>0309-0167</issn><eissn>1365-2559</eissn><abstract>While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1-positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere-specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence.
Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases.
ARX reactivity correlated with worse disease-free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT-positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT-negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX-positive tumours and 7.5% (5/67) of ARX-negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX-positive tumours recurred compared to 0 of 33 ARX-negative tumours and 33.3% (3/9) ALT-positive tumours showed recurrence versus 4.4% (2/45) ALT-negative tumours.
Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low-grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37455385</pmid><doi>10.1111/his.14996</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-4047-0926</orcidid><orcidid>https://orcid.org/0000-0003-0174-2754</orcidid><orcidid>https://orcid.org/0000-0002-5224-7764</orcidid><orcidid>https://orcid.org/0000-0001-7837-1299</orcidid><orcidid>https://orcid.org/0000-0001-5321-190X</orcidid></addata></record> |
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| source | Wiley Online Library Journals Frontfile Complete |
| subjects | Beta cells Fluorescence in situ hybridization Immunohistochemistry Neuroendocrine tumors Pancreas Telomeres Transcriptomes |
| title | Predicting recurrence in pancreatic neuroendocrine tumours: role of ARX and alternative lengthening of telomeres (ALT) |
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