Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization
The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase...
Gespeichert in:
| Veröffentlicht in: | Modern pathology 2020-12, Vol.33 (12), p.2458-2472 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2472 |
|---|---|
| container_issue | 12 |
| container_start_page | 2458 |
| container_title | Modern pathology |
| container_volume | 33 |
| creator | Chu, Ying-Hsia Wirth, Lori J. Farahani, Alexander A. Nosé, Vânia Faquin, William C. Dias-Santagata, Dora Sadow, Peter M. |
| description | The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6–480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas. |
| doi_str_mv | 10.1038/s41379-020-0638-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7688509</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0893395222004173</els_id><sourcerecordid>2473251944</sourcerecordid><originalsourceid>FETCH-LOGICAL-c522t-964ff28981a427bb59c077972c646c4b0c59b163f66fbfa32d33c730f1a8dc873</originalsourceid><addsrcrecordid>eNp9kcuKFDEYhQtRnHH0AdxIwI2b0lwriYIgjTcYcKPrkEr96c5YnbRJqqXd-Oqm6XG8LGYVfvKdk8vXdY8Jfk4wUy8KJ0zqHlPc44GpXtzpzolgbaJK3O3OsdKsZ1rQs-5BKVcYEy4Uvd-dMSqZ5Fyfdz9Xc4jBpZ2tmzSndXDIg61LhoKSR19DtAWQX0pIsc8w2woTqptDTmFCzmYXYtra8hLZiEKssM62hj200c6HEgr6HuoGbdMMbpltRm5js3UVcvjRwBQfdve8nQs8ul4vui_v3n5efegvP73_uHpz2TtBae31wL2nSitiOZXjKLTDUmpJ3cAHx0fshB7JwPww-NFbRifGnGTYE6smpyS76F6fenfLuIXJQazZzmaXw9bmg0k2mH93YtiYddobOSglsG4Fz64Lcvq2QKlmG4qDebYR0lIM5VTLYeAMN_Tpf-hVWnL7kCMlGRVEc94ocqJcTqVk8DeXIdgc9ZqTXtP0mqNeI1rmyd-vuEn89tkAegJK24pryH-Ovq311SkETcA-tFBxAaKDKWRw1Uwp3JL-BdlRx0o</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2473251944</pqid></control><display><type>article</type><title>Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>ProQuest Central UK/Ireland</source><source>Alma/SFX Local Collection</source><creator>Chu, Ying-Hsia ; Wirth, Lori J. ; Farahani, Alexander A. ; Nosé, Vânia ; Faquin, William C. ; Dias-Santagata, Dora ; Sadow, Peter M.</creator><creatorcontrib>Chu, Ying-Hsia ; Wirth, Lori J. ; Farahani, Alexander A. ; Nosé, Vânia ; Faquin, William C. ; Dias-Santagata, Dora ; Sadow, Peter M.</creatorcontrib><description>The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6–480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas.</description><identifier>ISSN: 0893-3952</identifier><identifier>EISSN: 1530-0285</identifier><identifier>DOI: 10.1038/s41379-020-0638-5</identifier><identifier>PMID: 32737449</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>13/51 ; 14/63 ; 45/23 ; 45/91 ; 631/208/68 ; 631/67/1459/1843 ; Adolescent ; Adult ; Aged ; AKT2 protein ; Antineoplastic Agents - therapeutic use ; Biomarkers, Tumor - genetics ; Carcinoma - enzymology ; Carcinoma - genetics ; Carcinoma - secondary ; Carcinoma - therapy ; Cdc4 protein ; Copy number ; Databases, Factual ; Disease Progression ; E-cadherin ; Enzyme inhibitors ; Epidermal growth factor receptors ; Female ; Fibrosis ; Gene Fusion ; Gene Rearrangement ; Genetic Predisposition to Disease ; Genotypes ; Histology ; Humans ; Iodine ; Iodine Radioisotopes - therapeutic use ; Janus kinase 2 ; Laboratory Medicine ; Lymph nodes ; Male ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Middle Aged ; Molecular Diagnostic Techniques ; Molecular Targeted Therapy ; Mutation ; Neoplasm Recurrence, Local ; p53 Protein ; Papillary thyroid carcinoma ; Pathology ; Phenotype ; Protein Kinase Inhibitors - therapeutic use ; Protein Kinases - genetics ; Radiopharmaceuticals - therapeutic use ; Retrospective Studies ; Thyroid cancer ; Thyroid gland ; Thyroid Neoplasms - enzymology ; Thyroid Neoplasms - genetics ; Thyroid Neoplasms - pathology ; Thyroid Neoplasms - therapy ; Thyroidectomy ; Time Factors ; Treatment Outcome ; Tumors ; VHL protein ; Young Adult</subject><ispartof>Modern pathology, 2020-12, Vol.33 (12), p.2458-2472</ispartof><rights>2020 United States & Canadian Academy of Pathology</rights><rights>The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020</rights><rights>The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c522t-964ff28981a427bb59c077972c646c4b0c59b163f66fbfa32d33c730f1a8dc873</citedby><cites>FETCH-LOGICAL-c522t-964ff28981a427bb59c077972c646c4b0c59b163f66fbfa32d33c730f1a8dc873</cites><orcidid>0000-0002-0977-530X ; 0000-0003-1036-6367</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2473251944?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,64385,64387,64389,72341</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32737449$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chu, Ying-Hsia</creatorcontrib><creatorcontrib>Wirth, Lori J.</creatorcontrib><creatorcontrib>Farahani, Alexander A.</creatorcontrib><creatorcontrib>Nosé, Vânia</creatorcontrib><creatorcontrib>Faquin, William C.</creatorcontrib><creatorcontrib>Dias-Santagata, Dora</creatorcontrib><creatorcontrib>Sadow, Peter M.</creatorcontrib><title>Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization</title><title>Modern pathology</title><addtitle>Mod Pathol</addtitle><addtitle>Mod Pathol</addtitle><description>The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6–480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas.</description><subject>13/51</subject><subject>14/63</subject><subject>45/23</subject><subject>45/91</subject><subject>631/208/68</subject><subject>631/67/1459/1843</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>AKT2 protein</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Carcinoma - enzymology</subject><subject>Carcinoma - genetics</subject><subject>Carcinoma - secondary</subject><subject>Carcinoma - therapy</subject><subject>Cdc4 protein</subject><subject>Copy number</subject><subject>Databases, Factual</subject><subject>Disease Progression</subject><subject>E-cadherin</subject><subject>Enzyme inhibitors</subject><subject>Epidermal growth factor receptors</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Gene Fusion</subject><subject>Gene Rearrangement</subject><subject>Genetic Predisposition to Disease</subject><subject>Genotypes</subject><subject>Histology</subject><subject>Humans</subject><subject>Iodine</subject><subject>Iodine Radioisotopes - therapeutic use</subject><subject>Janus kinase 2</subject><subject>Laboratory Medicine</subject><subject>Lymph nodes</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Molecular Diagnostic Techniques</subject><subject>Molecular Targeted Therapy</subject><subject>Mutation</subject><subject>Neoplasm Recurrence, Local</subject><subject>p53 Protein</subject><subject>Papillary thyroid carcinoma</subject><subject>Pathology</subject><subject>Phenotype</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Protein Kinases - genetics</subject><subject>Radiopharmaceuticals - therapeutic use</subject><subject>Retrospective Studies</subject><subject>Thyroid cancer</subject><subject>Thyroid gland</subject><subject>Thyroid Neoplasms - enzymology</subject><subject>Thyroid Neoplasms - genetics</subject><subject>Thyroid Neoplasms - pathology</subject><subject>Thyroid Neoplasms - therapy</subject><subject>Thyroidectomy</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>VHL protein</subject><subject>Young Adult</subject><issn>0893-3952</issn><issn>1530-0285</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kcuKFDEYhQtRnHH0AdxIwI2b0lwriYIgjTcYcKPrkEr96c5YnbRJqqXd-Oqm6XG8LGYVfvKdk8vXdY8Jfk4wUy8KJ0zqHlPc44GpXtzpzolgbaJK3O3OsdKsZ1rQs-5BKVcYEy4Uvd-dMSqZ5Fyfdz9Xc4jBpZ2tmzSndXDIg61LhoKSR19DtAWQX0pIsc8w2woTqptDTmFCzmYXYtra8hLZiEKssM62hj200c6HEgr6HuoGbdMMbpltRm5js3UVcvjRwBQfdve8nQs8ul4vui_v3n5efegvP73_uHpz2TtBae31wL2nSitiOZXjKLTDUmpJ3cAHx0fshB7JwPww-NFbRifGnGTYE6smpyS76F6fenfLuIXJQazZzmaXw9bmg0k2mH93YtiYddobOSglsG4Fz64Lcvq2QKlmG4qDebYR0lIM5VTLYeAMN_Tpf-hVWnL7kCMlGRVEc94ocqJcTqVk8DeXIdgc9ZqTXtP0mqNeI1rmyd-vuEn89tkAegJK24pryH-Ovq311SkETcA-tFBxAaKDKWRw1Uwp3JL-BdlRx0o</recordid><startdate>20201201</startdate><enddate>20201201</enddate><creator>Chu, Ying-Hsia</creator><creator>Wirth, Lori J.</creator><creator>Farahani, Alexander A.</creator><creator>Nosé, Vânia</creator><creator>Faquin, William C.</creator><creator>Dias-Santagata, Dora</creator><creator>Sadow, Peter M.</creator><general>Elsevier Inc</general><general>Nature Publishing Group US</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0977-530X</orcidid><orcidid>https://orcid.org/0000-0003-1036-6367</orcidid></search><sort><creationdate>20201201</creationdate><title>Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization</title><author>Chu, Ying-Hsia ; Wirth, Lori J. ; Farahani, Alexander A. ; Nosé, Vânia ; Faquin, William C. ; Dias-Santagata, Dora ; Sadow, Peter M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c522t-964ff28981a427bb59c077972c646c4b0c59b163f66fbfa32d33c730f1a8dc873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/51</topic><topic>14/63</topic><topic>45/23</topic><topic>45/91</topic><topic>631/208/68</topic><topic>631/67/1459/1843</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>AKT2 protein</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Carcinoma - enzymology</topic><topic>Carcinoma - genetics</topic><topic>Carcinoma - secondary</topic><topic>Carcinoma - therapy</topic><topic>Cdc4 protein</topic><topic>Copy number</topic><topic>Databases, Factual</topic><topic>Disease Progression</topic><topic>E-cadherin</topic><topic>Enzyme inhibitors</topic><topic>Epidermal growth factor receptors</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Gene Fusion</topic><topic>Gene Rearrangement</topic><topic>Genetic Predisposition to Disease</topic><topic>Genotypes</topic><topic>Histology</topic><topic>Humans</topic><topic>Iodine</topic><topic>Iodine Radioisotopes - therapeutic use</topic><topic>Janus kinase 2</topic><topic>Laboratory Medicine</topic><topic>Lymph nodes</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Molecular Diagnostic Techniques</topic><topic>Molecular Targeted Therapy</topic><topic>Mutation</topic><topic>Neoplasm Recurrence, Local</topic><topic>p53 Protein</topic><topic>Papillary thyroid carcinoma</topic><topic>Pathology</topic><topic>Phenotype</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Protein Kinases - genetics</topic><topic>Radiopharmaceuticals - therapeutic use</topic><topic>Retrospective Studies</topic><topic>Thyroid cancer</topic><topic>Thyroid gland</topic><topic>Thyroid Neoplasms - enzymology</topic><topic>Thyroid Neoplasms - genetics</topic><topic>Thyroid Neoplasms - pathology</topic><topic>Thyroid Neoplasms - therapy</topic><topic>Thyroidectomy</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><topic>VHL protein</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chu, Ying-Hsia</creatorcontrib><creatorcontrib>Wirth, Lori J.</creatorcontrib><creatorcontrib>Farahani, Alexander A.</creatorcontrib><creatorcontrib>Nosé, Vânia</creatorcontrib><creatorcontrib>Faquin, William C.</creatorcontrib><creatorcontrib>Dias-Santagata, Dora</creatorcontrib><creatorcontrib>Sadow, Peter M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Biological Science Journals</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Modern pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chu, Ying-Hsia</au><au>Wirth, Lori J.</au><au>Farahani, Alexander A.</au><au>Nosé, Vânia</au><au>Faquin, William C.</au><au>Dias-Santagata, Dora</au><au>Sadow, Peter M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization</atitle><jtitle>Modern pathology</jtitle><stitle>Mod Pathol</stitle><addtitle>Mod Pathol</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>33</volume><issue>12</issue><spage>2458</spage><epage>2472</epage><pages>2458-2472</pages><issn>0893-3952</issn><eissn>1530-0285</eissn><abstract>The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6–480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>32737449</pmid><doi>10.1038/s41379-020-0638-5</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-0977-530X</orcidid><orcidid>https://orcid.org/0000-0003-1036-6367</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0893-3952 |
| ispartof | Modern pathology, 2020-12, Vol.33 (12), p.2458-2472 |
| issn | 0893-3952 1530-0285 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7688509 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | 13/51 14/63 45/23 45/91 631/208/68 631/67/1459/1843 Adolescent Adult Aged AKT2 protein Antineoplastic Agents - therapeutic use Biomarkers, Tumor - genetics Carcinoma - enzymology Carcinoma - genetics Carcinoma - secondary Carcinoma - therapy Cdc4 protein Copy number Databases, Factual Disease Progression E-cadherin Enzyme inhibitors Epidermal growth factor receptors Female Fibrosis Gene Fusion Gene Rearrangement Genetic Predisposition to Disease Genotypes Histology Humans Iodine Iodine Radioisotopes - therapeutic use Janus kinase 2 Laboratory Medicine Lymph nodes Male Medicine Medicine & Public Health Metastases Metastasis Middle Aged Molecular Diagnostic Techniques Molecular Targeted Therapy Mutation Neoplasm Recurrence, Local p53 Protein Papillary thyroid carcinoma Pathology Phenotype Protein Kinase Inhibitors - therapeutic use Protein Kinases - genetics Radiopharmaceuticals - therapeutic use Retrospective Studies Thyroid cancer Thyroid gland Thyroid Neoplasms - enzymology Thyroid Neoplasms - genetics Thyroid Neoplasms - pathology Thyroid Neoplasms - therapy Thyroidectomy Time Factors Treatment Outcome Tumors VHL protein Young Adult |
| title | Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T01%3A11%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Clinicopathologic%20features%20of%20kinase%20fusion-related%20thyroid%20carcinomas:%20an%20integrative%20analysis%20with%20molecular%20characterization&rft.jtitle=Modern%20pathology&rft.au=Chu,%20Ying-Hsia&rft.date=2020-12-01&rft.volume=33&rft.issue=12&rft.spage=2458&rft.epage=2472&rft.pages=2458-2472&rft.issn=0893-3952&rft.eissn=1530-0285&rft_id=info:doi/10.1038/s41379-020-0638-5&rft_dat=%3Cproquest_pubme%3E2473251944%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2473251944&rft_id=info:pmid/32737449&rft_els_id=S0893395222004173&rfr_iscdi=true |