A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma
Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAF mutation but common RET gene rearrangements. Using strict criteria,...
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| Published in: | Modern pathology Vol. 36; no. 12; p. 100329 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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01.12.2023
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| ISSN: | 1530-0285, 1530-0285 |
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| Abstract | Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAF
mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAF
mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAF
-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAF
-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions. |
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| AbstractList | Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions. Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAF mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAF mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAF -mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAF -negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions. |
| Author | Sywak, Mark Wright, Dale Crayton, Henry Robinson, Bruce G Gill, Anthony J Wang, Bin Ahadi, Mahsa S Aniss, Ahmad Glover, Anthony R Chou, Angela Gild, Matti L Tsang, Venessa Clarkson, Adele Sheen, Amy Sidhu, Stanley B Qiu, Min Ru Delbridge, Leigh Graf, Nicole Singh, Nisha Turchini, John Sioson, Loretta Rathi, Vivek Leong, David Benitez-Aguirre, Paul Kumar, Amit Clifton-Bligh, Roderick J |
| Author_xml | – sequence: 1 givenname: Angela surname: Chou fullname: Chou, Angela email: AngelaShihYuan.Chou@health.nsw.gov.au organization: NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia. Electronic address: AngelaShihYuan.Chou@health.nsw.gov.au – sequence: 2 givenname: Min Ru surname: Qiu fullname: Qiu, Min Ru organization: Department of Anatomical Pathology, SydPATH, St Vincent's Hospital, Darlinghurst, New South Wales, Australia; University of NSW, Randwick, New South Wales, Australia – sequence: 3 givenname: Henry surname: Crayton fullname: Crayton, Henry organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia – sequence: 4 givenname: Bin surname: Wang fullname: Wang, Bin organization: Department of Anatomical Pathology, SydPATH, St Vincent's Hospital, Darlinghurst, New South Wales, Australia – sequence: 5 givenname: Mahsa S surname: Ahadi fullname: Ahadi, Mahsa S organization: NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia – sequence: 6 givenname: John surname: Turchini fullname: Turchini, John organization: Department of Anatomical Pathology, Douglass Hanly Moir Pathology (A Sonic Healthcare Practice), Macquarie Park, New South Wales, Australia; Discipline of Pathology, Macquarie Medical School, Macquarie University, New South Wales, Australia – sequence: 7 givenname: Adele surname: Clarkson fullname: Clarkson, Adele organization: NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia – sequence: 8 givenname: Loretta surname: Sioson fullname: Sioson, Loretta organization: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia – sequence: 9 givenname: Amy surname: Sheen fullname: Sheen, Amy organization: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia – sequence: 10 givenname: Nisha surname: Singh fullname: Singh, Nisha organization: NSW Health Pathology, Cytogenetics Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia – sequence: 11 givenname: Roderick J surname: Clifton-Bligh fullname: Clifton-Bligh, Roderick J organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia – sequence: 12 givenname: Bruce G surname: Robinson fullname: Robinson, Bruce G organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia – sequence: 13 givenname: Matti L surname: Gild fullname: Gild, Matti L organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia – sequence: 14 givenname: Venessa surname: Tsang fullname: Tsang, Venessa organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia – sequence: 15 givenname: David surname: Leong fullname: Leong, David organization: Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, University of Sydney, New South Wales, Australia – sequence: 16 givenname: Stanley B surname: Sidhu fullname: Sidhu, Stanley B organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, University of Sydney, New South Wales, Australia – sequence: 17 givenname: Mark surname: Sywak fullname: Sywak, Mark organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, University of Sydney, New South Wales, Australia – sequence: 18 givenname: Leigh surname: Delbridge fullname: Delbridge, Leigh organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, University of Sydney, New South Wales, Australia – sequence: 19 givenname: Ahmad surname: Aniss fullname: Aniss, Ahmad organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, University of Sydney, New South Wales, Australia – sequence: 20 givenname: Dale surname: Wright fullname: Wright, Dale organization: Cytogenetics Department, Sydney Genome Diagnostics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; Specialty of Genome Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia – sequence: 21 givenname: Nicole surname: Graf fullname: Graf, Nicole organization: Histopathology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia – sequence: 22 givenname: Amit surname: Kumar fullname: Kumar, Amit organization: Diagnostic Genomics, Monash Health Pathology, Monash Health, Clayton, Victoria, Australia – sequence: 23 givenname: Vivek surname: Rathi fullname: Rathi, Vivek organization: LifeStrands Genomics, Mount Waverley, Victoria, Australia – sequence: 24 givenname: Paul surname: Benitez-Aguirre fullname: Benitez-Aguirre, Paul organization: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia – sequence: 25 givenname: Anthony R surname: Glover fullname: Glover, Anthony R email: Anthony.Glover@sydney.edu.au organization: Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, University of Sydney, New South Wales, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address: Anthony.Glover@sydney.edu.au – sequence: 26 givenname: Anthony J surname: Gill fullname: Gill, Anthony J email: affgill@med.usyd.edu.au organization: NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Faculty of Medicine and Health Sciences and Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia. Electronic address: affgill@med.usyd.edu.au |
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| Keywords | ALK RET gene fusions BRAF NTRK papillary thyroid carcinoma diffuse sclerosing |
| Language | English |
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| Snippet | Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes,... |
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| SubjectTerms | Carcinoma, Papillary - genetics Carcinoma, Papillary - pathology Child Humans Lung Neoplasms Mutation Proto-Oncogene Proteins B-raf - genetics Receptor Protein-Tyrosine Kinases - genetics Thyroid Cancer, Papillary - genetics Thyroid Neoplasms - genetics Thyroid Neoplasms - pathology Young Adult |
| Title | A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma |
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