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A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma
Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcin...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760464/ https://www.ncbi.nlm.nih.gov/pubmed/35993574 http://dx.doi.org/10.1097/PAS.0000000000001945 |
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author | Fuchs, Talia L. Luxford, Catherine Clarkson, Adele Sheen, Amy Sioson, Loretta Elston, Marianne Croxson, Michael S. Dwight, Trisha Benn, Diana E. Tacon, Lyndal Field, Michael Ahadi, Mahsa S. Chou, Angela Clifton-Bligh, Roderick J. Gill, Anthony J. |
author_facet | Fuchs, Talia L. Luxford, Catherine Clarkson, Adele Sheen, Amy Sioson, Loretta Elston, Marianne Croxson, Michael S. Dwight, Trisha Benn, Diana E. Tacon, Lyndal Field, Michael Ahadi, Mahsa S. Chou, Angela Clifton-Bligh, Roderick J. Gill, Anthony J. |
author_sort | Fuchs, Talia L. |
collection | PubMed |
description | Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)—tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk. |
format | Online Article Text |
id | pubmed-9760464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-97604642022-12-20 A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma Fuchs, Talia L. Luxford, Catherine Clarkson, Adele Sheen, Amy Sioson, Loretta Elston, Marianne Croxson, Michael S. Dwight, Trisha Benn, Diana E. Tacon, Lyndal Field, Michael Ahadi, Mahsa S. Chou, Angela Clifton-Bligh, Roderick J. Gill, Anthony J. Am J Surg Pathol Original Articles Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)—tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk. Lippincott Williams & Wilkins 2023-01 2022-08-22 /pmc/articles/PMC9760464/ /pubmed/35993574 http://dx.doi.org/10.1097/PAS.0000000000001945 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Articles Fuchs, Talia L. Luxford, Catherine Clarkson, Adele Sheen, Amy Sioson, Loretta Elston, Marianne Croxson, Michael S. Dwight, Trisha Benn, Diana E. Tacon, Lyndal Field, Michael Ahadi, Mahsa S. Chou, Angela Clifton-Bligh, Roderick J. Gill, Anthony J. A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma |
title | A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma |
title_full | A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma |
title_fullStr | A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma |
title_full_unstemmed | A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma |
title_short | A Clinicopathologic and Molecular Analysis of Fumarate Hydratase–deficient Pheochromocytoma and Paraganglioma |
title_sort | clinicopathologic and molecular analysis of fumarate hydratase–deficient pheochromocytoma and paraganglioma |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760464/ https://www.ncbi.nlm.nih.gov/pubmed/35993574 http://dx.doi.org/10.1097/PAS.0000000000001945 |
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