{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:12:20Z","timestamp":1792239140896,"version":"4.4.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"European Renal Association"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications, the vast majority of FH-deficient RCCs exhibit an aggressive behaviour with invasive growth and the potential for early metastatic spread. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland and Leydig cell tumours. The aggressive behaviour of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining<\/jats:p>\n                  <jats:p>predisposition for de novo primary renal tumours in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. Vascular endothelial growth factor\/epidermal growth factor receptor\u2013directed treatment regimes, such as erlotinib\/bevacizumab, demonstrate efficacy against HLRCC-associated RCC. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 World Health Organization classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to discuss this impact and raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.<\/jats:p>","DOI":"10.1093\/ndt\/gfaf032","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T15:23:41Z","timestamp":1738855421000},"page":"1428-1432","source":"Crossref","is-referenced-by-count":11,"title":["The impact of the new WHO classification of renal cell carcinoma on the diagnosis of hereditary leiomyomatosis and renal cell carcinoma"],"prefix":"10.1093","volume":"40","author":[{"given":"Jan","family":"Degenhardt","sequence":"first","affiliation":[{"name":"University of Cologne Department II of Internal Medicine, , Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Tolkach","sequence":"additional","affiliation":[{"name":"University Hospital Cologne Institute of Pathology, , Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahul B","family":"Amin","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center Department of Pathology and Laboratory Medicine, College of Medicine, , Memphis, TN ,","place":["USA"]},{"name":"University of Southern California Department of Urology, Keck School of Medicine, , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Mosiello","sequence":"additional","affiliation":[{"name":"Bambino Gesu Children's Hospital IRCCS Division of Pediatric Urology\/Neuro-Urology, , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilek","family":"Ertoy Baydar","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Pathology, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1958-4459","authenticated-orcid":false,"given":"Emilie","family":"Cornec-Le Gall","sequence":"additional","affiliation":[{"name":"GGB, CHU Brest, Centre de r\u00e9f\u00e9rence Maladies R\u00e9nales H\u00e9r\u00e9ditaires de l\u2032Enfant et l\u2032Adulte, Brest Universit\u00e9 de Brest, UMR 1078, ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"DiCola","sequence":"additional","affiliation":[{"name":"HLRCC Foundation , Coralville , IA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Elhag","sequence":"additional","affiliation":[{"name":"HLRCC Foundation , Coralville , IA ,","place":["USA"]},{"name":"John Stoddard Cancer Center , Coralville , IA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Frezza","sequence":"additional","affiliation":[{"name":"Institute for Metabolomics in Ageing, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases University of Cologne, Faculty of Medicine and University Hospital Cologne, , Cologne ,","place":["Germany"]},{"name":"Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases University of Cologne Faculty of Mathematics and Natural Sciences, Institute of Genetics, , Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Halbritter","sequence":"additional","affiliation":[{"name":"Charite \u2013 Universitatsmedizin Berlin Department of Nephrology and Medical Intensive Care, , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Blanco","sequence":"additional","affiliation":[{"name":"Hospital Germans Trias i Pujol Department of Clinical Genetics, , Badalona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A S","family":"Jewett","sequence":"additional","affiliation":[{"name":"The Netherlands International Kidney Cancer Coalition, Utrecht,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Baptiste","family":"Lattouf","sequence":"additional","affiliation":[{"name":"University of Montreal Hospital Centre Department of Surgery-Urology, , Montreal, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Lovitt","sequence":"additional","affiliation":[{"name":"HLRCC Foundation , Coralville , IA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-Olof","family":"Lundgren","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Department of Urology, , Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6226-6918","authenticated-orcid":false,"given":"Eamonn R","family":"Maher","sequence":"additional","affiliation":[{"name":"Aston University Aston Medical School, , Birmingham ,","place":["UK"]},{"name":"Birmingham Women's and Children's NHS Foundation Trust , Birmingham ,","place":["UK"]},{"name":"Cambridge University Hospitals NHS Foundation Trust Department of Medical Genetics, , Cambridge ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Mulders","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center Department of Urology, , Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Shuch","sequence":"additional","affiliation":[{"name":"University of California at Los Angeles Department of Urology, David Geffen School of Medicine, , Los Angeles , CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander University of Erlangen\u2013Nuremberg Institute of Pathology, Faculty of Medicine, , Bavaria ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-0745","authenticated-orcid":false,"given":"Roman-Ulrich","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"University of Cologne Department II of Internal Medicine, , Cologne ,","place":["Germany"]},{"name":"University of Cologne Department II of Internal Medicine and Center for Molecular Medicine, , Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"2025063007572100400_bib1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/ng849","article-title":"Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer","volume":"30","author":"Tomlinson","year":"2002","journal-title":"Nat Genet"},{"key":"2025063007572100400_bib2","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1086\/376435","article-title":"Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America","volume":"73","author":"Toro","year":"2003","journal-title":"Am J Hum Genet"},{"key":"2025063007572100400_bib3","doi-asserted-by":"publisher","first-page":"3387","DOI":"10.1073\/pnas.051633798","article-title":"Inherited susceptibility to uterine leiomyomas and renal cell cancer","volume":"98","author":"Launonen","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025063007572100400_bib4","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1111\/aogs.14248","article-title":"Uterine leiomyomas in hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome can be identified through distinct clinical characteristics and typical morphology","volume":"100","author":"Uimari","year":"2021","journal-title":"Acta Obstet Gynecol Scand"},{"key":"2025063007572100400_bib5","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1007\/s10689-014-9735-2","article-title":"Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment","volume":"13","author":"Menko","year":"2014","journal-title":"Fam Cancer"},{"key":"2025063007572100400_bib6","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.1002\/cncr.32914","article-title":"Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer","volume":"126","author":"Shuch","year":"2020","journal-title":"Cancer"},{"key":"2025063007572100400_bib7","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.3390\/cancers12113277","article-title":"Hereditary leiomyomatosis and renal cell cancer syndrome in Spain: clinical and genetic characterization","volume":"12","author":"S\u00e1nchez-Heras","year":"2020","journal-title":"Cancers (Basel)"},{"key":"2025063007572100400_bib8","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1111\/his.14859","article-title":"Fumarate hydratase-deficient testicular sex cord-stromal tumour (FH-TSCST): proposal for reclassification of a subset of Leydig cell tumours with distinct molecular and clinicopathologic features","volume":"82","author":"Acosta","year":"2023","journal-title":"Histopathology"},{"key":"2025063007572100400_bib9","doi-asserted-by":"publisher","first-page":"3071","DOI":"10.1210\/jc.2006-0183","article-title":"Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations","volume":"91","author":"Carvajal-Carmona","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2025063007572100400_bib10","doi-asserted-by":"publisher","first-page":"3345","DOI":"10.1158\/1078-0432.CCR-13-0304","article-title":"Molecular pathways: fumarate hydratase-deficient kidney cancer\u2014targeting the Warburg effect in cancer","volume":"19","author":"Linehan","year":"2013","journal-title":"Clin Cancer Res"},{"key":"2025063007572100400_bib11","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1038\/s41416-023-02412-w","article-title":"Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism","volume":"129","author":"Valcarcel-Jimenez","year":"2023","journal-title":"Br J Cancer"},{"key":"2025063007572100400_bib12","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.euo.2019.11.002","article-title":"Hereditary leiomyomatosis and renal cell cancer: clinical, molecular, and screening features in a cohort of 185 affected individuals","volume":"3","author":"Forde","year":"2020","journal-title":"Eur Urol Oncol"},{"key":"2025063007572100400_bib13","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1007\/s10689-021-00268-8","article-title":"A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven","volume":"21","author":"Taniguchi","year":"2022","journal-title":"Fam Cancer"},{"key":"2025063007572100400_bib14","doi-asserted-by":"publisher","first-page":"4539","DOI":"10.1200\/JCO.2022.40.16_suppl.4539","article-title":"Real-world treatment patterns in von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC): costs of tumor reduction procedures and their complications","volume":"40(16 Suppl)","author":"Sundaram","year":"2022","journal-title":"J Clin Oncol"},{"key":"2025063007572100400_bib15","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/S1470-2045(09)70188-3","article-title":"Birt-Hogg-Dub\u00e9 syndrome: diagnosis and management","volume":"10","author":"Menko","year":"2009","journal-title":"Lancet Oncol"},{"key":"2025063007572100400_bib16","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1038\/s41431-024-01671-2","article-title":"ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dub\u00e9 syndrome","volume":"32","author":"Geilswijk","year":"2024","journal-title":"Eur J Hum Gene"},{"key":"2025063007572100400_bib17","article-title":"NCCN Clinical Practice Guidelines in Oncology, Kidney Cancer, Version 1.2025","author":"National Comprehensive Cancer Network","year":"2024"},{"key":"2025063007572100400_bib18","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.eururo.2022.06.016","article-title":"The 2022 World Health Organization classification of tumours of the urinary system and male genital organs\u2014Part A: renal, penile, and testicular tumours","volume":"82","author":"Moch","year":"2022","journal-title":"Eur Urol"},{"key":"2025063007572100400_bib19","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1097\/PAS.0000000000001288","article-title":"Papillary renal neoplasm with reverse polarity: a morphologic, immunohistochemical, and molecular study","volume":"43","author":"Al-Obaidy","year":"2019","journal-title":"Am J Surg Pathol"},{"key":"2025063007572100400_bib20","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1097\/PAS.0000000000001467","article-title":"Biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC): a distinctive neoplasm associated with somatic: NF2: mutations","volume":"44","author":"Argani","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"2025063007572100400_bib21","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1097\/PAS.0000000000000639","article-title":"Biphasic squamoid alveolar renal cell carcinoma: a distinctive subtype of papillary renal cell carcinoma?","volume":"40","author":"Hes","year":"2016","journal-title":"Am J Surg Pathol"},{"key":"2025063007572100400_bib22","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1097\/PAS.0b013e31818cb8f5","article-title":"Primary thyroid-like follicular carcinoma of the kidney: report of 6 cases of a histologically distinctive adult renal epithelial neoplasm","volume":"33","author":"Amin","year":"2009","journal-title":"Am J Surg Pathol"},{"key":"2025063007572100400_bib23","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/s41379-018-0017-7","article-title":"Pattern multiplicity and fumarate hydratase (FH)\/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration","volume":"31","author":"Muller","year":"2018","journal-title":"Mod Pathol"},{"key":"2025063007572100400_bib24","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/s41379-018-0017-7","article-title":"Pattern multiplicity and fumarate hydratase (FH)\/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration","volume":"31","author":"Muller","year":"2018","journal-title":"Mod Pathol"},{"key":"2025063007572100400_bib25","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1097\/PAS.0000000000000163","article-title":"Hereditary leiomyomatosis and renal cell carcinoma syndrome\u2013associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry","volume":"38","author":"Chen","year":"2014","journal-title":"Am J Surg Pathol"},{"key":"2025063007572100400_bib26","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/path.2932","article-title":"Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status","volume":"225","author":"Bardella","year":"2011","journal-title":"J Pathol"},{"key":"2025063007572100400_bib27","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.urology.2022.11.053","article-title":"Fumarate hydratase variants and their association with paraganglioma\/pheochromocytoma","volume":"176","author":"Zavoshi","year":"2023","journal-title":"Urology"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfaf032\/62017316\/gfaf032.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/40\/7\/1428\/62017316\/gfaf032.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/40\/7\/1428\/62017316\/gfaf032.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T07:57:27Z","timestamp":1751270247000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/article\/40\/7\/1428\/8026894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":27,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,2,20]]},"published-print":{"date-parts":[[2025,6,30]]}},"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfaf032","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,7]]},"published":{"date-parts":[[2025,2,20]]}}}