{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:30:46Z","timestamp":1789522246483,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-15-00069"],"award-info":[{"award-number":["23-15-00069"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Fumarate hydratase-deficient leiomyomas (dFH-LMs) are a rare subtype of uterine smooth muscle tumors (USMTs) with implications for hereditary leiomatosis and renal cell carcinoma (HLRCC). Although several morphologic clues have been proposed, their diagnostic reproducibility is poorly defined. We aimed to determine the diagnostic significance of histopathologic features associated with fumarase deficiency and the reproducibility of key morphologic criteria for defining dFH-LMs. Methods: A retrospective analysis was performed on 45 USMTs that were initially classified as atypical leiomyomas (ALMs). The cohort comprised patients aged 21 to 75 years who had surgery at one tertiary medical care center from 2016 to 2025. Hematoxylin\u2013eosin (H&amp;E) slides were independently examined by three pathologists for features associated with FH deficiency, including eosinophilic globules, staghorn-like vessels, diffuse nuclear atypia, \u201cbizarre\u201d nuclei, and prominent nucleoli with halos. Molecular status was determined by immunohistochemistry (IHC) for fumarate hydratase (FH) and S-(2-succino)-cysteine (2SC). Interobserver agreement was quantified using Fleiss\u2019s \u03ba and Cohen\u2019s \u03ba. Results: Loss of FH expression was detected in 26\/45 tumors (57.7%). Eosinophilic globules occurred in 88.5% of dFH-LMs, but only in 15.8% of ALMs (p &lt; 0.001). By majority consensus (\u22652 of 3 reviewers), the eosinophilic globules predicted FH deficiency with a sensitivity of 88.0% and a specificity of 85.0%; interobserver reproducibility was substantial (\u03ba = 0.63). Staghorn-like vessels occurred in 73.1% of dFH-LMs vs. 26.3% of ALMs (p = 0.02) and diffuse nuclear atypia (84.6%) was also more frequent in dFH-LMs (p = 0.01). Patients with dFH-LMs were significantly younger than those with ALMs (Median, 34 vs. 41 years). Conclusions: Eosinophilic globules, staghorn-like vessels and diffuse nuclear atypia have been shown to have high diagnostic value and could be considered morphologic indicators of dFH-LMs. The substantial interobserver reproducibility of eosinophilic globules makes this feature particularly promising for routine clinical practice.<\/jats:p>","DOI":"10.3390\/diagnostics15233006","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T13:56:34Z","timestamp":1764165394000},"page":"3006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnostic Value and Interobserver Reproducibility of Histopathological Features in Fumarate Hydratase-Deficient Uterine Leiomyomas"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6244-1219","authenticated-orcid":false,"given":"Aleksandra","family":"Rogozhina","sequence":"first","affiliation":[{"name":"National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5223-9767","authenticated-orcid":false,"given":"Alina","family":"Badlaeva","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, 117513 Moscow, Russia"},{"name":"Department of Pathological Anatomy and Clinical Pathological Anatomy, Pirogov Russian National Research Medical University, Bldg. 1, Ostrovitianov Street, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4601-1330","authenticated-orcid":false,"given":"Anna","family":"Tregubova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8739-5209","authenticated-orcid":false,"given":"Aleksandra","family":"Asaturova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, 117513 Moscow, Russia"},{"name":"Department of Pathological Anatomy and Clinical Pathological Anatomy, Pirogov Russian National Research Medical University, Bldg. 1, Ostrovitianov Street, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3790-0427","authenticated-orcid":false,"given":"Maria","family":"Kuznetsova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennady","family":"Sukhikh","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of the Ministry of Health of Russia, Bldg. 4, Oparina Street, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1038\/s41379-020-0596-y","article-title":"Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants","volume":"33","author":"Popp","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1097\/PAS.0000000000000703","article-title":"Fumarase-deficient Uterine Leiomyomas: An Immunohistochemical, Molecular Genetic, and Clinicopathologic Study of 86 Cases","volume":"40","author":"Miettinen","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1097\/PGP.0000000000000918","article-title":"Fumarate hydratase and S-(2-Succinyl)-cysteine immunohistochemistry shows evidence of fumarate hydratase deficiency in 2% of uterine leiomyosarcomas: A cohort study of 348 tumors","volume":"42","author":"Chapel","year":"2023","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s00428-018-2292-6","article-title":"Fumarate hydratase (FH) deficiency in uterine leiomyomas: Recognition by histological features versus blind immunoscreening","volume":"472","author":"Siegler","year":"2018","journal-title":"Virchows Arch."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1002\/jcu.24046","article-title":"Assessing the Clinical Characteristics and the Role of Imaging Modalities in Uterine Sarcoma: A Single-Center Retrospective Study From Vietnam","volume":"53","author":"Nguyen","year":"2025","journal-title":"J. Clin. Ultrasound"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1097\/PAS.0000000000000573","article-title":"Fumarate Hydratase\u2013deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings","volume":"40","author":"Harrison","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1097\/PAS.0000000000000520","article-title":"Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas from Young Patients","volume":"39","author":"Joseph","year":"2015","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1038\/modpathol.2017.56","article-title":"Leiomyoma with bizarre nuclei: A morphological, immunohistochemical and molecular analysis of 31 cases","volume":"30","author":"Bennett","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1097\/PAS.0000000000001293","article-title":"Detailed Morphologic and Immunohistochemical Characterization of Myomectomy and Hysterectomy Specimens from Women with Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)","volume":"43","author":"Chan","year":"2019","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1097\/PAS.0000000000000646","article-title":"Two Subtypes of Atypical Leiomyoma: Clinical, Histologic, and Molecular Analysis","volume":"40","author":"Ubago","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e05513","DOI":"10.1002\/ccr3.5513","article-title":"Rare variant in the fumarate hydratase gene found in patients with clinical features of hereditary leiomyomatosis and renal cell cancer (HLRCC): A case series","volume":"10","author":"Franke","year":"2022","journal-title":"Clin. Case Rep."},{"key":"ref_12","doi-asserted-by":"crossref","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":"ref_13","first-page":"236","article-title":"The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: A retrospective study from a large academic tertiary referral center","volume":"13","author":"Scharnitz","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e24449","DOI":"10.1016\/j.heliyon.2024.e24449","article-title":"FH deficient uterine leiomyomas-a case series","volume":"10","author":"Kamboj","year":"2024","journal-title":"Heliyon"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/modpathol.2013.215","article-title":"Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: Detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry","volume":"27","author":"Reyes","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Spari\u0107, R., Andji\u0107, M., Babovi\u0107, I., Nejkovi\u0107, L., Mitrovi\u0107, M., \u0160tuli\u0107, J., Pupovac, M., and Tinelli, A. (2022). Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179728"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yang, Q., Falahati, A., Khosh, A., Mohammed, H., Kang, W., Corach\u00e1n, A., Bariani, M.V., Boyer, T.G., and Al-Hendy, A. (2022). Targeting Class I Histone Deacetylases in Human Uterine Leiomyosarcoma. Cells, 11.","DOI":"10.3390\/cells11233801"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Uimari, O., Subramaniam, K.S., Vollenhoven, B., and Tapmeier, T.T. (2022). Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding. Front. Reprod. Health, 4.","DOI":"10.3389\/frph.2022.818243"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhang, C., Li, L., Zhang, Y., and Zeng, C. (2021). Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.686556"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yang, M., Soga, T., Pollard, P.J., and Adam, J. (2012). The emerging role of fumarate as an oncometabolite. Front. Oncol., 2.","DOI":"10.3389\/fonc.2012.00085"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, P., Wu, Y., Wu, H., Xiong, Q., Zhao, N., Chen, G., Wu, C., and Xiao, H. (2022). Functional Characterization of FH Mutation c.557G>A Underlies Uterine Leiomyomas. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031452"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1136\/jclinpath-2021-207830","article-title":"Gene of the month: FH","volume":"74","author":"Zyla","year":"2021","journal-title":"J. Clin. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lindner, A.K., Tulchiner, G., Seeber, A., Siska, P.J., Thurnher, M., and Pichler, R. (2022). Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.906014"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bateman, N.W., Tarney, C.M., Abulez, T., Soltis, A.R., Zhou, M., Conrads, K., Litzi, T., Oliver, J., Hood, B., and Driggers, P. (2021). Proteogenomic landscape of uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer patients. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-88585-x"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e28142","DOI":"10.1097\/MD.0000000000028142","article-title":"Uterine leiomyoma with fumarate hydratase deficiency: A case report","volume":"100","author":"Huang","year":"2021","journal-title":"Medicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e23229","DOI":"10.1002\/gcc.23229","article-title":"Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation","volume":"63","author":"Fontanges","year":"2024","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100084","DOI":"10.1016\/j.modpat.2022.100084","article-title":"Molecular-Based Immunohistochemical Algorithm for Uterine Leiomyosarcoma Diagnosis","volume":"36","author":"Yousefi","year":"2023","journal-title":"Mod. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1158\/1940-6207.CAPR-23-0535","article-title":"Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata","volume":"17","author":"Kipnis","year":"2024","journal-title":"Cancer Prev. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.humpath.2022.05.016","article-title":"Clinicopathological and molecular characteristics of fumarate hydratase\u2013deficient uterine smooth muscle tumors: A single-center study of 52 cases","volume":"126","author":"Li","year":"2022","journal-title":"Hum. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1097\/PGP.0000000000000447","article-title":"Fumarate Hydratase Mutations and Alterations in Leiomyoma with Bizarre Nuclei","volume":"37","author":"Zhang","year":"2018","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.2147\/IJWH.S388278","article-title":"Leiomyoma with Bizarre Nuclei: A Current Update","volume":"14","author":"Guo","year":"2022","journal-title":"Int. J. Womens Health"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"276","DOI":"10.11613\/BM.2012.031","article-title":"Interrater reliability: The kappa statistic","volume":"22","author":"McHugh","year":"2012","journal-title":"Biochem. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"980","DOI":"10.4103\/0973-1482.157304","article-title":"Breast carcinoma with numerous large \u201cthanatosomes\u201d","volume":"11","author":"Panicker","year":"2015","journal-title":"J. Cancer Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"896","DOI":"10.4254\/wjh.v13.i8.896","article-title":"Solid pseudopapillary neoplasm of the pancreas","volume":"13","author":"Omiyale","year":"2021","journal-title":"World J. Hepatol."},{"key":"ref_35","first-page":"393","article-title":"Pancreatic Intraductal Papillary Mucinous Neoplasm with Hyaline Globules (Thanatosomes): Report of Two Cases","volume":"14","author":"Tachibana","year":"2021","journal-title":"Int. Med. Case Rep. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"279","DOI":"10.4103\/jomfp.JOMFP_125_15","article-title":"A review of artifacts in histopathology","volume":"22","author":"Taqi","year":"2018","journal-title":"J. Oral Maxillofac. Pathol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/23\/3006\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:55:47Z","timestamp":1774612547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/23\/3006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":36,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["diagnostics15233006"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15233006","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}