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Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5\u20132%), showing distinctive histomorphology and <jats:italic>FH<\/jats:italic> inactivation. The majority of FH-d ULs are sporadic, caused by somatic <jats:italic>FH<\/jats:italic> inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline <jats:italic>FH<\/jats:italic> inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy\/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary\/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic <jats:italic>FH<\/jats:italic> variants in both cases (c.1256C\u2009&gt;\u2009T; p.Ser419Leu in Case 1 and c.425A\u2009&gt;\u2009G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.<\/jats:p>","DOI":"10.1007\/s00428-024-03806-8","type":"journal-article","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T04:01:42Z","timestamp":1713585702000},"page":"223-231","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases"],"prefix":"10.1007","volume":"485","author":[{"given":"Xiaoxue","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruqaiya","family":"Al Shamsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima S.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiza","family":"Al Kindi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyi","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Al Masqari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linmao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas","family":"Agaimy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,20]]},"reference":[{"key":"3806_CR1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1055\/s-0035-1558451","volume":"33","author":"SE Bulun","year":"2015","unstructured":"Bulun SE, Moravek MB, Yin P, Ono M, Coon JST, Dyson MT, Navarro A, Marsh EE, Zhao H, Maruyama T, Chakravarti D, Kim JJ, Wei JJ (2015) Uterine leiomyoma stem cells: linking progesterone to growth. Semin Reprod Med 33:357\u2013365. https:\/\/doi.org\/10.1055\/s-0035-1558451","journal-title":"Semin Reprod Med"},{"key":"3806_CR2","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12943-017-0672-1","volume":"16","author":"N Makinen","year":"2017","unstructured":"Makinen N, Kampjarvi K, Frizzell N, Butzow R, Vahteristo P (2017) Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. 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Int J Gynecol Pathol 42:120\u2013135. https:\/\/doi.org\/10.1097\/PGP.0000000000000918","journal-title":"Int J Gynecol Pathol"},{"key":"3806_CR4","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1007\/s00428-018-2292-6","volume":"472","author":"L Siegler","year":"2018","unstructured":"Siegler L, Erber R, Burghaus S, Brodkorb T, Wachter D, Wilkinson N, Bolton J, Stringfellow H, Haller F, Beckmann MW, Hartmann A, Agaimy A (2018) Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening. Virchows Arch 472:789\u2013796. https:\/\/doi.org\/10.1007\/s00428-018-2292-6","journal-title":"Virchows Arch"},{"key":"3806_CR5","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s12905-023-02237-y","volume":"23","author":"T Tong","year":"2023","unstructured":"Tong T, Fan Q, Wang Y, Li Y (2023) Benign metastasizing uterine leiomyoma with lymphatic and pulmonary metastases: a case report and literature review. 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