The objective of this study was to explore the clinical diagnostic indicators and treatment approaches for intravenous leiomyomatosis (IVL), particularly when it extends into the inferior vena cava and the right heart system. Nine patients with IVL admitted to our hospital were enrolled in this study. The ultrasonographic, CT, MRI, pathological findings and surgical details of these patients were comprehensively analysed. All patients underwent surgical procedures. Postoperative pathological examination confirmed the presence of IVL, along with intramural leiomyoma of the uterus. Immunohistochemical results demonstrated that smooth muscle actin, smooth muscle myosin heavy chain, Desmin, Caldesmon, oestrogen receptor and progesterone receptor were highly positive. The Ki-67 index of most specimens was <3%, except for case 4. In case 4, which invaded the right atrium, the Ki-67 index ranged from 2% to 5%. Through molecular testing, this case with extension to the right atrium and inferior vena cava was identified as intraventricular smooth muscle neoplasia with fumarate hydratase deficiency. No copy number variation mutations were detected in all cases. Although IVL is a rare histologically benign tumour, it exhibits the capacity to infiltrate cardiac chambers and pulmonary vasculature. Therefore, early diagnosis via imaging techniques, precise assessment of the extent of intravenous leiomyoma involvement, complete lesion resection and perioperative administration of anti-oestrogen medications are pivotal for enhancing patient prognosis. Additionally, for cases with atypical nuclei or high Ki-67 levels, multidisciplinary collaboration is required to personalised treatment.

Diffuse adult-type gliomas are delineated based on their molecular composition including the presence or absence of mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2), a key enzyme in the citric acid cycle. IDH-mutant tumors are associated with better survival than IDH-wildtype counterparts and can be further subdivided into astrocytoma or oligodendroglioma. Rare gliomas with fumarate hydratase (FH) deficiency have been reported. Given that FH is also a critical enzyme in the citric acid cycle, such tumors seem to be epigenetically similar to IDH-mutant tumors and, despite meeting criteria as IDH-wildtype gliomas per the current recommendations set forth by the World Health Organization, may behave in a manner akin to IDH-mutant neoplasms. Hereditary leiomyoma and renal cell cancer syndrome is associated with cutaneous and uterine leiomyomas and renal cell carcinoma caused by a germline FH alteration. To date, only rare examples of patients with known germline FH mutation subsequently diagnosed with a glioma have been reported. We report a case of a young patient with a glioma harboring features of IDH-mutant astrocytoma without evidence of IDH1/2 alterations. After the identification of cutaneous FH-deficient leiomyomas, a retrospective analysis of his brain tumor revealed FH deficiency and a germline FH alteration was ultimately identified after further molecular studies. Although rare, we conclude that FH mutations seem to be part of the spectrum of alterations in diffuse gliomas.

While the morphologic and immunophenotypic features of smooth muscle neoplasms of the uterus and skin have been well-described in relationship to fumarate hydratase (FH) deficiency (FHD), a potential association of urinary bladder smooth muscle tumors with FH tumor predisposition syndrome (FHTPS) has not been previously investigated. Given an index urinary bladder leiomyoma which showed some of the purported morphologic features seen in uterine FHD leiomyomas, we performed a multi-institutional search for bladder smooth muscle tumors to further evaluate a putative FHTPS association. Cases were re-reviewed for the presence of the following well-described FHD-associated cytomorphologic features: macronucleoli ("cherry red") surrounded by halo, isolated nuclear pleomorphism ("symplastic" nuclei), cytoplasmic eosinophilic globules, staghorn vasculature, alveolar-pattern edema, and chain-like distribution of smooth muscle fibers. Tumors with available material underwent whole-slide staining for FH and 2SC immunohistochemistry. A total of 40 bladder smooth muscle tumors (35 leiomyomas, 5 leiomyosarcomas) were collected from patients (33 females, 17 males) of ages 30-86 years (mean=56.3 years). Among leiomyomas, cytoplasmic eosinophilic globules were seen most frequently (31%), followed by CMV-like macronucleoli (17%), staghorn-type vasculature (11%), "symplastic" nuclei (9%), and alveolar-pattern edema (6%). Among the leiomyosarcomas, cytoplasmic eosinophilic globules or CMV-like macronucleoli were infrequently seen (20%), while staghorn-type vasculature was seen in 60% and "symplastic" nuclei were seen in all (100%) tumors. No cases exhibited chain-like muscle fibers. Of the stained tumors, all (100%) showed retained FH expression and negative 2SC immunoreactivity. Three female patients with bladder leiomyomas had a prior history of uterine leiomyomas all lacking FHD histology. Although a subset of bladder smooth muscle tumors show overlapping morphologic features with uterine FHD leiomyomas, they do not appear to harbor FHD or an association with FHTPS, although the findings warrant confirmation in future studies, perhaps inclusion of FH and/or 2SC immunohistochemistry.

Objective: To explore the clinicopathological characteristics and prognosis of fumarate hydratase-deficient uterine leiomyoma (FH-dUL). Methods: Clinical data and follow-up information for 117 patients with FH-dUL diagnosed through surgical pathology and immunohistochemistry in the First Affiliated Hospital of Nanjing Medical University from January 2020 to December 2024, were collected. A control group of 130 patients with common uterine leiomyomas was also included. The differences between the two groups in clinical, imaging, and pathological characteristics were compared. Additionally, recurrence rates, fertility outcomes for FH-dUL patients, and the incidence of renal cancer in FH germline mutation carriers were monitored. Results: (1) Comparison of clinicopathological characteristics: the median age of 117 FH-dUL patients was 35 years, and the median age at first diagnosis of uterine leiomyomas was 29 years, both significantly younger than the control group (41 and 36 years; both P<0.01). The FH-dUL group showed significantly higher incidences of uterine myomectomy, multiple leiomyomas, diffusion restriction on pelvic magnetic resonance imaging diffusion weighted imaging, and typical pathological features (candelabra-like vessels, bizarre nuclei, cytoplasmic eosinophilic globules, perinuclear halo, cellular atypia) and higher ultrasound blood flow score (all P<0.05). Of the 30 FH-dUL patients who underwent genetic testing, 9 had germline mutations, 3 had somatic mutations, and 6 had mutations of unclear origin. Among the 9 FH gene germline mutation patients, 2 had already developed renal cell carcinoma. (2) Recurrence analysis: among the 56 patients who underwent uterine myomectomy, 22 (39.3%, 22/56) experienced recurrence during follow-up, compared to 12 (21.8%, 12/55) of the 55 patients in the control group, the difference between the two groups was statistically significant (P=0.046). Multivariate binary logistic regression analysis showed that cellular leiomyomas (OR=9.489, 95%CI: 1.740-51.755; P=0.009) and multiple uterine leiomyomas (OR=10.709, 95%CI: 1.354-84.683; P=0.025) were significant risk factors for recurrence in FH-dUL. (3) Fertility analysis: among the 66 FH-dUL patients who underwent fertility-preserving surgery, 16 had the intention to have fertility desire, only 2 (2/16) completed their fertility plans during follow-up. Conclusions: Clinicopathological features and imaging features help to differentiate FH-dUL from common type uterine fibroids, but lack specificity, and the diagnosis of FH-dUL is based on immunohistochemistry. The recurrence rate after resection of FH-dUL is high, and cellular and multiple leiomyomas are important predictors of recurrence. It is crucial to perform genetic testing, genetic counseling, drug treatment to prevent recurrence, fertility guidance, and long-term comprehensive management after surgery for FH-dUL management. 目的： 探讨延胡索酸水合酶缺失型子宫平滑肌瘤（FH-dUL）的临床病理特征及预后情况。 方法： 收集2020年1月至2024年12月南京医科大学第一附属医院经手术病理检查及免疫组化检测诊断的117例FH-dUL患者（FH-dUL组）的临床病理资料及随访资料，以同期经免疫组化检测证实为非FH-dUL的130例普通型子宫肌瘤患者（普通肌瘤组）作为对照，比较两组患者的临床病理特征及影像学特征的差异，并随访FH-dUL患者的复发情况、生育结局及FH基因胚系突变患者的肾细胞癌发生情况。 结果： （1）临床病理特征比较：117例FH-dUL组患者的中位年龄、首次发现子宫肌瘤的中位年龄（35、29岁）均显著早于普通肌瘤组（41、36岁；P均<0.01）；FH-dUL组患者的子宫肌瘤剔除术史、多发性肌瘤发生率、肌瘤血流评分、盆腔磁共振成像检查弥散加权成像序列扩散受限比例、常见病理特征（包括鹿角状血管、奇异核、胞质嗜酸小球、核周透明晕、细胞异型性）的发生率均明显高于普通肌瘤组（P均<0.05）。30例进行基因检测的FH-dUL患者中，18例（60.0%）存在FH基因突变，包括9例胚系突变、3例体系突变、6例无法明确变异来源的突变。9例FH基因胚系突变患者中，2例（2/9）患者发生肾细胞癌。（2）复发情况及影响因素分析：FH-dUL组患者的中位随访时间为20个月，肌瘤剔除术后随访时间满3个月者56例，其中22例复发，复发率为39.3%（22/56）；普通肌瘤组患者的中位随访时间为18个月，肌瘤剔除术后随访时间满3个月者55例，其中12例复发，复发率为21.8%（12/55）；两组复发率比较，差异有统计学意义（P=0.046）。多因素二元logistic回归分析显示，多发性子宫肌瘤（OR=10.709，95%CI为1.354~84.683；P=0.025）、富于细胞性子宫平滑肌瘤（OR=9.489，95%CI为1.740~51.755；P=0.009）均是影响FH-dUL患者肌瘤剔除术后复发的独立危险因素。（3）生育结局：66例行肌瘤剔除术的FH-dUL患者中，16例有生育意愿，随访期间仅有2例（2/16）完成了生育计划。 结论： 临床病理特征及影像学特征有助于鉴别FH-dUL与普通型子宫肌瘤，但缺乏特异性，FH-dUL的诊断依据免疫组化检测。FH-dUL肌瘤剔除术后复发率高，多发性子宫肌瘤和富于细胞性子宫平滑肌瘤是影响FH-dUL复发的独立危险因素。对FH-dUL患者术后进行基因检测、遗传咨询、药物治疗预防复发、生育力指导和长期全程管理至关重要。.

The morphologic features of uterine smooth muscle tumors (USMTs) are subject to interobserver variability and are complicated by consideration of features of fumarate hydratase deficiency (FHd) and other morphologic subtypes, with difficult cases occasionally diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP). We compare immunohistochemical findings and detailed morphologic analysis of 45 USMTs by 4 fellowship-trained gynecologic pathologists with comprehensive molecular analysis, focusing on FHd leiomyomas (n=15), compared to a variety of other USMTs with overlapping morphologic features, including 9 STUMPs, 8 usual-type leiomyomas (ULM), 11 apoplectic leiomyomas, and 2 leiomyomas with bizarre nuclei (LMBN). FHd leiomyomas, defined by immunohistochemical (IHC) loss of FH and/or 2SC accumulation, showed FH mutations and/or FH copy loss in all cases, with concurrent TP53 mutations in 2 tumors. Severe and/or symplastic-type cytologic atypia was seen more often in FHd leiomyomas with only FH copy loss (6/8, and 2/2 with concurrent TP53 mutations) compared to those with FH mutations (2/7) and typically showed increased genomic instability. This subset of FHd tumors often showed morphologic overlap with STUMPs and LMBN, but all cases of FHd tumors showed 2SC accumulation and/or FH loss by IHC. In conclusion, we highlight the importance of investigating USMTs with severe and/or symplastic-type cytologic atypia with FH and 2SC IHC, as many of these tumors are FH-deficient via focal deep deletion (2-copy loss) of the FH locus. In addition, we report the presence of concurrent TP53 mutations in FHd tumors with more severe cytologic atypia; further data about clinical outcomes for these tumors are needed.