The clinicopathologic and molecular features, and treatment outcome of fumarate hydratase-deficient renal cell carcinoma: a retrospective comparison with type 2 papillary renal cell carcinoma.

BACKGROUND: To compare clinicopathologic, molecular features, and treatment outcome between fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and type 2 papillary renal cell carcinoma (T2 pRCC). METHODS: Data of T2 pRCC patients and FH-dRCC patients with additional next-generation sequencing information were retrospectively analyzed. The cancer-specific survival (CSS) and disease-free survival (DFS) were primary endpoint. RESULTS: A combination of FH and 2-succino-cysteine (2-SC) increased the rate of negative predictive value of FH-dRCC. Compared with T2 pRCC cases, FH-dRCC cases displayed a greater prevalence in young patients, a higher frequency of radical nephrectomy. Seven FH-dRCC and two T2 pRCC cases received systemic therapy. The VEGF treatment was prescribed most frequently, with an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 30%. A combined therapy with VEGF and checkpoint inhibitor reported an ORR of 40% and a DCR of 100%. FH-dRCC cases showed a shortened CSS (P = 0.042) and DFS (P < 0.001). The genomic sequencing revealed 9 novel mutations. CONCLUSIONS: Coupled with genetic detection, immunohistochemical biomarkers (FH and 2-SC) can distinguish the aggressive FH-dRCC from T2 pRCC. Future research is awaited to illuminate the association between the novel mutations and the clinical phenotypes of FH-dRCC in the disease progression.

Different clinical diagnosis end up in the same pathological diagnosis of intravascular leiomyomatosis: Two case reports.

RATIONALE: Intravascular/intravenous leiomyomatosis (IVL) is a peculiar variant of uterine leiomyoma that is classified as a histologically benign smooth muscle tumor with a biological behavior similar to that of a malignant tumor. It is characterized by the proliferation of leiomyomas spreading along the uterine and extrauterine venous circulation. PATIENT CONCERNS: Herein, we present 2 cases of IVL who had completely different clinical manifestations to stress the need for constant vigilance of IVL diagnosis and the understanding of uterine leiomyoma heterogenicity. Case 1 was registered for fever without specific triggering factors, irregular menstruation and clinically diagnosed uterine diverticula, while no information about fibroids was mentioned. Case 2 was characterized by an aggressively growing abdominal mass. With a large space-occupying lesion in the right abdominopelvic cavity and no imaging evidence of involvement of the iliac vein or above vein, the patient was initially diagnosed with multiple myomata. DIAGNOSES: Both patients' diagnoses were confirmed as IVL by histopathology. To our knowledge, the mass of case 1 is the minimum IVL in the English literature. INTERVENTIONS: Subtotal hysterectomy with bilateral salpingectomy was performed on the former, while total hysterectomy with bilateral salpingectomy was performed on the latter. OUTCOMES: Both patients were comfortable, and no relapse occurred. LESSONS: Two cases in the study showed 2 different proceeding stages of the same disease and corroborated multiple pathogeneses, which have been mentioned in the available literature on IVL. Our work provides both supplement for clinical data to facilitate further research and better understanding of special types of fibroids to clinicians.

The use of Clinicopathological, immunohistochemistry and molecular detection in the diagnosis of fumarate hydratase-deficient uterine leiomyomas.

BACKGROUND: Fumarate hydratase-deficient uterine leiomyomas (FH-dUL) are rare, accounting for only 0.4-1.6% of uterine leiomyomas. FH germline mutation gene is associated with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). METHODS: In this study, we aim to investigate Clinicopathological features and FH mutation in FH-dUL. We performed a retrospective analysis of 300 cases of uterine leiomyoma, diagnosed from January 2017 to December 2021, within the archives of the Department of Pathology at Peking University People's Hospital. In our review of the immunohistochemical(IHC) staining was performed on 300 uSMTs to detect FH deficiency. RESULTS: We identified 21cases (21/300,7%) of FH-dUL. Nineteen cases (6.33%) displayed negative FH. Twenty-one cases (7%) displayed 2SC diffuse plasma and nuclear staining. The most common FH-d morphological features included staghorn vasculature ( 100%,21/21), alveolar-pattern oedema (71.43%, 15/21), scattered bizarre nuclei (23.81%, 5/21), eosinophilic cytoplasmic (rhabdoid) inclusions (47.62%, 10/21), significant eosinophilic nucleolus with peri-nucleolus hollowing (23.81%, 5/21), ovoid nuclei sometimes arranged in chains (9.52%, 2/21). DNA sequencing for the 21 cases was performed using Next Generation Sequencing (NGS). 6 cases were detected significant variations for the FH gene, 11 cases were detected FH gene mutation forvariants of uncertain significance (VUS), and 2 cases were detected a TP53 gene mutation. No related mutations were detected in the other two cases. CONCLUSIONS: FH-dUL is rare. The combination of predictive Clinicopathological evaluation,FH and 2SC IHC test, and molecular test were helpful for the screening of FH-dUL from uSMTs,or even the screening of HLRCC.

[Diagnosis and treatment of intravenous leiomyomatosis].

Intravenous leiomyomatosis is a rare type of tumor that is histologically benign but biologically invasive. It originates from the smooth muscle of the uterine or the uterine vein. It can grow through the uterus and extend into the pelvic cavity, or grow along the veins without invading the wall of the venous vessel itself. The tumors are estrogen-dependent and can metastasize through the bloodstream. Thus, in addition to continuous growth, some tumors exhibit isolated growths in the venous system and heart chambers or show disseminated growth in the lungs, although distant metastasis to other regions usually do not occur. Currently, there is limited research on this disease, the majority of which are case reports, surgical experience summaries, and differentiation from ordinary gynecological myomas in terms of pathogenesis and radiological diagnostic experience. There are two main theories on the origin of the disease: uterine smooth muscle and smooth muscle of the uterine veins. Some studies have verified the role of estrogen, progesterone receptor-related pathways, and angiogenesis in the development of the disease. The clinical symptoms of this disease are varied, depending on the affected area. In the early stages, when the tumor only affects the pelvic cavity, patients show mild symptoms resulting from pelvic organ compression. When it progresses to the inferior vena cava and heart, patients show more complex symptoms resulting from venous return obstruction, cardiac obstruction, and hemodynamics appearing. Different institutions have proposed different disease staging and classification strategies for different clinical purposes. Some are based on the affected area of the lesion; others are based on the size of the tumor. Although surgery remains the main treatment for this disease, the specific surgical approach, adjuvant drug therapy, and prognosis still need further exploration.

The Role of Morphology in Predicting Fumarate Hydratase-deficient Uterine Leiomyomas in Young Women.

Hereditary leiomyomatosis and renal cell carcinoma is caused by germline mutations in the fumarate hydratase (FH) gene and is associated with an increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma. Pathologic evaluation of uterine leiomyoma can provide an opportunity for early recognition of the syndrome. We reviewed all archived slides of the cases to identify the characteristic morphologic features described for FH-deficient leiomyomas. We performed immunohistochemistry on whole sections of patients with uterine leiomyoma to evaluate for both FH and 2-succinocysteine (2SC) expression. Of the 106 cases, 19 showed the characteristic eosinophilic nucleoli with perinuclear halos, and 24 revealed a characteristic eosinophilic cytoplasmic inclusion consisting of pink globules present within the cytoplasm. Both of these morphologic findings were present together in 15 cases, and hemangiopericytomatous vessels were detected in 23 cases. The loss of FH protein expression was detected in 14 out of 106 cases (13%), and 13 out of 106 cases (12%) were positive for 2SC. We detected 10 cases with both 2SC-positive and FH expression loss. The presence of eosinophilic nucleoli with perinuclear halos and eosinophilic cytoplasmic inclusion was associated with both loss of FH protein expression and 2SC positivity ( P < 0.001). These findings underscore the importance of hematoxylin and eosin-based predictive morphology in FH-deficient uterine leiomyomas. Therefore, morphologic assessment of uterine leiomyomas for features of FH deficiency can serve as a screening tool for hereditary leiomyomatosis and renal cell carcinoma syndrome, allowing patients to be divided according to their hereditary risk assessment.

Laterally extended endopelvic resection as part of the surgical management of disseminated retroperitoneal leiomyomatosis mimicking low-grade sarcoma in a patient with a solitary kidney.

Leiomyomas are common benign uterine smooth muscle tumours. Rarer subsets may demonstrate aggressive extrauterine growth which mimic metastatic disease. We discuss the case of a female patient in her 40s, with a long-standing atrophic right kidney, presenting with a 17 cm uterine mass demonstrating bilateral para-aortic and pelvic sidewall spread. Although biopsies favoured the diagnosis of a benign tumour, a leiomyosarcoma could not be excluded. The surgical complexity of the case was compounded by a tumour residing close to the only functioning kidney and engulfment of the inferior mesenteric artery. The surgical procedures indicated were a radical hysterectomy, the laterally extended endopelvic resection procedure to achieve clear margins in the pelvic sidewall and a left hemicolectomy. In the absence of formal guidelines, we present this challenging case to provide clarity into the histological assessment and surgical management of rare leiomyomas, as well as an overview of the current literature.

[Fumarate hydratase deficient uterine leiomyoma: a clinicopathological and molecular analysis of 80 cases].

Objective: To investigate the clinicopathologic and molecular characteristics of fumarate hydratase (FH) deficient uterine leiomyoma. Methods: Eighty cases of FH deficient uterine leiomyoma were diagnosed from April 2018 to September 2022 in Department of Pathology, Peking University Third Hospital. Sanger sequencing of FH gene exons (exon 1-10) were performed on tumor tissues and matched non-tumor tissues/peripheral blood for all cases. FH immunohistochemistry were performed in 74 cases; S-(2-succino)-cysteine (2SC) were also detected by immunohistochemistry in five cases. Results: Patients' age ranged from 18 to 54 (36.0±7.5) years, with more than 60% exhibiting clinical symptoms of multiple and large leiomyomas (the median diameter was 70 mm). More than four histologic features, including staghorn vasculature, alveolar-pattern edema, bizarre nuclei, oval nuclei arranged in chains, prominent eosinophilic nucleoli with perinucleolar haloes and eosinophilic intracytoplasmic globules were observed in 98.5% (67/68) patients. The immunohistochemical sensitivity of FH and 2SC were 97.3% and 100%, respectively. Based on the Sanger sequencing results, the cases were divided into germline variant group (31 cases), somatic variant group (29 cases) and no variant group (20 cases). Sixty-nine percent (20/29) of the patients with FH germline variation had clear family history. Conclusions: Clinical features, histological morphology, FH and 2SC immunohistochemistry and Sanger sequencing have their own significance and limitations in differential diagnosis of FH deficient uterine leiomyoma. In clinical practice, the above information should be fully integrated and studied for accurate pathologic diagnosis and selection of patients with FH germline variation.

[FH (Fumarate Hydratase)-deficient renal cell carcinoma: A case report]. / Carcinome à cellules rénales FH (fumarate hydratase)-déficient : à propos d'un cas.

Fumarate hydratase deficient renal cell carcinoma (FH-RCC) is a rare malignant neoplasia caused by constitutive or somatic mutations in the FH gene whose diagnosis is primordial, requiring genetic counselling. Because of histological heterogeneity, such tumors have been in the past misclassified as "type 2 papillary carcinoma", "tubulo-cystic renal cell carcinoma" or "high grade papillary carcinoma". We report here a case of FH deficient renal cell carcinoma (FH-RCC) in a 69years old patient. Through this observation, we precise the epidemiological and histological aspects and diagnosis criteria of this rare tumor.

Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

PURPOSE: To determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking. METHODS: We developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed. RESULTS: In the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI -£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs -£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI -£4202 to £2652). CONCLUSION: Annual CERMRI in HLRCC is cost-effective across age groups modelled.

A RARE UTERINE TUMOR: DISSEMINATED PERITONEAL LEIOMYOMATOSIS. CLINICAL OBSERVATIONS.

BACKGROUND: Disseminated peritoneal leiomyomatosis (DPL) is an extremely rare benign disease characterized by widespread lesions of the abdominal cavity, pelvis, and retroperitoneal space with tumor nodules of varying size and number, which are benign neoplasms consisting of smooth muscle fibers in their histological structure. AIM: To analyze clinical cases of DPL with a concise review of the current state of the DPL diagnosis and treatment. MATERIALS AND METHODS: We analyzed 5 clinical cases of DPL of female patients aged 39-50 years (mean age 46.2 years) who underwent surgical treatment at the National Cancer Institute from 2010 to 2021. In all 5 patients, the diagnosis of DPL (8898/1) was verified according to pathological (using routine hematoxylin/eosin staining) and immunohistochemical (IHC) studies. RESULTS: All patients underwent surgical treatment with a laparotomy approach, the extent and radicality of which depended on the location and number of tumor lesions. At the time of follow-up, all 5 patients were alive and did not receive any special oncological treatment. CONCLUSIONS: DPL is characterized by a variety of clinical manifestations from polyserositis to acute abdomen, depending on the location and size of the main tumor focus. IHC analysis is the criterion for the final diagnosis, and radical removal of all tumor foci provides the best therapeutic prognosis. The treatment should be carried out in highly specialized cancer centers where surgeons have gained sufficient experience in performing cytoreductive surgery.

Benign Metastasizing Leiomyomatosis to the Skin and Lungs, Intravenous Leiomyomatosis, and Leiomyomatosis Peritonealis Disseminata: A Series of Five Cases.

Benign metastasizing leiomyomatosis (BML) is a rare disease that typically occurs in women with a history of uterine leiomyomatosis. Benign metastasizing leiomyomatosis occurs more frequently in the lungs but may also develop in other organs and tissues. Other unusual variants of extra-uterine leiomyomatosis include intravenous leiomyomatosis (IVL) and leiomyomatosis peritonealis disseminata (LPD). In this article, three cases of BML are presented. One case, in a premenopausal woman, presented cutaneous metastases. We also present a case of IVL and a case of LPD, which occurred in postmenopausal women. Given the rarity of BML, IVL, and LPD, the authors reviewed the literature and herein discuss the implications for treatment in all five cases. Evidence for treating BML, IVL, and LPD is still scarce, and data available from our series and other small series seem to point to the patient's hormonal status playing a fundamental part in the treatment plan. Furthermore, a collecting bag when performing excision of uterine leiomyomas may help avoid the potential spreading of leiomyomatosis. Hysterectomized patients with chronic cough, frequent respiratory infections, abdominal discomfort, right heart failure, or non-specific symptoms should be actively screened for BML, IVL, and LPD. Treatment should be individualized according to each patient's hormonal status and desires.

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression.

Aims. Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare aggressive renal malignancy associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Tumors exhibiting heterogeneous (ie, patchy) FH loss by immunohistochemistry have rarely been described, may be diagnostically challenging, and have never been the focus of a study. We aimed to investigate the FH mutational status of FH-deficient RCC with heterogeneous versus complete FH loss, to characterize additional genetic drivers, and to evaluate 2SC immunohistochemistry in this setting. Methods and Results. We studied FH-deficient RCC with heterogeneous (n = 3) and complete (n = 4) FH loss. Targeted next-generation sequencing (NGS) was performed on all tumors. No patients had a known history of HLRCC. All tumors had histological features within the morphologic spectrum described for FH-deficient RCC. All 7 tumors were immunoreactive for 2SC. Molecularly, all 7 tumors revealed multiple hits involving the FH locus resulting in complete loss of wild-type alleles. All tumors with heterogeneous FH loss harbored FH missense variants within domain 2 of the protein, and each had concomitant copy neutral loss of heterozygosity (CN-LOH). In complete FH loss tumors, FH alterations included splice variants with concomitant loss of heterozygosity (n = 2) and homozygous gene deletions (n = 2). Other non-recurrent alterations included biallelic alterations of TP53, NF2, SMAD4 and activation of PIK3CA. Conclusions. Our series highlights how heterogeneous FH loss (patchy positive staining) is an important staining pattern to recognize since it is compatible with a diagnosis of FH-deficient RCC and should prompt additional ancillary studies (confirmatory 2SC immunohistochemistry and/or molecular testing) and genetic evaluation.

DISSEMINATED PERITONEAL LEIOMYOMATOSIS - A RARE ENTITY, COMPLICATED BY LATE BLEEDING FROM THE ILEOCOLIC VEIN.

Leiomyomatosis peritonei or disseminated peritoneal leiomyomatosis (DPL) is an extremely rare condition affecting mainly women of childbearing age with estrogen hypersecretion. It is characterized by the presence of multiple histologically benign smooth muscle nodules on the peritoneal surface and subperitoneal tissue mimicking peritoneal carcinomatosis. There are no clear guidelines for the primary management and follow-up o these patients. Case report: We represent a 44-years-old woman admitted due to two retroperitoneal tumors diagnosed on routine ultrasound screening. There was a past history of hysterectomy for uterine leiomyoma. The blood assay was normal. MRI revealed two well-circumcised tumors with a size of 15 cm and 6 cm, respectively, with a characteristic of leiomyoma. The tumors were removed completely. Macroscopically, they appeared as well-circumscribed masses with grey to white color, a rubbery texture, and a whorled cut surface. On the first postoperative day, due to a sudden drop of hemoglobin from 127 g/L to 6.8 g/L and clinical signs of acute intra-abdominal bleeding, the patient was reoperated. The site of bleeding was from the ileocolic vein located at the lower pole of the tumor. It was successfully controlled by ligation. The patient had an uneventful recovery. After five years she is free of recurrence. DPL is a rare disease, sometimes mimicking peritoneal carcinomatosis. The preoperative diagnosis should be suspected in women of childbearing age with estrogen hypersecretion and concurrent uterine leiomyomas. The management depends on the patient's age, reproductive plans, multiplicity, and symptomatology of DPL. Single tumors are best treated by surgery with synchronous hysterectomy or myomectomy in case of uterine myomatosis. In the case of symptomatic multiple DPL and fulfilled reproductive plan, bilateral salpingo-oophorectomy or treatment with Gonadotropin-releasing hormone analogs is indicated. In asymptomatic multiple DPL, the removal of all nodules is not mandatory because of the benign indolent course. The long-term prognosis of DPL is excellent.