Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome.

In hereditary leiomyomatosis and renal cell carcinoma syndrome, fumarate hydratase-deficient renal cell carcinomas typically present as aggressive, unilateral, often cystic masses with heterogeneous enhancement. These tumors can metastasize early, making appropriate imaging and staging critical for diagnosis and management. Teaching point: When a renal lesion suspected of RCC is identified in a patient with cutaneous and uterine leiomyomas, HLRCC should be evaluated, which is important for future genetic counseling.

Clinical and molecular risk factors for repeat interventions due to symptomatic uterine leiomyomas.

BACKGROUND: Repeat leiomyoma occurrence or even reintervention is common after myomectomy. Little is known about the factors related to repeat interventions. OBJECTIVE: This study aimed to determine the frequency of leiomyoma-related reintervention after an initial laparoscopic or abdominal myomectomy and to analyze both clinical and molecular risk factors for reinterventions. Another objective was to define the frequency of clonally related tumors from repeat operations. STUDY DESIGN: This retrospective cohort study included 234 women who had undergone laparoscopic or abdominal myomectomy in 2009 to 2014. Information on repeat leiomyoma-related interventions as well as on other clinical factors was collected from medical records after a median follow-up time of 11.4 years (range 7.9-13.8 years) after the index procedure. The effect of clinical risk factors on the risk of reintervention was analyzed by the Kaplan-Meier estimator and the Cox proportional hazards model. For molecular analyses, we examined the mutation profiles of 133 formalin-fixed paraffin-embedded leiomyoma samples from 33 patients with repeat operations. We screened the tumors for the 3 primary leiomyoma driver alterations-mediator complex subunit 12 mutations, high mobility group AT-hook 2 overexpression, and fumarate hydratase-deficiency-utilizing Sanger sequencing and immunohistochemistry. To further assess the clonal relationship of the tumors, we executed whole-exome sequencing for 52 leiomyomas from 21 patients who exhibited the same driver alteration in tumors obtained from multiple procedures. RESULTS: Reintervention rate at 11.4 years after myomectomy was 20% (46/234). Number of leiomyomas removed at the index myomectomy was a risk factor (hazard ratio 1.21; 95% confidence interval 1.09-1.34). Age at index myomectomy (hazard ratio 0.94; 95% confidence interval 0.89-0.99) and postoperative parity (hazard ratio 0.23; 95% confidence interval 0.09-0.60) were protective factors. Molecular characterization of tumors from index and nonindex operations confirmed a clonal relationship of the tumors in 3/33 (9%) patients. None of the leiomyomas harboring a mediator complex subunit 12 mutation-the most common leiomyoma driver-were confirmed clonally related. Fumarate hydratase-deficiency was detected in repeat leiomyomas from 3/33 (9%) patients. All these patients harbored a germline fumarate hydratase mutation, which is distinctive for the hereditary leiomyomatosis and renal cell cancer syndrome. Finally, we identified 3 (3/33; 9%) patients with 2 tumors each displaying somatic mutations in a recently identified novel leiomyoma driver gene, YEATS domain-containing protein 4. All YEATS domain-containing protein 4 mutations were different and thus the tumors were not clonally related. CONCLUSION: Our study shows that reintervention is common after surgical myomectomy. Uterine leiomyomas typically develop independently, but some share a clonal origin. Repeat leiomyoma occurrence may be due to genetic predisposition, such as a germline fumarate hydratase mutation. Distinct somatic YEATS domain-containing protein 4 mutations identified in multiple leiomyomas from the same patient indicate a possible role for YEATS domain-containing protein 4 in repeat leiomyomas.

Case report: response to immunotherapy and association with the fh gene in hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.

Functional implications of fumarate-induced cysteine succination.

Mutations in metabolic enzymes are associated with hereditary and sporadic forms of cancer. For example, loss-of-function mutations affecting fumarate hydratase (FH), the tricarboxylic acid (TCA) cycle enzyme, result in the accumulation of millimolar levels of fumarate that cause an aggressive form of kidney cancer. A distinct feature of fumarate is its ability to spontaneously react with thiol groups of cysteines in a chemical reaction termed succination. Although succination of a few proteins has been causally implicated in the molecular features of FH-deficient cancers, the stoichiometry, wider functional consequences, and contribution of succination to disease development remain largely unexplored. We discuss the functional implications of fumarate-induced succination in FH-deficient cells, the available methodologies, and the current challenges in studying this post-translational modification.

Benign metastasizing fumarate hydratase (FH)-deficient uterine leiomyomas: clinicopathological and molecular study with first documentation of multi-organ metastases.

Leiomyoma is the most prevalent benign tumor of the female reproductive system. 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 (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH 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 FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; 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.

A new missense mutation c.1240A>G in fumarate hydratase gene leads to uterine leiomyoma associated hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome in Chinese.

OBJECTIVE: This study presents a detailed analysis of the clinical and genetic characteristics of uterine leiomyoma associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), combined with exploration of family history, pathology, and management procedures, supported by thorough evidence collection. METHODS: Blood samples were collected from the proband, and the pathogenic variant was verified using Sanger sequencing. A comprehensive review of family history, FH deficiency pathology, FH and 2SC immunohistochemistry staining was conducted. Functional evidence was derived from clinical and genetic information, supplemented by a literature collection and mutation was reclassified based on ACMG/AMP guidelines. RESULTS: The study successfully identifies a novel missense mutation (c.1240A>G; p.Lys414Glu) in exon 9 of FH, with no prior reports in existing databases. The patient's phenotype and family history, coupled with evidence collected from the literature, contribute to the preliminary determination of the variant as likely pathogenic. We also emphasize that the importance of combining FH-deficient morphology and immunohistochemical staining with 2SC for enhanced sensitivity. CONCLUSION: This research adds a novel missense mutation to the repertoire of FH gene variants, emphasizing its likely pathogenic nature based on a multidimensional analysis of phenotype, family history, and literature evidence. The findings enhance our understanding of the genetic landscape associated with FH and underscore the importance of thorough characterization for accurate variant classification.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

FH deficient uterine leiomyomas-a case series.

Introduction: Fumarate hydratase (FH) deficient uterine leiomyomas account for only 0.4 % of all uterine leiomyomas. They are characterized by some distinct histological features and may be associated with Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Methods: Herein we present a series of five cases of FH deficient uterine leiomyomas in patients with a mean age of 30 years. All five patients underwent myomectomy. Three of these cases had an outside histopathologic diagnosis ranging from Smooth muscle tumor of uncertain malignant potential (STUMP) to Leiomyosarcoma while two cases were operated at our centre. All five cases were reported as suggestive of FH deficient leiomyomas and were advised germline testing along with genetic counselling. Results: Immunohistochemically four of the cases showed moderate to strong positivity for 2-SC with a complete loss or reduced expression of FH while one case showed absence of 2-SC staining. Discussion: Mutations in FH lead to reduced enzyme activity and accumulation of fumarate leading to a complete loss or aberrant reduced expression seen on immunohistochemistry, which confirms the diagnosis. It is important to differentiate it from a leiomyosarcoma or other malignant spindle cell tumors as these tumors follow a benign course. Their association with HLRCC also needs to be established for a suitable follow up since HLRCC-associated RCCs are often aggressive. Conclusion: Management of such leiomyomas is myomectomy or hysterectomy with advice of genetic testing to rule out HLRCC. Histomorphology and immunohistochemistry are imperative for a correct and timely diagnosis.

Fumarate Hydratase-Deficient Leiomyoma of the Uterine Corpus: Comparative Morphologic Analysis of Protein-Deficient Tumors With and Without Pathogenic Germline Fumarate Hydratase Gene Mutations.

Deficiency of fumarate hydratase (FH) protein expression in uterine corpus leiomyomas may be attributable to either germline or somatic mutations of the FH gene, the former being definitional for the hereditary leiomyomatosis and renal cell cancer syndrome. The authors assess whether, using previously reported FH-associated morphologic features, FH protein-deficient uterine corpus leiomyomas associated with a pathogenic germline mutations of the FH gene (group 1) are distinguishable from FH protein-deficient uterine corpus leiomyomas without such mutations (and whose FH protein loss is presumed to be attributable to somatic/epigenetic inactivation or other unknown phenomena: group 2). Groups 1 and 2 were compared regarding a variety of clinicopathologic features, including 7 core "FH-associated" tumoral morphologic features: staghorn vasculature; alveolar-type edema; bizarre nuclei; chain-like tumor nuclei; hyaline cytoplasmic globules; prominent nucleoli, intranuclear inclusions, and perinucleolar halos; and prominent eosinophilic/fibrillary cytoplasm. Among 2418 patients diagnosed with uterine corpus leiomyoma during the study period, FH-associated morphologic features were reported in 1.5% (37 patients), and FH immunohistochemistry was performed in 29 (1.19%). Fourteen (48.27%) of the 29 patients showed FH protein deficiency by immunohistochemistry. Twelve patients underwent germline testing, of which 8 (66.7%) were classified as group 1 and 4 (33.3%) as group 2. FH protein-deficient tumors were larger (10.44 vs 4.08 cm, P = 0.01) and associated with younger patients (42.05 vs 47.97, P = 0.004) than 370 randomly selected uterine leiomyoma controls. Groups 1 and 2 showed no significant differences in patient age and tumor size. In group 1 tumors, the FH-associated morphologic features were generally present diffusely; all group 1 tumors displayed ≥5 FH-associated features, whereas all group 2 tumors displayed <5 FH-associated features (means 6.5 ± 0.53 vs 3.5 ± 1.00, P < 0.001). Notably, eosinophilic/fibrillary cytoplasm and alveolar-type edema were each significantly more prevalent in group 1 tumors than group 2 tumors (P = 0.018 for both). No single morphologic feature was found to be completely sensitive and specific in making the distinction between group 1 and 2 tumors. Our findings suggest that groups 1 and 2 are unlikely to be morphologically distinguishable by individual morphologic features. Whether there is a combination of features that can reliably make this distinction is unclear and will require additional studies with larger cohorts.

Fumarase Deficiency and Its Effect on Infertility: A Case Series.

Background: Fumarase deficiency is an autosomal recessive condition characterized by severe neurologic abnormalities due to homozygous mutations in the fumarate hydratase (FH) gene. Heterozygous carriers of FH mutations have increased risk of developing uterine fibroids that can be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). The association between FH mutations and infertility remains uncertain. The objective of our study was to characterize the infertility diagnoses, treatments, and outcomes in women presenting to a fertility center who were found to be carriers of fumarase deficiency based on the presence of heterozygous FH mutations. Case Presentation: A retrospective case series was conducted including 10 women presenting to an academic fertility center who were found to be FH carriers based on genetic carrier screening. Of the 9 women who were engaged in further workup, 2 had imaging results consistent with uterine fibroids. One woman underwent hysteroscopic myomectomy prior to two courses of ovulation induction with timed intercourse (OI/TIC) followed by one successful cycle of IVF. Of the remaining patients, only 1 woman successfully delivered after a cycle of ovulation induction with intrauterine insemination (OI/IUI). Other patients pursuing OI/IUI, OI/TIC, or monitored natural cycles had unsuccessful experiences. Conclusion: Patients with infertility who are offered genetic testing should be screened for FH mutations, as the carriers are at risk of developing HLRCC-associated uterine fibroids, which can influence fertility and pregnancy. Additional research is needed to investigate the impacts of FH mutations on infertility.

Investigating Fumarate Hydratase-Deficient Uterine Fibroids: A Case Series.

Uterine leiomyomas or uterine fibroids are the most common benign soft tissue tumor in reproductive-aged women. Fumarate hydratase deficient (FH-d) uterine fibroids are a rare subtype that is diagnosed only on pathologic evaluation. FH-d uterine fibroids may be the first indicator of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Therefore, identifying and understanding the clinical implication and diagnosis of FH-d uterine fibroids is critical for early diagnosis of HLRCC. This case series investigates the uncommon yet significant condition of FH-d uterine fibroids. We examined the clinical manifestation, diagnostic imaging, and histopathological characteristics of FH-d uterine fibroids in five cases identified at our institution over the last ten years. All diagnoses were confirmed by pathologic evaluation after surgical treatment. Gynecologists and pathologists play a critical role in the early diagnosis of FH-d uterine fibroids and must recognize the relevant clinical and pathologic findings that raise suspicion about this diagnosis. The detection of these cases is largely dependent on the pathologist's ability to recognize unique histopathologic features. Once these characteristics are identified, it should prompt a referral to a gynecologist to consider conducting germline genetic testing. The management of FH-d uterine fibroids necessitates a multidisciplinary approach, including proper genetic screening and regular surveillance, especially for renal tumors.

A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata.

BACKGROUND: HLRCC syndrome is a hereditary cancer predisposition syndrome caused by heterozygous germline pathogenic variant of the fumarate hydratase (FH) gene and characterized by cutaneous leiomyomas (CL), uterine leiomyomas (UL), and renal cell carcinoma (RCC). Loss of function variant of FH gene inactivates the Kreb's cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC. METHODS: Next-generation sequencing (NGS) and Sanger confirmation were given to family members accessible. Following that, a functional study in vitro was performed to further confirm the pathogenicity of the variant. FH-Wild type (FH-WT) and FH-mutant (FH-MUT) (E378K) plasmid were constructed and transfected into 293T and uterine leiomyoma cell lines, respectively. Proliferation assessment was executed to show how this mutation affects the growth of uterine leiomyoma. qPCR and Western blotting were performed to investigate the change of transcription and translation of FH with mutation (E378K), and FH enzyme assay activity were tested in 293T cells with mutation and wild-type plasmids. RESULTS: Here, we presented two families with the same missense variant (c.1132G > A) that has not been reported as a germline mutation in hereditary uterine leiomyomas before and classified as VUS in gene databases. Our in vitro experiments supported the pathogenicity of this missense variant, especially in uterine leiomyomata. CONCLUSIONS: According to the American College of Medical Genetics (ACMG) guideline, the E378K variant was classified as likely pathogenic (with evidence PS4_support, PS3_support, PM2_support, PP1, PP3 and PP4 evidence). Further insights into clinical management in uterine leiomyomata were discussed and should be practiced in gynecological clinical settings.

Diseases of Hereditary Renal Cell Cancers.

Germline mutations in tumor suppressor genes and oncogenes lead to hereditary renal cell carcinoma (HRCC) diseases, characterized by a high risk of RCC and extrarenal manifestations. Patients of young age, those with a family history of RCC, and/or those with a personal and family history of HRCC-related extrarenal manifestations should be referred for germline testing. Identification of a germline mutation will allow for testing of family members at risk, as well as personalized surveillance programs to detect the early onset of HRCC-related lesions. The latter allows for more targeted and therefore more effective therapy and better preservation of renal parenchyma.

[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.

Characterization of protein S-(2-succino)-cysteine (2SC) succination as a biomarker for fumarate hydratase-deficient renal cell carcinoma.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is an aggressive, rare genetic disease affecting the kidney and other organ systems. We constructed a specialized multi-institutional cohort of 20 primary FH-deficient RCC cases with aims of characterizing a new commercially available antibody, S-(2-succino)-cysteine (2SC). Herein, we present our findings on the biomarker characterization and performance of 2SC expression by immunohistochemistry (IHC) in FH-deficient RCC and other common and rare RCC subtypes. Morphological assessment revealed characteristic cytomorphologic features and a majority (55%) of FH-deficient RCC had mixed architectural growth patterns. We observed predominantly diffuse and strong cytoplasmic staining with limited nuclear positivity for 2SC staining on IHC. Receiver operating characteristic curves (ROC) for 2SC identified the threshold IHC score (cutoff) as 90, with the sensitivity and specificity being 100% and 91%, respectively. The findings of the present study along with the prior evidence in literature encourage utilization of 2SC as a positive marker along with the loss of FH expression by anti-FH IHC staining as a negative marker, in clinical and/or pathologic scenarios when considering FH-deficient RCC in the differential diagnosis. FH-/2SC+ may serve as a comprehensive IHC panel in identifying such cases and excluding morphologically similar entities.

Recurrent Cushing Syndrome From Metastatic Adrenocortical Carcinoma With Fumarate Hydratase Allelic Variant.

Background: Adrenal Cushing syndrome (CS) is usually benign in etiology; however, although rarely, it can be due to adrenocortical carcinoma (ACC); in which case, diagnosis and management are quite complicated. Case Report: A 34-year-old woman presented with worsening confusion, weight gain, new-onset diabetes, and hypertension. Her history was significant for a 7.4-cm left adrenal mass and CS, which were treated with left adrenalectomy 2 years ago. She received hydrocortisone replacement therapy after the surgery, which was discontinued on admission when evaluation showed hypokalemia, hypercortisolemia, and undetectable adrenocorticotropic hormone. Subsequent testing included 1-mg and 8-mg dexamethasone suppression tests, which did not suppress cortisol; late-night salivary cortisol measurement, which yielded a very high salivary cortisol level; and 24-hour urinary cortisol measurement. The level of 11-deoxycortisol was elevated. A computed tomography scan revealed multiple hepatic lesions, which were fluorodeoxyglucose avid, and a biopsy confirmed metastatic ACC. She received treatment with mitotane, metyrapone (later changed to mifepristone), doxorubicin, cisplatin, and etoposide. Over 8 weeks, mitotane levels became therapeutic at 20 mcg/mL, the hepatic masses decreased in size, and she transitioned to adrenal insufficiency and improved glycemic control. Next-generation sequencing of liver biopsy and germline testing revealed a frameshift loss-of-function allelic variant in the FH gene that encodes the protein fumarate hydratase. Discussion: We report a case of recurrent CS due to metastatic ACC in a patient with a previously resected adrenal adenoma and FH allelic variant. Conclusion: Metastatic ACC presenting with severe CS presents a diagnostic and management challenge where combination therapy guided by a multidisciplinary team is essential. FH allelic variant may contribute to ACC progression.

Hereditary Leiomyomatosis and Renal Cell Cancer-Recognizing Patterns May Save Lives.

In 2001, Finish investigators described a rare familiar syndrome characterized by an inherited susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). Hereditary leiomyomatosis and renal cell cancer (HLRCC) is now linked to a germline mutation in the fumarate hydratase (FH) gene that encodes a Krebs cycle enzyme, transforming fumarate to malate. The accumulation of fumarate, an oncometabolite, promotes tumorigenesis. We present a case of a 41-year-old female diagnosed with HLRCC after a radical nephrectomy due to renal cell cancer. Genetic analyses confirmed a novel FH mutation. Close follow-up allowed for a precocious diagnosis of a metachronous renal tumor and later a hepatic metastasis. Her family was also counseled and offered genetic testing. As observed in this case, the diagnosis of HLRCC is of paramount importance for patients and their families: there is a 15% cumulative lifetime risk of developing RCC, which frequently occurs in young patients and metastasizes at an early stage. Implementing a regular follow-up with adequate imaging examinations may help save lives.