Journal articles: 'HLRCC'

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Skala, Stephanie L., Saravana M. Dhanasekaran, and Rohit Mehra. "Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC): A Contemporary Review and Practical Discussion of the Differential Diagnosis for HLRCC-Associated Renal Cell Carcinoma." Archives of Pathology & Laboratory Medicine 142, no. 10 (October 1, 2018): 1202–15. http://dx.doi.org/10.5858/arpa.2018-0216-ra.

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Context.— Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an uncommon disorder with germline-inactivating mutations in the fumarate hydratase (FH) gene. The kidney cancers that develop in patients with HLRCC are often unilateral and solitary, with a potentially aggressive clinical course; morphologic identification of suspicious cases is of the utmost importance. Objective.— To review classic morphologic features of HLRCC-associated renal cell carcinoma, the reported morphologic spectrum of these tumors and their mimics, and the evidence for use of immunohistochemistry and molecular testing in diagnosis of these tumors. Data Sources.— University of Michigan cases and review of pertinent literature about HLRCC and the morphologic spectrum of HLRCC-associated renal cell carcinoma. Conclusions.— Histologic features, such as prominent nucleoli with perinucleolar halos and multiple architectural patterns within one tumor, are suggestive of HLRCC-associated renal cell carcinoma. However, the morphologic spectrum is broad. Appropriate use of FH immunohistochemistry and referral to genetic counseling is important for detection of this syndrome.

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Furuya, Mitsuko, Yasuhiro Iribe, Yoji Nagashima, Naotomo Kambe, Chisato Ohe, Hidefumi Kinoshita, Chika Sato, et al. "Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas." Journal of Clinical Pathology 73, no. 12 (May 6, 2020): 819–25. http://dx.doi.org/10.1136/jclinpath-2020-206548.

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AimsHereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies.MethodsTen Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours.ResultsAll patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence.ConclusionsHLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

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Hol, J. A., M. C. J. Jongmans, A. S. Littooij, R. R. de Krijger, R. P. Kuiper, J. J. T. van Harssel, A. Mensenkamp, et al. "Renal cell carcinoma in young FH mutation carriers: case series and review of the literature." Familial Cancer 19, no. 1 (December 2, 2019): 55–63. http://dx.doi.org/10.1007/s10689-019-00155-3.

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AbstractHereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC), which is usually adult-onset. HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small. Data on children and adolescents are scarce. Herein, we report two patients from unrelated Dutch families, with HLRCC-related RCC at the ages of 15 and 18 years, and a third patient with an FH mutation and complex renal cysts at the age of 13. Both RCC’s were localized and successfully resected, and careful MRI surveillance was initiated to monitor the renal cysts. One of the patients with RCC subsequently developed an ovarian Leydig cell tumor. A review of the literature identified 10 previously reported cases of HLRCC-related RCC in patients aged younger than 20 years, five of them presenting with metastatic disease. These data emphasize the importance of recognizing HLRCC in young patients to enable early detection of RCC, albeit rare. They support the recommendations from the 2014 consensus guideline, in which genetic testing for FH mutations, and renal MRI surveillance, is advised for HLRCC family members from the age of 8–10 years onwards.

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Yonese, Ichiro, Masaya Ito, Kosuke Takemura, Takao Kamai, and Fumitaka Koga. "A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy." Journal of Kidney Cancer and VHL 7, no. 2 (July 20, 2020): 6–10. http://dx.doi.org/10.15586/jkcvhl.2020.148.

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Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) associated renal cell carcinoma (RCC) is an aggressive form of type 2 papillary RCC caused by deficiency of the fumarate hydratase gene. For patients with metastatic disease, no standard treatment has been established with dismal prognosis. We report a case of metastatic HLRCC-associated RCC in a 65-year-old Japanese male whose clinical features mimicked advanced renal pelvic cancer. A durable response was achieved with a sequence of axitinib and nivolumab after cytoreductive and diagnostic nephrectomy. Their potential therapeutic roles in the management of metastatic HLRCC-associated RCC have been discussed based on its molecular and biological backgrounds.

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Sudarshan, Sunil, Carole Sourbier, Hye-Sik Kong, Karen Block, Vladimir A. Valera Romero, Youfeng Yang, Cynthia Galindo, et al. "Fumarate Hydratase Deficiency in Renal Cancer Induces Glycolytic Addiction and Hypoxia-Inducible Transcription Factor 1α Stabilization by Glucose-Dependent Generation of Reactive Oxygen Species." Molecular and Cellular Biology 29, no. 15 (May 26, 2009): 4080–90. http://dx.doi.org/10.1128/mcb.00483-09.

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ABSTRACT Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive—the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension—is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the α subunit of the hypoxia-inducible transcription factor (HIF-1α). Under normoxic conditions, proline hydroxylation of HIF-1α permits VHL recognition and subsequent targeting for proteasomal degradation. Here, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1α stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1α stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.

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Sandhu, Ivraj Singh, Nicholas James Maksim, Eva Alice Amouzougan, Bryce Wilson Gallion, Anthony L. J. Raviele, and Aikseng Ooi. "Sustained NRF2 activation in hereditary leiomyomatosis and renal cell cancer (HLRCC) and in hereditary tyrosinemia type 1 (HT1)." Biochemical Society Transactions 43, no. 4 (August 1, 2015): 650–56. http://dx.doi.org/10.1042/bst20150041.

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The nuclear erythroid 2-like 2 transcription factor (NRF2), is a major regulator of cellular redox balance. Although NRF2 activation is generally regarded as beneficial to human health, recent studies have identified that sustained NRF2 activation is over-represented in many cancers. This raises the question regarding the role of NRF2 activation in the development and progression of those cancers. This review focuses on the mechanisms and the effects of NRF2 activation in two hereditary cancer predisposition syndromes: hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary tyrosinemia type 1 (HT1). Because the cancer initiating mutations in these hereditary syndromes are well defined, they offer a unique opportunity to explore the roles of NRF2 activation in the early stages of carcinogenesis. Over the years, a variety of approaches have been utilized to study the biology of HLRCC and HT1. In HLRCC, in vitro studies have demonstrated the importance of NRF2 activation in sustaining cancer cell proliferation. In the mouse model of HT1 however, NRF2 activation seems to protect cells from malignant transformation. In both HT1 and HLRCC, NRF2 activation promotes the clearance of electrophilic metabolites, enabling cells to survive cancer-initiating mutations. Biological insights gained from the hereditary syndromes’ studies may shed light on to the roles of NRF2 activation in sporadic tumours.

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Woolner, Kathryn, Ashley O’Toole, and Lauren LaBerge. "First Presentation of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Pregnancy." Journal of Cutaneous Medicine and Surgery 20, no. 4 (February 22, 2016): 334–36. http://dx.doi.org/10.1177/1203475416634091.

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Background: Reed’s syndrome, also known as hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, is an autosomal dominant condition in which affected individuals may develop cutaneous leiomyomas, uterine fibroids, and renal cell carcinoma. Objective: This report describes a unique case of HLRCC because it presented in pregnancy with development of cutaneous pilar leiomyomas. Methods: Review of the literature for previous cases of Reed’s syndrome during pregnancy including PubMed and Medline search. Results: Genetic testing of this patient demonstrated a mutation in the fumarate hydratase ( FH) gene. Review of the literature showed only 1 previous case series that described the onset of cutaneous lesions during pregnancy. Conclusion: This case serves as a reminder that there may exist a correlation between pregnancy and the first manifestation of cutaneous lesions in patients with HLRCC, and thus an increased clinical suspicion is warranted during this period.

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Ristau, Benjamin T., Sonal N. Kamat, and Tatum V. Tarin. "Abnormal Cystic Tumor in a Patient with Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome: Evidence of a Precursor Lesion?" Case Reports in Urology 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/303872.

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The hereditary leiomyomatosis and renal cell cancer (HLRCC) association is a rare syndrome caused by mutation of the Kreb’s cycle enzyme, fumarate hydratase (FH). It is characterized by unusually aggressive type 2 papillary renal cell histology. FH is responsible for catalyzing the conversion of fumarate to malate. Its absence leads to a state of “pseudohypoxia,” inducing hypoxia inducible factor 1α(HIF-1α) and leading to increased growth factor transcription (e.g., vascular endothelial growth factor, VEGF; glucose transporter 1, GLUT1). Ultimately, this results in tumorigenesis. We present a patient who was diagnosed with HLRCC and underwent bilateral nephrectomies. One of the nephrectomy specimens was notable for benign cystic lesions that stained positive immunohistochemically for succinated proteins, a finding only noted in FH-deficient cells. Thus, we posit a potential precursor lesion to type 2 papillary renal cell carcinoma in the HLRCC syndrome.

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Srinivasan, Ramaprasad, Sandeep Gurram, Munjid Al Harthy, Eric A. Singer, Abhinav Sidana, Brian M. Shuch, Mark Wayne Ball, et al. "Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 5004. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5004.

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5004 Background: HLRCC is a familial cancer syndrome associated with a type 2 papillary RCC (pRCC) variant. HLRCC is caused by germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH). FH inactivation results in VHL-independent upregulation of hypoxia inducible factor, a reliance on aerobic glycolysis, and activation of the NRF2 pathway, features also shared by some sporadic pRCC tumors. We hypothesized that the metabolic alterations underlying these tumors would be susceptible to targeted therapy with a combination of bevacizumab and erlotinib. Methods: Patients with advanced pRCC were eligible to enroll on this phase II study. To enrich for patients with FH deficiency, those with 1) HLRCC and 2) sporadic pRCC were enrolled into parallel, independent cohorts. All patients received bevacizumab 10 mg/kg IV every 2 weeks and erlotinib 150 mg orally daily. Patients who had received no more than two agents targeting the VEGFR pathway were included. Patients remained on treatment until unacceptable toxicity or progression. The primary endpoint was overall response rate (ORR); secondary endpoints were progression free survival (PFS) and duration of response. Results: A total of 83 patients with pRCC, including 42 in the HLRCC cohort and 41 in the sporadic cohort were enrolled on study. The majority of patients were IMDC intermediate risk (53/83, 64%) and 27 (33%) had at least one prior treatment. The ORR was 51% (42/83; 95% CI, 40 – 61) in all patients, 64% (27/42; 95% CI, 49 – 77) in the HLRCC cohort, and 37% (15/41; 95% CI, 24 – 52) in the sporadic cohort. The median PFS was 14.2 months (95% CI, 11.4 – 18.6) in all patients, 21.1 months (95% CI, 15.6 – 26.6) in the HLRCC cohort, and 8.7 months (95% CI, 6.4 – 12.6) in the sporadic cohort. The majority of treatment related adverse events (TRAEs) were grade 1 or 2 with the most common being acneiform rash (92%), diarrhea (77%), proteinuria (71%), and dry skin (61%). Grade ≥3 TRAEs occurred in 47% of patients, including hypertension (34%) and proteinuria (13%), with one patient (1.2%) with a grade 5 GI hemorrhage possibly related to bevacizumab. Conclusions: The combination of bevacizumab and erlotinib is well tolerated and is associated with encouraging activity in advanced pRCC, particularly in patients with FH deficient tumors. This is the first and largest prospective study in HLRCC and provides the basis for considering bevacizumab and erlotinib as a preferred option in a patient population that has no widely accepted standard. Clinical trial information: NCT01130519 .

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Crooks, Daniel R., Nunziata Maio, Martin Lang, Christopher J. Ricketts, Cathy D. Vocke, Sandeep Gurram, Sevilay Turan, et al. "Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase–deficient renal cancer." Science Signaling 14, no. 664 (January 5, 2021): eabc4436. http://dx.doi.org/10.1126/scisignal.abc4436.

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Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)–encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

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Swarz, Jeffrey A., Arayamparambil C. Anilkumar, Douglas C. Miller, N. Scott Litofsky, and Tomoko Tanaka. "An Unusual Presentation of a Cervical Paraspinal Leiomyoma in an Adolescent Female." Pediatric and Developmental Pathology 21, no. 3 (April 21, 2017): 335–40. http://dx.doi.org/10.1177/1093526617706815.

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Objective We describe an apparently unique case of an extra-uterine leiomyoma in the cervical paraspinal tissue including its evaluation and management. Methods A 14-year-old girl was referred to the neurology clinic for an abnormal head CT following a concussion. MRI revealed a homogenously enhancing left cervical paraspinal mass. The patient underwent complete resection and subsequent genetic testing and counseling were obtained to determine the presence of Li–Fraumeni Syndrome (LFS) or Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) mutations. Result Histopathological examination proved that the tumor was a benign leiomyoma. Genomic testing for Fumarate Hydratase Gene, HLRCC, TP53 mutations or deletions, and LFS sequencing were negative. Further testing showed no immunosuppression. Conclusions To the best of our knowledge, this is the only case of paraspinal leiomyoma to have been reported to date. We emphasize the importance of considering immunosuppression, LFS, or HLRCC as an underlying cause in extra-uterine leiomyata.

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Singer, Eric A., Julia C. Friend, Geri Hawks, Cathy Vocke, Adam R. Metwalli, Peter A. Pinto, Gennady Bratslavsky, W. Marston Linehan, and Ramaprasad Srinivasan. "A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer (RCC)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS4680. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps4680.

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TPS4680 Background: There are currently no treatment options of proven efficacy for patients with advanced papillary RCC. The evaluation of families with inherited forms of RCC has allowed for the identification of genetic alterations associated with papillary RCC. HLRCC is one such familial condition with a propensity for the development of a clinically aggressive variant of papillary RCC characterized by unique histopathologic features. Germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH) are the genetic hallmark of HLRCC. Mutational inactivation of FH leads to von Hippel-Lindau-independent upregulation of hypoxia inducible factors (HIF) and their downstream transcriptional targets such as vascular endothelial growth factor (VEGF) and transforming growth factor-alpha (TGF-α) / epidermal growth factor receptor (EGFR). Upregulation of the HIF pathway may also be important in sporadic papillary RCC, although the prevalence of FH inactivation in these patients is unknown. We propose to evaluate the activity of dual VEGF/EGFR blockade with bevacizumab/erlotinib in patients with HLRCC-associated RCC and sporadic papillary RCC. Methods: This is a single arm phase II study based on an open label Simon two-stage minmax design with a maximum accrual of 20 patients in each of two cohorts: Cohort 1- patients with HLRCC; Cohort 2- patients with sporadic papillary RCC. The primary endpoint is RECIST overall response rate, assessed independently in each cohort. Patients will receive bevacizumab (10mg/Kg IV every 2 weeks) and erlotinib (150mg PO daily). Dose reductions and drug interruptions for toxicity are allowed. Patients will be evaluated for response every 8 weeks. Major eligibility criteria include: advanced RCC associated with HLRCC or sporadic papillary RCC; age >18 years; ECOG 0-2; measurable disease by RECIST; no brain metastases; no more than 2 prior regimens containing a VEGF inhibitor; and no prior therapy with bevacizumab. The prespecified activity goal for the first stage of accrual has been met for both cohorts. NCT01130519.

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Perez, Minervo, Daniel W. Bak, Sarah E. Bergholtz, Daniel R. Crooks, Bhargav Srinivas Arimilli, Youfeng Yang, Eranthie Weerapana, W. Marston Linehan, and Jordan L. Meier. "Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite." Journal of Biological Chemistry 295, no. 39 (August 19, 2020): 13410–18. http://dx.doi.org/10.1074/jbc.ac120.014993.

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An important context in which metabolism influences tumorigenesis is the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibition of epigenetic dioxygenases, as well as posttranslationally, via covalent modification of cysteine residues. To better understand the potential for metabolites to influence posttranslational modifications important to tumorigenesis and cancer cell growth, here we report a chemoproteomic analysis of a kidney-derived HLRCC cell line. Using a general reactivity probe, we generated a data set of proteomic cysteine residues sensitive to the reduction in fumarate levels caused by genetic reintroduction of active FH into HLRCC cell lines. This revealed a broad up-regulation of cysteine reactivity upon FH rescue, which evidence suggests is caused by an approximately equal proportion of transcriptional and posttranslational modification–mediated regulation. Gene ontology analysis highlighted several new targets and pathways potentially modulated by FH mutation. Comparison of the new data set with prior studies highlights considerable heterogeneity in the adaptive response of cysteine-containing proteins in different models of HLRCC. This is consistent with emerging studies indicating the existence of cell- and tissue-specific cysteine-omes, further emphasizing the need for characterization of diverse models. Our analysis provides a resource for understanding the proteomic adaptation to fumarate accumulation and a foundation for future efforts to exploit this knowledge for cancer therapy.

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Wedekind, Mary Frances, Jaydira Del Rivero, Fernanda Irene Arnaldez, Ramaprasad Srinivasan, Melissa Spencer, Seth M. Steinberg, Cody J. Peer, et al. "A phase II trial of the DNA methyl transferase inhibitor, SGI-110 (Guadecitabine), in children and adults with SDH-deficient GIST, pheochromocytoma, and paraganglioma, and HLRCC-associated kidney cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 11540. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.11540.

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11540 Background: Loss of activity of the Krebs cycle component succinate dehydrogenase (SDH) complex is a mechanism of tumorigenesis in SDH-deficient cancers. Accumulation of the metabolite succinate inhibits α-ketoglutarate-dependent dioxygenases leading to DNA hypermethylation. Guadecitabine is a small molecule DNA methyltransferase inhibitor. We conducted a Phase II study to test the hypothesis that guadecitabine will impact tumor growth by reversing DNA hypermethylation in tumors with Krebs cycle abnormalities (NCT03165721). Study Objectives: Our primary objective was to assess the clinical activity of guadecitabine in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Secondarily, we desired to evaluate the toxicities of patients on treatment with guadecitabine. Methods: We conducted a single site, open label, phase II study using a small optimal two-stage design to evaluate response in SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Patients >12 years of age received guadecitabine subcutaneously at 45mg/m2/day for 5 consecutive days on a 28-day cycle. Activity via imaging response was assessed utilizing RECISTv1.1. Toxicities were graded using version 4.0 of the NCI Common Toxicity Criteria. All patients were included in analysis. Results: We enrolled nine patients (6F:3M) with an age range of 18-57 years. Seven patients had SDH-deficient GIST (78%), one patient with paraganglioma (11%), and one with HLRCC-associated renal cell carcinoma (11%). No patients had a complete or partial response. Five patients came off study due to progression (56%) with one death due to disease progression in the patient with HLRCC-associated renal cell carcinoma (11%). Three patients (33%) withdrew due to lack of response with stable disease. One patient was withdrawn due to investigator’s discretion (11%). Toxicities possibly, probably, or definitely related to drug included grade 3 leukopenia (11%) febrile neutropenia (11%), grade 3-4 neutropenia (22%) requiring dose reductions, grade 3 hypertension (11%), grade 2 lung infection requiring hospitalization (11%). Conclusions: In this single site, open label, phase II study in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell cancer guadecitabine was tolerated by the majority of patients. No complete or partial responses were observed. Clinical trial information: NCT03165721 .

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Shuch, Brian, Kevin P. Asher, Clara Chen, Kelly Lin, Gennady Bratslavsky, W. Marston Linehan, and Ramaprasad Srinivasan. "Clinical evaluation of 2-(18F) fluoro-2 deoxy-D-glucose PET/ CT in hereditary leiomyomatosis and renal cell carcinoma." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 383. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.383.

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383 Background: 2-(18F) fluoro-2 deoxy-D-glucose (FDG) PET/CT is a useful tool in the staging of malignancies. In patients with kidney cancer, the role of FDG is limited in those with clear-cell histology and remains to be evaluated with other subtypes. Kidney cancer associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is characterized by a defect in the Krebs cycle rendering these tumors highly dependent on aerobic glycolysis (the ‘Warburg effect’) with high glucose uptake to fulfill their energy requirements; we hypothesized that FDG PET/CT may have excellent sensitivity for staging in this condition. Methods: We retrospectively reviewed patients with HLRCC kidney cancer that underwent FDG PET/CT in conjunction with anatomic imaging at our institution. The ability of FDG PET/CT to detect malignant lesions (defined using pathologic or radiologic criteria) was evaluated. Results: A total of 30 patients underwent 42 PET /CTs. Conventional imaging identified a total of 107 lesions. Both patient and lesion-based analyses were performed. A total of 90 lesions, including ten renal lesions, were classified as malignant. 76 of 80 extra-renal lesions were correctly identified as malignant by PET/CT (sensitivity, 95%, CI 88-98%). In contrast, only 4 of 10 renal lesions were correctly identified as malignant (sensitivity, 40%, CI 17-69%). 11 of 12 histologically confirmed extra-renal lesions were PET avid (sensitivity, 92%, CI-64-98%). 10 of 12 (83%) benign lesions associated with HLRCC including uterine/cutaneous leiomyomas and adrenal nodules were PET avid. In a patient based analysis, all 18 patients with extra-renal spread of kidney cancer were correctly identified (sensitivity 100%, CI 82-100%). Conclusions: FDG PET/CT is a highly sensitive diagnostic modality for identifying metastatic kidney cancer associated with HLRCC. Prospective studies evaluating the utility of PET/CT imaging to characterize response to systemic therapy are currently underway.

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Kiuru, Maija, and Virpi Launonen. "Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)." Current Molecular Medicine 4, no. 8 (December 1, 2004): 869–75. http://dx.doi.org/10.2174/1566524043359638.

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Udager, Aaron M., Ajjai Alva, Ying-Bei Chen, Javed Siddiqui, Amir Lagstein, Satish K. Tickoo, Victor E. Reuter, Arul M. Chinnaiyian, and Rohit Mehra. "Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)." American Journal of Surgical Pathology 38, no. 4 (April 2014): 567–77. http://dx.doi.org/10.1097/pas.0000000000000127.

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Sánchez-Heras, A. Beatriz, Adela Castillejo, Juan D. García-Díaz, Mercedes Robledo, Alexandre Teulé, Rosario Sánchez, Ángel Zúñiga, et al. "Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization." Cancers 12, no. 11 (November 5, 2020): 3277. http://dx.doi.org/10.3390/cancers12113277.

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Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

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Ueki, Arisa, Kokichi Sugano, Kumiko Misu, Eriko Aimono, Kohei Nakamura, Shigeki Tanishima, Nobuyuki Tanaka, et al. "Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7962. http://dx.doi.org/10.3390/ijms22157962.

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Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening.

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Kujala, M., K. Aittomäki, and M. Ruutu. "450 RENAL FOLLOW-UP OF HLRCC SYNDROME PATIENTS." European Urology Supplements 6, no. 2 (March 2007): 135. http://dx.doi.org/10.1016/s1569-9056(07)60448-5.

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Aissani, Brahim, Kui Zhang, Arjen R. Mensenkamp, Fred H. Menko, and Howard W. Wiener. "Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval." Endocrine-Related Cancer 22, no. 4 (June 25, 2015): 633–43. http://dx.doi.org/10.1530/erc-15-0208.

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Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re-sequenced 2.3 Mb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0×10−5) in the RGS7-FH interval in African Americans. In race-combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7×10−4). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.

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Koch, André, Jacqueline Schönlebe, Aleksandra Vojvodic, Torello Lotti, and Uwe Wollina. "Multiple Cutaneous Leiomyomas with Uterus Myomatosus (MCUL) – Two Case Reports and One New Mutation of FH Gene." Open Access Macedonian Journal of Medical Sciences 7, no. 18 (July 30, 2019): 3026–29. http://dx.doi.org/10.3889/oamjms.2019.625.

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BACKGROUND: Reed syndrome or multiple cutaneous leiomyomas with uterine leiomyomas are part of the spectrum of heterozygous hereditary disorders with cutaneous, genital and renal manifestations. CASE REPORTS: We report two female cases of multiple cutaneous leiomyomas with uterine leiomyomas (MCUL) without renal disease, in particular without cysts or papillary renal carcinoma, aged 52 and 55 years, respectively. The diagnosis of pilar leiomyomas was confirmed by histology and immunostaining for smooth muscle actin and desmin. Both females had a hysterectomy in the past because of uterus myomatosus. In one patient, a new mutation of the FH gene was detected, i.e. a heterozygote c1300_1301del (p.Cys434Argfs17) mutation in the exon 9 of the FH gene. CONCLUSION: Since MCUL shares features with the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), these patients need a regular follow-up to prevent the late diagnosis of renal cancer. carcinoma (HLRCC), these patients need a regular follow-up to prevent late diagnosis of renal cancer.

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Shuch, Brian, Christopher Ricketts, Carole Sourbier, Shinji Tsutsumi, Xiu-ying Zhang, Arie S. Belldegrun, Christopher G. Wood, W. Marston Linehan, and Len Neckers. "Metabolic evaluation of sporadic papillary kidney cancer." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 377. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.377.

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377 Background: Papillary kidney cancer, which occurs in 15% of patients with kidney cancer, can be aggressive and there is currently no effective form of therapy for this disease. To evaluate the metabolic characteristics of sporadic papillary kidney cancer, we have evaluated metabolic parameters of several papillary kidney cancer cell lines and available gene expression profiles. Methods: Established cell lines derived from patients with sporadic papillary kidney cancer (LABAZ, MDACC-55, HRC-86T2) and from a hereditary form of fumarate hydratase-deficient kidney cancer (UOK262) were evaluated. All sporadic lines were initially sequenced for fumarate hydratase (FH). All cell lines were metabolically profiled using the Seahorse Extracellular Flux Analyzer and further evaluated for reactive oxygen species (ROS), mitochondrial membrane potential, and glucose dependence. Finally gene expression profiles of publically available datasets of papillary and HLRCC tumors were downloaded, normalized, and analyzed. Results: Sporadic lines had no alterations in FH and metabolic analysis demonstrated normal oxygen consumption and minimal lactate production, in contrast to highly glycolytic UOK262. Also unlike UOK262, the sporadic papillary kidney cancer lines were not sensitive to glucose withdrawal, had low levels of ROS, and had normal mitochondria membrane potential. Principal component analysis (PCA) demonstrated that HLRCC tumor specimens are very different from sporadic papillary tumors at the molecular level. Conclusions: Our study of established sporadic papillary RCC and fumarate hydratase-deficient HLRCC cell line together with analysis of available gene expression profiles demonstrates that these sporadic papillary kidney cancer cell lines appear to have a distinct metabolic profile from those in the fumarate hydratase deficient kidney cancer cell line. Understanding the metabolic basis of papillary kidney cancer could provide the foundation for the development of targeted approaches to therapy for patients with this disease.

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Ooi, Aikseng. "Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research." Seminars in Cancer Biology 61 (April 2020): 158–66. http://dx.doi.org/10.1016/j.semcancer.2019.10.016.

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Yonamine, Tomoko, Tadashi Kaname, Yasutsugu Chinen, Kouichi Tamashiro, Noritake Kosuge, and Seiichi Saito. "Hereditary leiomyomatosis and renal cell cancer (HLRCC): A case report." Urology Case Reports 30 (May 2020): 101141. http://dx.doi.org/10.1016/j.eucr.2020.101141.

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Wong, Mei Hua, Chuen Seng Tan, Soo Chin Lee, Yvonne Yong, Aik Seng Ooi, Joanne Ngeow, and Min Han Tan. "Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC)." Familial Cancer 13, no. 2 (February 14, 2014): 281–89. http://dx.doi.org/10.1007/s10689-014-9703-x.

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Reda, Sarah Alicia, Emily A. Japp, Qiusheng Si, Ketan Badani, and Alice C. Levine. "A Case of Renal Cell Carcinoma and Pheochromocytoma Due to Germline Inactivating Mutation in Fumarate Hydratase (FH)." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A986. http://dx.doi.org/10.1210/jendso/bvab048.2017.

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Abstract A 60-year-old female with a history of well-controlled hypertension, prediabetes, status post hysterectomy for fibroids, presented for evaluation of hematuria and unintentional weight loss. She denied palpitations, headaches, tremors, and diaphoresis. Initial CT demonstrated a right renal mass suspicious for renal cell carcinoma and an adrenal mass. Magnetic resonance imaging (MRI) confirmed a hypervascular, right adrenal mass (6.7 x 6 x 5 cm) without loss of signal. Laboratory Testing: elevated 24-hour urine vanillylmandelic acid (VMA) 17.5 mg/24 h (<6), and urine normetanephrines 2276 ug/24 h (122-676) with normal urine metanephrines 158 ug/24 h (90-315). 24-hour urine free cortisol was normal. The patient underwent a right adrenalectomy and partial nephrectomy. Pathology confirmed a low-grade renal cell carcinoma (RCC) and a 6.8 cm pheochromocytoma (PCC). Genetic analysis revealed an inherited mutation in the fumarate hydratase (FH) gene, which is diagnostic of hereditary leiomyomatosis and renal cell cancer (HLRCC). Wildtype FH codes for an enzyme that converts fumarate to malate in the mitochondrial Krebs cycle. Inactivating mutations in FH trigger the hypoxia pathway by activating hypoxia-inducible factor (HIF) thereby promoting tumor growth and angiogenesis. In PCC, 30-40% are hereditary and another 40-50% are found to have somatic mutations in 1 of 20 PCC susceptibility genes. Several autosomal dominant heritable syndromes, including Neurofibromatosis type 1 (NF-1), von Hippel-Lindau (VHL), Multiple Endocrine Neoplasia Type 2 (MEN 2), and Paraganglioma Syndromes Types 1–5, have an increased incidence of PCC, most of which modulate hypoxia pathways. FH mutations are similarly inherited in an autosomal dominant fashion and cause HLRCC. HLRCC is associated with 75-80% risk for cutaneous and uterine leiomyomas, and a 10-16% risk for type II papillary renal cell carcinoma. The risk of RCC in patients with FH mutations is much greater than in the general population, where the prevalence is ~2% in those who lack the mutation. In one study, FH deficiencies attribute between 19-41% of all RCC cases. Rare families with PGL/PCC have also been found to carry this germline FH mutation. This FH mutation is associated with increased risk of metastasis in patients with PGL/PCC by a similar mechanism of carcinogenesis via the hypoxia pathway. Currently, there are no strict guidelines for surveillance in individuals with HLRCC, however, patients should have a yearly abdominal MRI, skin examination every 2 years, and an annual gynecological evaluation for leiomyosarcoma. Each first-degree relative should be offered genetic testing of the FH mutation, as 50% of relatives may carry the gene. This case underscores the importance of genetic workups in patients with PCC, especially if associated with other tumors.

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Podkalicka, Paulina, Olga Mucha, Szczepan Kruczek, Anna Biela, Kalina Andrysiak, Jacek Stępniewski, Maciej Mikulski, et al. "Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes." Biomolecules 10, no. 1 (January 16, 2020): 143. http://dx.doi.org/10.3390/biom10010143.

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Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)—an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.

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Popp, Bernt, Ramona Erber, Cornelia Kraus, Georgia Vasileiou, Juliane Hoyer, Stefanie Burghaus, Arndt Hartmann, Matthias W. Beckmann, André Reis, and Abbas Agaimy. "Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants." Modern Pathology 33, no. 11 (July 1, 2020): 2341–53. http://dx.doi.org/10.1038/s41379-020-0596-y.

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Abstract Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7–13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.

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Sanchez-Heras, Ana Beatriz, Adela Castillejo, Juan de Dios García-Diaz, Mercedes Robledo, Alex Teule, Rosario Sánchez, Angel Zuñiga, et al. "Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): Genotype and phenotype characteristics in a cohort of 197 patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1580. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1580.

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1580 Background: HLRCC is a hereditary condition with autosomal dominant inheritance due to germline mutations in the fumarate-hydratase gene ( FH). It is characterized by skin leiomyomas (SLM) in 48-84% of individuals, uterine leiomyomas (ULM) in 30-72%, renal cysts (RCy) and renal cell cancer (RCC) in 15-34%. We aimed to describe the genetics, the clinical features and the potential genotype-phenotype associations in the largest cohort of FH mutation carriers from Spain. Methods: We performed a multicenter, observational, retrospective study of individuals with genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records. We analyzed genetic variants and looked for genotype-phenotype associations. Statistical analyses were performed by IBM-SPSS Statistics-v.22. Results: We included 197 individuals (113 women, 84 men), 74 index cases and 123 relatives. Twenty-seven different variants were detected, 26 pathogenic (12 missense, 5 frameshift, 4 large-deletions, 3 splice-site and 2 nonsense) and 1 variant of unknown significance (missense). Of 182 patients with full skin examination, 64.8% presented SLM (median age 36 years; range 8-85). ULM were diagnosed in 90.3% of 103 women with gynecologic exam (median age 30 years; range 17- 55). Hysterectomy was performed in 62.9% (median age 34 years; range 21-54). Of 153 patients with radiological records, 37.3 % presented RCy. Nineteen patients (10.9%) presented RCC, 11 males and 8 females (median age 37 years; range 10-67). The histological diagnoses were: 14 papillary, of which 10 were type 2; 3 clear cell carcinoma and 2 unclassified carcinoma. Six tumors had stage I, 2 stage II, 3 stage III, 4 stage IV, and 4 not available. The median overall survival among patients at stages 3-4 was 2.9 years [1.3-4.5]. Patients with missense pathogenic variants showed higher risk of developing SLM (p = 0.043) and ULM (p = 0.002) than those with loss of function variants. Conclusions: In our cohort, the frequency of RCC (10.9%) is lower than that published in cohorts of similar sample size. The most frequent histology was the papillary type-2; however, other histological patterns do not exclude HLRCC. Individuals with missense pathogenic variants show higher incidence of SLM and ULM.

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Fondriest, Sara A., John M. Gowdy, Manish Goyal, Katherine C. Sheridan, and Daniel A. Wasdahl. "Concurrent renal-cell carcinoma and cutaneous leiomyomas: A case of HLRCC." Radiology Case Reports 10, no. 1 (2015): 962. http://dx.doi.org/10.2484/rcr.v10i1.962.

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Carvajal-Carmona, Luis G., N. Afrina Alam, Patrick J. Pollard, Angela M. Jones, Ella Barclay, Noel Wortham, Massimo Pignatelli, et al. "Adult Leydig Cell Tumors of the Testis Caused by Germline Fumarate Hydratase Mutations." Journal of Clinical Endocrinology & Metabolism 91, no. 8 (August 1, 2006): 3071–75. http://dx.doi.org/10.1210/jc.2006-0183.

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Abstract Context: Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of the testis. LCTs are often hormonally active and can result in precocious virilization or in adult feminization. We identified an LCT in an affected individual from a kindred with hereditary leiomyomatosis and renal cell cancer (HLRCC) and a germline fumarate hydratase (FH) mutation (N64T). Objective: Our objective was to investigate the role of FH mutations in predisposition to LCTs. Design: We tested for pathogenic effects of the N64T mutation and screened an additional 29 unselected adult LCTs for FH alterations. We also tested these LCTs for mutations in two genes, the LH/choriogonadotropin receptor (LHCGR) and the guanine nucleotide-binding protein α (GNAS) that had been implicated in LCT tumorigenesis. Results: No mutations were found in GNAS, and one tumor had a LHCGR somatic substitution. In addition to the HLRCC case with the N64T germline FH mutation, we identified one other LCT with a previously unreported FH mutation (M411I). Both LCTs from these patients showed loss of the wild-type FH allele. Immunohistochemical and in situ hybridization analyses demonstrated activation of the hypoxia/angiogenesis pathway not only in the tumors belonging to the FH mutation carriers but also in several other mutation-negative LCTs. Conclusions: Our study shows that some LCTs are caused by FH mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor.

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Suda, Kentaro, Hidenori Fukuoka, Yuto Yamazaki, Katsumi Shigemura, Miki Mukai, Yukiko Odake, Ryusaku Matsumoto, et al. "Cardiac Myxoma Caused by Fumarate Hydratase Gene Deletion in Patient With Cortisol-Secreting Adrenocortical Adenoma." Journal of Clinical Endocrinology & Metabolism 105, no. 6 (April 6, 2020): 1957–62. http://dx.doi.org/10.1210/clinem/dgaa163.

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Abstract Context Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. Case Description A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. Conclusions This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.

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Choi, Grace, Virginia Kimonis, Katherine Hall, and Wei Ling Lau. "Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): Report of a Family Pedigree." American Journal of the Medical Sciences 360, no. 6 (December 2020): 724–27. http://dx.doi.org/10.1016/j.amjms.2020.05.048.

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Duong, Bich-Thu, Ravi Savarirayan, and Ingrid Winship. "Incidental diagnosis of HLRCC following investigation for Asperger Syndrome: actionable and actioned." Familial Cancer 15, no. 1 (August 15, 2015): 25–29. http://dx.doi.org/10.1007/s10689-015-9829-5.

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Paschall, Anna K., Moozhan Nikpanah, Faraz Farhadi, Elizabeth C. Jones, Paul G. Wakim, Andrew J. Dwyer, Rabindra Gautam, et al. "Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome: Spectrum of imaging findings." Clinical Imaging 68 (December 2020): 14–19. http://dx.doi.org/10.1016/j.clinimag.2020.06.010.

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Zhuang, L. Q., F. Maclean, A. J. Gill, and M. Gorji. "Two patients with presumed HLRCC presenting with multiple fumarate hydratase deficient cutaneous leiomyomas." Pathology 50 (February 2018): S131. http://dx.doi.org/10.1016/j.pathol.2017.11.024.

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38

Menko, Fred H., Eamonn R. Maher, Laura S. Schmidt, Lindsay A. Middelton, Kristiina Aittomäki, Ian Tomlinson, Stéphane Richard, and W. Marston Linehan. "Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment." Familial Cancer 13, no. 4 (July 11, 2014): 637–44. http://dx.doi.org/10.1007/s10689-014-9735-2.

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Gurruchaga Sotés, Ibon, Ana Nuño Alves, Sandra Vicente Arregui, and Carmen Santander Lobera. "Response to Combination of Pembrolizumab and Axitinib in Hereditary Leyomiomatosis and Renal Cell Cancer (HLRCC)." Current Oncology 28, no. 4 (June 25, 2021): 2346–50. http://dx.doi.org/10.3390/curroncol28040216.

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In current clinical guidelines, such as those provided by the National Comprehensive Cancer Network (NCCN), evidence for treatment is based on a small clinical trial that included patients with HLRCC. They support the use of the combination of erlotinib and bevacizumab as the first therapeutic option in this rare condition. In the present study, we report a rare case of this condition in an 18-year-old male with a family history of kidney cancer whom we successfully treated with surgery and a novel drug treatment modality based on the combination of an immune check-point inhibitor (ICPI) and a tyrosine-kinase inhibitor (TKI) with excellent and promising results.

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Vahteristo, Pia, Taru A. Koski, Laura Näätsaari, Maija Kiuru, Auli Karhu, Riitta Herva, Satu-Leena Sallinen, et al. "No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome." Familial Cancer 9, no. 2 (December 20, 2009): 245–51. http://dx.doi.org/10.1007/s10689-009-9312-2.

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41

Stratton, P., A. Runyan, A. M. Thomas, L. Middelton, M. J. Merino, J. Segars, A. M. Venkatesan, and W. M. Linehan. "Diagnosis and management of hereditary leiomyoma and renal cell cancer (HLRCC)-associated uterine leiomyomas." Fertility and Sterility 102, no. 3 (September 2014): e285. http://dx.doi.org/10.1016/j.fertnstert.2014.07.971.

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Sanz-Ortega, Julian, Cathy Vocke, Pamela Stratton, William Marston Linehan, and Maria J. Merino. "Morphologic and Molecular Characteristics of Uterine Leiomyomas in Hereditary Leiomyomatosis and Renal Cancer (HLRCC) Syndrome." American Journal of Surgical Pathology 37, no. 1 (January 2013): 74–80. http://dx.doi.org/10.1097/pas.0b013e31825ec16f.

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Merino, Maria J., Carlos Torres-Cabala, Peter Pinto, and William Marston Linehan. "The Morphologic Spectrum of Kidney Tumors in Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) Syndrome." American Journal of Surgical Pathology 31, no. 10 (October 2007): 1578–85. http://dx.doi.org/10.1097/pas.0b013e31804375b8.

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Grubb, Robert L., Michael E. Franks, Jorge R. Toro, Kathleen Hurley, Gladys M. Glenn, Peter Choyke, Jonathan Coleman, et al. "1398: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): An Aggressive form of Inherited Renal Cancer." Journal of Urology 173, no. 4S (April 2005): 379. http://dx.doi.org/10.1016/s0022-5347(18)35532-0.

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Barrisford, Glen W., Eric A. Singer, Inger L. Rosner, W. Marston Linehan, and Gennady Bratslavsky. "Familial Renal Cancer: Molecular Genetics and Surgical Management." International Journal of Surgical Oncology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/658767.

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Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dubé (BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer.

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Schwartzman, William, Roy Elias, Viral M. Patel, Alex Isaac Bowman, Suneetha Chintalapati, Payal Kapur, Hans J. Hammers, and James Brugarolas. "Safety and efficacy of immune checkpoint inhibitors (ICI) in metastatic non-clear cell renal cell carcinoma (nccRCC): An institutional experience." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 640. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.640.

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640 Background: ICIs have improved outcomes in clear cell RCC patients (pts), and emerging data suggest that they may be effective against nccRCC. nccRCC comprises ~25% of renal tumors and consist of a diverse group of diseases. Despite recent evidence, data regarding the efficacy of ICIs in nccRCC remain limited, especially among rarer nccRCC subtypes. Methods: We identified all cases of metastatic nccRCC that received at least one dose of ICI therapy at UT Southwestern Medical Center from 2014 – 2018. Baseline characteristics and IMDC criteria were evaluated at the time of ICI initiation. Outcomes included objective response rate (ORR) per RECIST v1.1 criteria, time to next treatment (TNT), and overall survival (OS). Immune-related adverse events (irAE) were graded per CTCAE 4.0 criteria. Survival estimates were evaluated using Kaplan Meier methods. Results: We identified 28 pts with metastatic nccRCC; 12 (42.9%) unclassified RCC (uRCC), 8 (28.6%) papillary RCC (pRCC), 3 (10.7%) chromophobe RCC (chRCC), 3 (10.7%) hereditary leiomyomatosis and renal cell cancer (HLRCC), 1 (3.6%) translocation RCC (tRCC) and 1 (3.6%) acquired cystic disease-associated RCC (ACD-RCC). 23 (82.1%) pts were intermediate or poor risk by IMDC criteria. In total, 13 (46.4%) pts received nivolumab monotherapy, and 15 (53.6%) in combination with ipilimumab. 12 (42.9%) pts received ICI in the first line. The median TNT and OS amongst all nccRCC subtypes was 4.9 (95% CI: 1.7-8.1) and 15.9 (95% CI: 5.9 – 25.9) months respectively. The ORR was 3/28 (10.7%), with 2 complete responses. All responses were restricted to the pRCC and uRCC subtypes. 11 (39.3%) pts experienced any irAE and 5 (17.9%) had a grade 3/4 irAE, including one case of grade 4 myocarditis. The median time to onset of an irAE was 1.9 months (Range: 0.1 to 12.0). At a median follow up of 10.8 months (95% CI: 10.2 – 17.9), 4 pts remain on therapy and 13 pts have died. Conclusions: ICI therapy demonstrated modest efficacy in this cohort with comparable irAE profiles to ccRCC. Objective responses were not seen in pts with HLRCC, ACD-RCC, tRCC, or chRCC in this study.

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Vanevski, K. M., M. Malik, D. Joseph, M. Payson, and W. H. Catherino. "Leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) are highly dependent upon glycolysis for energy homeostasis." Fertility and Sterility 88 (September 2007): S218. http://dx.doi.org/10.1016/j.fertnstert.2007.07.744.

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De Velasco, Guillermo, Cesar Munoz, Juan M. Sepulveda, and Daniel Castellano. "Sequential treatments in Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC). Case report and review of the literature." Canadian Urological Association Journal 9, no. 3-4 (April 13, 2015): 243. http://dx.doi.org/10.5489/cuaj.2264.

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Bell, Robert C., Evan T. Austin, Stacy J. Arnold, Frank C. Lin, Jonathan R. Walker, and Brandon T. Larsen. "Rare Leiomyoma of the Tunica Dartos: A Case Report with Clinical Relevance for Malignant Transformation and HLRCC." Case Reports in Pathology 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/6471520.

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Background. Genital leiomyomas fall under the broader category of cutaneous leiomyomas, which are rare smooth muscle neoplasms accounting for 5% of all leiomyomas. Genital leiomyomas arising from the dartos muscle are exceedingly rare with fewer than 30 cases reported in the literature. They are typically benign and adequately treated with simple surgical excision; however, previously reported cases of malignant transformation and a possible link to the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome warrant closer follow-up.Case Presentation. We report a case of a 47-year-old male refugee from Rwanda found to have a mobile, pea-sized, mildly painful scrotal lesion near the left penoscrotal junction and 1.5 cm indeterminate vascular mass in the right kidney. Surgical excision of the scrotal nodule was performed and the diagnosis of a dartoic leiomyoma was rendered. The presence of moderate nuclear atypia, rare mitotic activity, and close surgical margins prompted a wide reexcision. We report the surgical approach, pathologic findings, and clinical follow-up related to this scrotal lesion.Conclusion. Scrotal leiomyomas demonstrate a high rate of recurrence and pose a risk for malignant transformation. They may also indicate an underlying autosomal dominant syndrome associated with increased risk for development of an aggressive form of renal cell carcinoma. When discovered, management should include surgical excision, screening for syndromic features, and routine follow-up.

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Dow, Eryn, and Ingrid M. Winship. "Hemangioblastoma in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome: a phenotypic overlap between VHL and HLRCC Syndromes." Familial Cancer 18, no. 1 (April 4, 2018): 91–95. http://dx.doi.org/10.1007/s10689-018-0081-7.

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Journal articles on the topic 'HLRCC'

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