A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma

Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH, NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs.

Complete Response of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)-Associated Renal Cell Carcinoma to Pembrolizumab Immunotherapy: A Case Report

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase (FH) gene; it manifests as 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. Here, we describe aggressive HLRCC in a 26-year-old man who presented with RCC that exhibited a novel heterozygous germline insertion mutation in exon 2 of the FH gene (c.191dupA: p.N64fs). Systemic lymph node metastasis had already occurred. The patient underwent robot-assisted laparoscopic resection of the right kidney, but new metastases appeared within 5 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1). The patient was treated with anti-PD-1 antibody as first-line therapy. After 2 years of immune checkpoint inhibitor (ICI) treatment, all lesions had disappeared; this response was maintained at 51 months. To our knowledge, this is the first successful treatment of HLRCC-RCC with single-agent immunotherapy. Our approach might be effective for patients with advanced HLRCC-RCC.

Cutaneous Leiomyoma: A Clinical Study of 152 Patients

<b><i>Background:</i></b> Cutaneous leiomyoma (CL) is a benign smooth muscle tumour included in painful skin tumours. Multiple CLs are cutaneous markers of hereditary leiomyomatosis and renal cell cancer (HLRCC). <b><i>Objectives:</i></b> To retrospectively review our series of patients with CLs to analyse their clinical features and the association with HLRCC. <b><i>Methods:</i></b> Cases coded as CL in the database of the pathology department between 2004 and 2019 were included in the study. Medical records were retrospectively reviewed to obtain the following data: age, sex, location, number of lesions, diameter, evolution time at diagnosis, suspected clinical diagnosis, tenderness, status of resection margins, development of recurrence, follow-up time, and association with HLRCC. <b><i>Results:</i></b> 152 patients had CLs, 89 women and 63 men, mean age 56.26, SD 16.030 years. Subtypes were piloleiomyoma in 62 patients, angioleiomyoma in 80, and genital leiomyoma in 10. All of our 11 patients with multiple lesions corresponded to piloleiomyomas, and HLRCC was confirmed in 8 of them (73%). Patients with HLRCC were younger than patients with piloleiomyomas without HLRCC (34.88 vs. 56.17 years, <i>p</i> = 0.009). Vascular and genital leiomyomyomas were solitary and were not associated with HLRCC. <b><i>Conclusion:</i></b> In patients with multiple piloleiomyomas HLRCC must be ruled out as it is confirmed in a high proportion of cases. The probability of fumarate hydratase mutation is greater in multiple piloleiomyomas involving both the trunk and upper extremities in the same patient.

Birt-Hogg-Dubé Syndrome and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome: An Effective Multidisciplinary Approach to Hereditary Renal Cancer Predisposing Syndromes

AimWe aimed to describe and analyse clinical features, characteristics, and adherence to surveillance guidelines in an Australian Birt-Hogg-Dubé syndrome (BHD) and hereditary leiomyomatosis and renal cell cancer (HLRCC) cohort.MethodsAll identified patients with a diagnosis of BHD or HLRCC at RBWH 01/01/2014-01/09/2019 were included (HREC/17/QRBW/276). All patients were initially assessed and counselled by a clinical geneticist and then referred to an adult nephrologist. Baseline and incidental clinical variables were extracted and analysed.ResultsFifty-seven patients were identified (28 BHD, 29 HLRCC) with a median age of 47 years. The median and cumulative follow-up were 1 and 99 years, respectively. Baseline renal MRI occurred in 40/57 patients, and 33/57 had regular MRI as per the national guidelines (eviQ). Of 18/57 without baseline imaging, nine were yet to have imaging, seven were lost follow-up, and two patients had logistic difficulties. RCC was diagnosed in 11/57 patients: two of 28 with BHD were diagnosed with RCC aged 73 and 77, both prior to commencement of surveillance. Nine of 29 patients with HLRCC were diagnosed with RCC (one of 29 during surveillance at 47 years of age) and eight of 29 prior to commencement of surveillance (11–55 years). Amongst BHD patients, cutaneous fibrofolliculomas were noted in 15 patients, lung cysts were detected in seven patients, spontaneous pneumothoraces in five patients, and parotid oncocytoma in two of 28. Amongst those with HLRCC, cutaneous leiomyomas were noted in 19/29, cutaneous leiomyosarcoma diagnosed in one of 29, and uterine fibroids in 13 female patients.ConclusionEvidence-based RCC screening in BHD and HLRCC cohort is feasible and able to identify incidental renal lesions. Multidisciplinary patient management enables expedited genetic counselling, diagnosis, longitudinal screening, and RCC management. The success of this clinical model warrants consideration of undertaking longitudinal screening of BHD and HLRCC patients by nephrologists.

Hereditary leiomyomatosis and renal cell cancer presenting as urothelial carcinoma

Hereditary leiomyomatosis is a genetic disorder that follows an autosomal dominant pattern of inheritance. Along with a variety of leiomyomas, affected individuals are predisposed to developing an aggressive form of type 2 papillary renal malignancy known as Hereditary Leiomyomatosis Associated Renal Cell Carcinoma (HLRCC) that can occur in both the tubulo-papillary and collecting-duct systems. We present a rare case of HLRCC with components of urothelial carcinoma. The patient was treated with cisplatin-based neoadjuvant chemotherapy followed by left radical nephroureterectomy to achieve complete remission of disease.