Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), caused by a germline mutation in the fumarate hydratase (FH) gene, predisposes patients to uterine and cutaneous smooth muscle tumors and an aggressive type of renal cell carcinoma.
None of the tumors showed mutational profiles characteristic of other renal neoplasms, including those seen in fumarate hydratase-deficient renal cell carcinoma.
Diffuse nuclear and cytoplasmic 2SC staining, with retained FH expression was seen in one case (suggestive of dysfunctional FH protein), while absent FH was seen in 3 cases (2/400 papillary RCCs, 0.5% and 2/46 unclassified RCCs, 4.35%).
Inactivating FH germline mutations are found in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome comprising benign cutaneous/uterine leiomyomas and renal cell carcinoma.
In this review, we consider these developments, with emphasis on renal medullary carcinoma, closely related renal cell carcinoma, unclassified with medullary phenotype, and fumarate hydratase-deficient renal cell carcinoma.
In total, 24 cytologic and limited biopsy samples from 19 patients (6 women and 13 men; age range, 22-69 years) who had FH-deficient RCC and metastasis at presentation were evaluated.
Example of such entities are fumarate hydratase-deficient renal cell carcinoma (RCC), succinate dehydrogenase-deficient RCC, hereditary gastrointestinal stromal tumor syndromes and many other diseases.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by germline mutations in the FH gene, and is associated with increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma (HLRCC-associated RCC).
No progression has been noted at 3 and 7 years in the cases with only the SDH-like lesions; the two cases with separate, typical FH-deficient RCCs progressed.
CDC, RMC, fumarate hydratase-deficient RCC (including hereditary leiomyomatosis and RCC-associated RCCHLRCC-RCC), and recently reported anaplastic lymphoma kinase (ALK)-rearrangement RCC have significant morphologic overlaps, but they are separately distinct entities having different molecular pathway and clinical settings.
First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes-including FH-performed on a subset.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma.
Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways).