Malignancy of Renal Angiomyolipoma from Tuberous Sclerosis Complex with TSC2 Mutation
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by the development of benign tumors in multiple organ systems, including the brain, skin, kidneys, heart, and lungs. With an estimated birth incidence of 1 in 6,000, TSC arises from mutations in either the TSC1 or TSC2 genes, leading to dysregulation of the mammalian target of rapamycin (mTOR) signaling pathway. Renal manifestations, particularly angiomyolipomas (AMLs), are common in TSC, affecting 60–80% of patients. While AMLs are typically benign, malignant transformation into epithelioid angiomyolipoma (EAML) is exceedingly rare, with fewer than 200 cases reported globally. This article presents a comprehensive analysis of a case involving malignant renal EAML in a young male with TSC2 mutation, emphasizing clinical, radiological, genetic, and histopathological findings.
Clinical Presentation and Diagnostic Evaluation
A 24-year-old male presented with a 3-month history of progressive abdominal bloating, left upper quadrant pain, and a palpable mass. His medical history revealed recurrent facial hypomelanotic macules since early childhood, consistent with TSC. Physical examination identified multiple cutaneous features: facial angiofibromas, ungual fibromas (2–5 mm in diameter), a lingual fissure (2 mm × 1 mm), and a firm, tender left upper quadrant mass measuring 130 mm × 100 mm. Systemic symptoms such as fever (38.4°C), anemia (hemoglobin: 76.1 g/L), and leukocytosis (15.7 × 10⁹/L, 78.6% neutrophils) were noted. Renal function remained preserved (serum creatinine: 53.8 µmol/L), and urinalysis showed mild hematuria and leukocyturia.
Contrast-enhanced abdominal computed tomography (CT) revealed extensive bilateral renal AMLs, with a massive left renal tumor measuring 20 cm × 14 cm × 12 cm (CT attenuation values: 28–89 Hounsfield units). The tumor exhibited heterogeneous enhancement, with tumor thrombi extending into the left renal vein and inferior vena cava (Figure 1A–E). Hepatic AMLs and cerebral subependymal nodules with calcifications in the left frontal lobe and basal ganglia were also observed.
Genetic and Histopathological Confirmation
Genetic testing identified a novel heterozygous pathogenic variant in TSC2 (NM_000548.3): a frameshift mutation (c.1000delG, p.Val334fs) in exon 11. This mutation disrupts the tuberin protein’s C-terminal functional domain, critical for mTOR pathway regulation. Multiplex ligation-dependent probe amplification (MLPA) ruled out large deletions or duplications in TSC1 or TSC2.
Histopathological examination of the resected left kidney confirmed EAML. The tumor comprised three classical AML components—dysmorphic blood vessels, smooth muscle bundles, and mature adipose tissue—alongside sheets of epithelioid cells with eosinophilic granular cytoplasm. Malignant features included pathologic mitoses (≥5 per high-power field), coagulative necrosis, and vascular invasion. Immunohistochemistry demonstrated strong positivity for HMB-45 (melanocytic marker) and CD68 (macrophage marker), while markers for epithelial (CK-pan), neural (S-100), and myogenic (smooth muscle actin, MyoD1) differentiation were negative. P53 overexpression suggested potential tumor suppressor pathway dysregulation.
TSC Diagnostic Criteria and Genotype-Phenotype Correlation
The patient met definitive diagnostic criteria for TSC, including ≥4 major features (facial angiofibromas, hypomelanotic macules, subependymal nodules, renal AMLs) and ≥2 minor features (oral fibromas, hepatic hamartomas). The TSC2 c.1000delG mutation, unreported in prior literature, likely contributed to both TSC and α-thalassemia, as the α-globin gene cluster resides on chromosome 16p13.3 near TSC2. Familial screening was declined, but the absence of TSC features in parents and a sibling suggested a de novo mutation.
Malignant Transformation in Renal AML: Clinical Implications
EAML represents a rare, potentially aggressive AML subtype, accounting for 7 cm, extrarenal extension, vascular invasion, necrosis, and association with TSC. In this case, the massive tumor size (27 cm × 18 cm × 11 cm), venous thrombi, and necrosis aligned with high-risk features.
Therapeutic Challenges and Management
Current guidelines recommend active surveillance for asymptomatic AMLs <3 cm. For larger lesions, mTOR inhibitors (e.g., sirolimus, everolimus) are first-line therapies to reduce tumor size and hemorrhage risk. However, this patient underwent left radical nephrectomy due to financial constraints and tumor complexity. Postoperative cachexia and rapid progression highlighted the aggressive nature of TSC-associated EAML.
mTOR inhibitors, which suppress aberrant signaling driven by TSC1/2 mutations, have shown efficacy in sporadic EAMLs with TSC2 loss. However, limited data exist on their role in TSC-related EAML. Early intervention with mTOR inhibitors might have mitigated disease progression in this case.
Conclusion
This case underscores the malignant potential of renal AMLs in TSC, particularly with TSC2 mutations. The novel TSC2 c.1000delG variant expands the genetic spectrum of TSC and highlights the need for personalized management in high-risk patients. Multidisciplinary approaches integrating genetic testing, advanced imaging, and mTOR-targeted therapies are essential to improve outcomes in TSC-associated malignancies.
doi.org/10.1097/CM9.0000000000000026
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