Malignancy of Renal Angiomyolipoma from Tuberous Sclerosis Complex with TSC2 Mutation

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Malignancy of Renal Angiomyolipoma from Tuberous Sclerosis Complex with TSC2 Mutation

Tuberous sclerosis complex (TSC) is a rare genetic disorder affecting approximately 1 in 6,000 people worldwide, causing benign tumors and tissue abnormalities in organs like the brain, kidneys, and skin. While kidney tumors called angiomyolipomas (AMLs) are common in TSC—occurring in 60–80% of patients—their transformation to cancer is extremely rare. A 2019 case study from Chinese researchers highlights this unusual progression in a young man, shedding light on the genetic and clinical factors behind malignant renal AML.

The Case: A Young Man with TSC and Malignant Kidney Tumor

The study, led by Yu-Jing Huang (The First People’s Hospital of Zhaoqing) and Meng-Jun Liang (The Sixth Affiliated Hospital of Sun Yat-sen University), details the case of a 24-year-old man with a 19-year history of recurrent facial “macules” (light-colored spots). For three months before admission, he experienced abdominal bloating, a painful left abdominal mass, and anemia—but no fever, vomiting, or urinary symptoms.

On exam, the man had a low-grade fever (38.4°C) and small fibromas (2–5 mm bumps) on his cheeks, tongue, scalp, back, and nail beds. A large, immobile mass (13 cm × 10 cm) in his left upper abdomen was tender to touch. Lab tests revealed high white blood cells (a sign of inflammation), low hemoglobin (anemia linked to alpha-thalassemia), and trace blood in his urine.

Imaging provided critical clues:

  • Abdominal CT: Multiple AMLs in his liver and both kidneys, plus a massive (20 cm × 14 cm × 12 cm) tumor in the left kidney. The tumor had spread to the left renal vein and vena cava (the body’s largest vein).
  • Brain CT: Nodules and calcifications in the frontal lobe, basal ganglia, and brain lining—classic signs of TSC.

Genetic testing confirmed a heterozygous pathogenic mutation in the TSC2 gene: c.1000delG, p.(Val334fs) in exon 11. This “frameshift” mutation disrupts protein production and had never been reported before. Notably, the alpha-globin gene (linked to his thalassemia) sits near TSC2 on chromosome 16, suggesting a possible genetic link between his TSC and anemia.

Treatment and Outcome

Due to financial constraints, the man underwent a complete left nephrectomy (kidney removal) at a local hospital. Pathologists identified epithelioid angiomyolipoma (EAML), a rare malignant subtype of AML. Key findings:

  • Histology: Epithelioid cells (skin-like cells) with granular, pinkish cytoplasm, plus cancerous features like necrosis (tissue death), abnormal cell division, and vascular invasion.
  • Immunohistochemistry: Positive for HMB-45 (a melanocyte marker, common in AML) and P53 (a tumor suppressor often altered in cancer); negative for epithelial (CK) or neural (S-100) markers—ruling out other cancers.

Eight months after surgery, the man developed cachexia (severe weight loss and muscle wasting), a sign of advanced disease.

Context: TSC, AML, and EAML

TSC is an autosomal dominant disorder caused by mutations in TSC1 or TSC2, genes that regulate cell growth. Renal AMLs—composed of blood vessels, smooth muscle, and fat—are usually benign, but they can bleed (a life-threatening complication). They are more common in women and grow rapidly during pregnancy (linked to estrogen/progesterone).

EAML is a rare, aggressive subtype of AML with only ~160 reported cases worldwide. It typically affects adults aged 30–80 and has a slight female predominance (11:9). Risk factors for EAML progression (recurrence, metastasis, death) include:

  • TSC diagnosis
  • Tumor size >7 cm
  • Extrarenal spread (e.g., to veins)
  • Necrosis or “carcinoma-like” growth

Guidelines for TSC-Related Renal AML

The 2012 International TSC Consensus Conference recommends:

  • Surveillance: Ultrasound scans every 1–3 years for adults with TSC to monitor AML growth.
  • Intervention: For AMLs >4 cm (or with aneurysms >5 mm), first-line treatment is embolization (blocking blood flow to the tumor) or nephron-sparing surgery (removing only the tumor). Complete nephrectomy is avoided to preserve kidney function.
  • Medication: For asymptomatic AMLs >3 cm, mTOR inhibitors (e.g., rapamycin, everolimus) are first-line therapy. These drugs target the overactive mTOR pathway in TSC cells. Some EAML patients with TSC2 mutations have responded well to mTOR inhibitors, though data are limited.

Why This Case Matters

This case is unique for two reasons:

  1. Age: Most EAML patients are middle-aged—this 24-year-old’s diagnosis highlights that TSC-related malignant AML can occur in young adults.
  2. Genetics: The TSC2 mutation (c.1000delG, p.(Val334fs)) is novel, adding to the growing list of TSC2 variants linked to severe disease.

The authors note that the case underscores the need for early surveillance and genetic testing in TSC patients—especially those with large or fast-growing AMLs. It also highlights the challenges of accessing targeted therapies (like mTOR inhibitors) in resource-limited settings.

References

The study was published in the Chinese Medical Journal (2019) by Yu-Jing Huang, Zong-Pei Jiang, Yu-Ping Chen, Jin-Quan Wu, Jia-Li Huang, Yan-Qiang Chen, and Meng-Jun Liang. Additional sources include:

  1. Wataya-Kaneda M et al. International Journal of Urology (2017): TSC manifestations and therapy.
  2. Kruger DA et al. Pediatric Neurology (2013): TSC surveillance guidelines.
  3. Eussen BH et al. Journal of Medical Genetics (2000): TSC and alpha-thalassemia link.
  4. Tsili AC et al. Journal of Clinical Imaging Science (2017): EAML imaging.
  5. Zhu J et al. Medicine (2018): EAML imaging review.
  6. Nese N et al. American Journal of Surgical Pathology (2011): EAML risk factors.
  7. Glushkova M et al. Journal of Genetics (2018): TSC1/TSC2 mutations in Bulgaria.
  8. Espinosa M et al. BMC Cancer (2018): EAML response to sirolimus.

doi.org/10.1097/CM9.0000000000000026

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