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Case Reports
. 2018 May 15;18(1):561.
doi: 10.1186/s12885-018-4467-6.

Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to TSC2 mutation

Marta Espinosa  1 , Juan Maria Roldán-Romero  2 , Ignacio Duran  3   4 , Enrique de Álava  5 , María Apellaniz-Ruiz  2 , Alberto Cascón  2   6 , Carmen Garrigos  7 , Mercedes Robledo  2   6 , Cristina Rodriguez-Antona  8   9
Affiliations
Case Reports

Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to TSC2 mutation

Marta Espinosa et al. BMC Cancer. .

Abstract

Background: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined.

Case presentation: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation.

Conclusion: NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.

Keywords: Renal epithelioid angiomyolipoma; Sirolimus; TSC2 mutation; mTOR pathway activation.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Hospital Institutional Review Board of the Hospital Universitario Virgen del Rocío (reference number 33140027), and the patient provided written informed consent to participate in the study.

Consent for publication

We obtained written informed consent of the patient for the publication of the case report and accompanying images.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Computed tomographic (CT) scans. Left renal mass of 10 × 12 cm at diagnosis (a and b). Liver recurrence (c) and response after 5 months of sirolimus treatment (d)
Fig. 2
Fig. 2
Immunohistochemical study. Hematoxylin and eosin staining of the EAML primary tumor (a). Representative images for HMB-45 (b; × 10) and Melan A (c; × 10). TSC2 staining (Cell Signalling 4308) of the tumor metastasis, where tumor cells are negative for TSC2 while normal hepatocytes (indicated with an arrow and “N”) show high intensity. (d; 10×). Phospho-ribosomal protein S6 (S235/S236; Cell Signaling 2211) expression in the primary tumor (e; × 40) and liver metastasis (f; × 10)
Fig. 3
Fig. 3
Tumor TSC2 point mutation. Targeted NGS revealed one frameshift mutation in TSC2 gene (c.2739dup; p.K914*) absent in the patient’s blood (a) and present in the liver metastasis (b). The primary tumor DNA failed NGS technique, but Sanger sequencing detected the TSC2 mutation (c). Representative genome images from the Integrative Genomics Viewer (Broad Institute) are shown together with Sanger chromatograms
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