{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T18:20:28Z","timestamp":1773080428808,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Angiomyolipoma (AML) is a mesenchymal tumor composed of blood vessels, smooth muscle, and adipose tissue, and is generally considered benign. However, epithelioid angiomyolipoma (eAML) is a rare and aggressive variant with metastatic potential. Molecular characterization utilizing the tuberous sclerosis complex (TSC)\u2013mTOR pathway is beneficial in advanced disease. This report describes the clinical course, histopathological findings, and molecular analysis of a patient with metastatic eAML.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 59-year-old Japanese man with no personal or family history of tuberous sclerosis (TSC) was admitted to the hospital with gradually worsening back pain and initially diagnosed with clear cell renal cell carcinoma (ccRCC). He underwent nephrectomy, followed by hepatic recurrence treated with pazopanib and subsequent axitinib. Both were discontinued due to intolerance, and the two remaining liver metastases were surgically resected. Histopathological examination of the resected lesions revealed eAML. After several recurrences and resections, unresectable hepatic and pulmonary metastases eventually developed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comprehensive genomic profiling (CGP) using the resected liver metastasis specimen identified two somatic\n                      <jats:italic>TSC2<\/jats:italic>\n                      mutations: a frameshift mutation (p. P677fs*21; variant allele frequency [VAF] 0.0789) and a nonsense mutation (p. S1469*; VAF 0.0736), suggesting biallelic loss of\n                      <jats:italic>TSC2.<\/jats:italic>\n                      Based on these findings, everolimus, a mammalian\/mechanistic target of rapamycin (mTOR) inhibitor, was recommended, which markedly reduced the size of the metastatic lesions and was continued for 24 months until disease progression without severe adverse events.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      This case suggests that CGP can help identify actionable alterations in eAML, such as\n                      <jats:italic>TSC2<\/jats:italic>\n                      mutations, to guide personalized therapy with mTOR inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1735690","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T05:25:55Z","timestamp":1769750755000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: mTOR inhibitor treatment for epithelioid angiomyolipoma harboring biallelic TSC2 mutations"],"prefix":"10.3389","volume":"16","author":[{"given":"Shiori","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology, Tohoku University Graduate School of Medicine","place":["Sendai, Japan"]},{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kota","family":"Ouchi","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Tohoku University Graduate School of Medicine","place":["Sendai, Japan"]},{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shonosuke","family":"Wakayama","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keigo","family":"Komine","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroo","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Saijo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuto","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanobu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Tohoku University Graduate School of Medicine","place":["Sendai, Japan"]},{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidekazu","family":"Shirota","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisato","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Tohoku University Graduate School of Medicine","place":["Sendai, Japan"]},{"name":"Department of Medical Oncology, Tohoku University Hospital","place":["Sendai, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.eururo.2016.01.048","article-title":"Natural history of renal angiomyolipoma (Aml): most patients with large amls >4cm can be offered active surveillance as an initial management strategy","volume":"70","author":"Bhatt","year":"2016","journal-title":"Eur Urol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1186\/s13256-021-03073-0","article-title":"A renal angiomyolipoma with a challenging presentation: A case report","volume":"15","author":"Bouaziz","year":"2021","journal-title":"J Med Case Rep"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00261-014-0129-6","article-title":"Prevalence of Sporadic Renal Angiomyolipoma: A Retrospective Analysis of 61,389 in- and out-Patients","volume":"39","author":"Fittschen","year":"2014","journal-title":"Abdom Imaging"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e318206f2a9","article-title":"Pure epithelioid pecomas (So-called epithelioid angiomyolipoma) of the kidney: A clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification","volume":"35","author":"Nese","year":"2011","journal-title":"Am J Surg Pathol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4274\/uob.galenos.2020.1438","article-title":"Renal angiomyolipoma: A clinicopathological study of seven cases and review of the literature","volume":"19","author":"G\u00fcrsoy","year":"2020","journal-title":"Bull Urooncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"41","DOI":"10.5334\/jbsr.1536","article-title":"Renal angiomyolipoma: the good, the bad, and the ugly","volume":"102","author":"Vos","year":"2018","journal-title":"J Belg Soc Radiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-199802000-00005","article-title":"Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of Malignant epithelioid angiomyolipoma","volume":"22","author":"Pea","year":"1998","journal-title":"Am J Surg Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4081\/rt.2013.e46","article-title":"Fatal Malignant metastastic epithelioid angiomyolipoma presenting in a young woman: case report and review of the literature","volume":"5","author":"Wyluda","year":"2013","journal-title":"Rare Tumors"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.610858","article-title":"Everolimus in invasive Malignant renal epithelioid angiomyolipoma","volume":"10","author":"Guo","year":"2020","journal-title":"Front Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5349","article-title":"Clinical decisions by the molecular tumor board on comprehensive genomic profiling tests in Japan: A retrospective observational study","volume":"12","author":"Shirota","year":"2023","journal-title":"Cancer Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s10038-023-01133-5","article-title":"Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility","volume":"68","author":"Kawamura","year":"2023","journal-title":"J Hum Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13073-021-00835-9","article-title":"Cadd-splice-improving genome-wide variant effect prediction using deep learning-derived splice scores","volume":"13","author":"Rentzsch","year":"2021","journal-title":"Genome Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2004.09.004","article-title":"Renal epithelioid angiomyolipoma\u2013a close mimic of renal cell carcinoma. Report of a case and review of the literature","volume":"200","author":"Svec","year":"2005","journal-title":"Pathol Res Pract"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00261-023-04034-5","article-title":"Differentiation between renal epithelioid angiomyolipoma and clear cell renal cell carcinoma using clear cell likelihood score","volume":"48","author":"Hao","year":"2023","journal-title":"Abdom Radiol (NY)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.17_suppl.LBA4500","article-title":"Everest: everolimus for renal cancer ensuing surgical therapy\u2014a phase iii study (Swog S0931, nct01120249)","volume":"40","author":"Ryan","year":"2022","journal-title":"J Clin Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1006242","DOI":"10.1371\/journal.pgen.1006242","article-title":"Whole exome sequencing identifies tsc1\/tsc2 biallelic loss as the primary and sufficient driver event for renal angiomyolipoma development","volume":"12","author":"Giannikou","year":"2016","journal-title":"PloS Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/path.2289","article-title":"Constant allelic alteration on chromosome 16p (Tsc2 gene) in perivascular epithelioid cell tumour (Pecoma): genetic evidence for the relationship of pecoma with angiomyolipoma","volume":"214","author":"Pan","year":"2008","journal-title":"J Pathol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1186\/s12885-018-4467-6","article-title":"Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to tsc2 mutation","volume":"18","author":"Espinosa","year":"2018","journal-title":"BMC Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2017.07.016","article-title":"Mtorc1 inhibition is an effective treatment for sporadic renal angiomyolipoma","volume":"3","author":"Pleniceanu","year":"2018","journal-title":"Kidney Int Rep"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2174\/0115748871258042230921052344","article-title":"Identification of a novel tsc2 C.170g>a missense variant: A case report and elaboration on the yield of targeted options against tuberous sclerosis complex manifestations","volume":"18","author":"Papageorgiou","year":"2023","journal-title":"Rev Recent Clin Trials"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.575750","article-title":"The correlation between tuberous sclerosis complex genotype and renal angiomyolipoma phenotype","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Genet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041743","article-title":"The role of mtor signaling as a therapeutic target in cancer","volume":"22","author":"Popova","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2007.01.028","article-title":"Activation of the mtor pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms","volume":"38","author":"Kenerson","year":"2007","journal-title":"Hum Pathol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s12894-022-01101-9","article-title":"Club suit symbolevaluation of clinicopathological profiles and development of a risk model in renal epithelioid angiomyolipoma patients: A large-scale retrospective cohort study","volume":"22","author":"Anwaier","year":"2022","journal-title":"BMC Urol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv249","article-title":"Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial","volume":"31","author":"Bissler","year":"2016","journal-title":"Nephrol Dial Transplant"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e420","DOI":"10.1038\/bcj.2016.25","article-title":"Clinical response to everolimus in a patient with hodgkin\u2019s lymphoma harboring a tsc2 mutation","volume":"6","author":"Perini","year":"2016","journal-title":"Blood Cancer J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a002220","article-title":"Exceptional response to everolimus in a novel tuberous sclerosis complex-2 mutation-associated metastatic renal-cell carcinoma","volume":"4","author":"Alsidawi","year":"2018","journal-title":"Cold Spring Harb Mol Case Stud"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4548","article-title":"Phase ii clinical trial of everolimus in a pan-cancer cohort of patients with mtor pathway alterations","volume":"27","author":"Adib","year":"2021","journal-title":"Clin Cancer Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1735690\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T05:25:56Z","timestamp":1769750756000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1735690\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":28,"alternative-id":["10.3389\/fonc.2026.1735690"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1735690","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]},"article-number":"1735690"}}