{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:11:48Z","timestamp":1790687508015,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"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:p>Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms. PI3K\/AKT\/mTOR pathway upregulation is critical for their pathogenesis and is often associated with TSC1\/TSC2 inactivation. Although first line mTOR inhibitors are an effective treatment, metastatic PEComas eventually progress. A 53-year-old woman presented a 4-month history of post-menopausal vaginal bleeding. Clinical and radiological examination detected a uterine mass and a single S1 bone lesion. The patient underwent a radical hysterectomy and bone biopsy. The anatomopathological evaluation concluded to an oligo-metastatic uterine PEComa. The tumor harbored a heterozygous deletion of 9q34 that contains the TSC1 gene. Concerning the primary lesion, the resection was complete and the single bone metastasis was treated with radiotherapy. Three months later, the patient presented bone, lung and subcutaneous metastatic progression. An everolimus and denosumab treatment was initiated. After 2 years of treatment, a clinically significant bone, lung and subcutaneous progression was detected. Following a literature review of the possible therapeutic options, we initiated a second line treatment by pazopanib. This treatment resulted in regression of the subcutaneous lesions and stability of lung and bone metastases. In this challenging, rare setting, our report suggests single agent, anti-angiogenic, tyrosine kinase inhibitor to be effective as second line treatment of metastatic uterine PEComa progressing on mTOR inhibitors.<\/jats:p>","DOI":"10.3389\/fonc.2021.641376","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T05:08:47Z","timestamp":1616735327000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["VEGFR Inhibitors for Uterine Metastatic Perivascular Epithelioid Tumors (PEComa) Resistant to mTOR Inhibitors. A Case Report and Review of Literature"],"prefix":"10.3389","volume":"11","author":[{"given":"Aikaterini","family":"Liapi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Mathevet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda G.","family":"Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delfyne","family":"Hastir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apostolos","family":"Sarivalasis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1136\/jclinpath-2015-202945","article-title":"Perivascular epithelioid tumours (PEComas) of the gynaecological tract","volume":"68","author":"Conlon","year":"2015","journal-title":"J Clin Pathol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1097\/00000478-199203000-00013","article-title":"PEC and sugar","volume":"16","author":"Bonetti","year":"1992","journal-title":"Am J Surg Pathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1111\/j.1365-2559.2005.02316.x","article-title":"PEComa: what do we know so far?","volume":"48","author":"Hornick","year":"2006","journal-title":"Histopathology."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1097\/01.pas.0000173232.22117.37","article-title":"Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature","volume":"29","author":"Folpe","year":"2005","journal-title":"Am J Surg Pathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"5295","DOI":"10.1158\/1078-0432.CCR-19-0288","article-title":"Role of chemotherapy, VEGFR inhibitors, and mTOR inhibitors in advanced perivascular epithelioid cell tumors (PEComas)","volume":"25","author":"Sanfilippo","year":"2019","journal-title":"Clin Cancer Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1067\/mob.2003.99","article-title":"High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence","volume":"188","author":"Baird","year":"2003","journal-title":"Am J Obstet Gynecol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2946","DOI":"10.3892\/ol.2017.7662","article-title":"Primary malignant perivascular epithelioid cell neoplasm (PEComa) of the bone mimicking granular cell tumor in core biopsy: a case report and literature review","volume":"15","author":"Sadigh","year":"2018","journal-title":"Oncol Lett."},{"key":"B8","doi-asserted-by":"publisher","first-page":"387","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":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijsu.2015.05.002","article-title":"Perivascular epithelioid cell neoplasm (PEComa) of the uterus: a systematic review","volume":"19","author":"Musella","year":"2015","journal-title":"Int J Surg."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1097\/PAS.0000000000001119","article-title":"Uterine PEComas: a morphologic, immunohistochemical, and molecular analysis of 32 tumors","volume":"42","author":"Bennett","year":"2018","journal-title":"Am J Surg Pathol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1097\/PAS.0000000000000349","article-title":"TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis","volume":"39","author":"Schoolmeester","year":"2015","journal-title":"Am J Surg Pathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1177\/1066896917701245","article-title":"Malignant PEComa with metastatic disease at diagnosis and resistance to several chemotherapy regimens and targeted therapy (m-TOR inhibitor)","volume":"25","author":"Machado","year":"2017","journal-title":"Int J Surg Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s12881-015-0155-4","article-title":"Targeted next generation sequencing reveals previously unidentified TSC1 and TSC2 mutations","volume":"16","author":"Nellist","year":"2015","journal-title":"BMC Med Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34","volume":"277","author":"van Slegtenhorst","year":"1997","journal-title":"Science."},{"key":"B15","doi-asserted-by":"publisher","first-page":"6161","DOI":"10.21873\/anticanres.11208","article-title":"Treatment of advanced malignant uterine perivascular epithelioid cell tumor with mTOR inhibitors: single-institution experience and review of the literature","volume":"36","author":"Starbuck","year":"2016","journal-title":"Anticancer Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1016\/S0140-6736(12)60651-5","article-title":"Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial","volume":"379","author":"van der Graaf","year":"2012","journal-title":"Lancet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1080\/0284186X.2017.1332779","article-title":"Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: results of the SPIRE study","volume":"56","author":"Gelderblom","year":"2017","journal-title":"Acta Oncol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"iv506","DOI":"10.1093\/annonc\/mdu354.39","article-title":"1450P - systemic therapy in perivascular epithelioid cell tumors (pecoma)","volume":"25","author":"Hindi","year":"2014","journal-title":"Ann Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"311","DOI":"10.2147\/RRU.S226005","article-title":"Metastatic perivascular epithelioid cell tumor of the kidney: a case report with emphasis on response to the tyrosine-kinase inhibitor sunitinib","volume":"11","author":"AlAzab","year":"2019","journal-title":"Res Rep Urol"},{"key":"B20","doi-asserted-by":"crossref","first-page":"e180219","DOI":"10.1001\/jamaoncol.2018.0219","article-title":"Anthracycline, gemcitabine, and pazopanib in epithelioid sarcoma: a multi-institutional case series","volume":"4","author":"Frezza","year":"2018","journal-title":"JAMA Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0221-7","article-title":"Phase II trial of VEGFR2 inhibitor apatinib for metastatic sarcoma: focus on efficacy and safety","volume":"51","author":"Liao","year":"2019","journal-title":"Exp Mol Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"48","DOI":"10.3390\/medsci7030048","article-title":"Real-world experiences with pazopanib in patients with advanced soft tissue and bone sarcoma in Northern California","volume":"7","author":"Seto","year":"2019","journal-title":"Med Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3126","DOI":"10.1200\/JCO.2008.21.3223","article-title":"Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043)","volume":"27","author":"Sleijfer","year":"2009","journal-title":"J Clin Oncol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1002\/cncr.29961","article-title":"The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: a Japanese Musculoskeletal Oncology Group (JMOG) study","volume":"122","author":"Nakamura","year":"2016","journal-title":"Cancer."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1361","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":"B26","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1200\/JCO.2009.25.2981","article-title":"Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors","volume":"28","author":"Wagner","year":"2010","journal-title":"J Clin Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1093\/annonc\/mdq044","article-title":"Treatment with the mTOR inhibitor temsirolimus in patients with malignant PEComa","volume":"21","author":"Italiano","year":"2010","journal-title":"Ann Oncol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1111\/tri.12567","article-title":"Successful treatment with sirolimus for an angiomyolipoma mimicking renal cell carcinoma in a transplanted kidney","volume":"28","author":"Chiu","year":"2015","journal-title":"Transpl Int."},{"key":"B29","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1186\/1477-7819-10-181","article-title":"Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epithelioid cell tumor","volume":"10","author":"Gennatas","year":"2012","journal-title":"World J Surg Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1002\/ijc.25843","article-title":"Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma","volume":"129","author":"Mahmood","year":"2011","journal-title":"Int J Cancer."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1016\/S1470-2045(16)30507-1","article-title":"Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial","volume":"17","author":"Mir","year":"2016","journal-title":"Lancet Oncol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3133","DOI":"10.1200\/JCO.2008.20.4495","article-title":"Phase II study of sorafenib in patients with metastatic or recurrent sarcomas","volume":"27","author":"Maki","year":"2009","journal-title":"J Clin Oncol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1080\/15384047.2016.1167290","article-title":"Combination targeted therapy of VEGFR inhibitor, sorafenib, with an mTOR inhibitor, sirolimus induced a remakable response of rapid progressive uterine PEComa","volume":"17","author":"Gao","year":"2016","journal-title":"Cancer Biol Ther"},{"key":"B34","doi-asserted-by":"publisher","first-page":"7135","DOI":"10.1200\/JCO.2005.16.139","article-title":"Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas","volume":"23","author":"D'Adamo","year":"2005","journal-title":"J Clin Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"5534","DOI":"10.1158\/1078-0432.CCR-20-1191","article-title":"Addition of antiestrogen treatment in patients with malignant PEComa PROGRESSING to mTOR inhibitors","volume":"26","author":"Sanfilippo","year":"2020","journal-title":"Clin Cancer Res."}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.641376\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T05:08:49Z","timestamp":1616735329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.641376\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":35,"alternative-id":["10.3389\/fonc.2021.641376"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.641376","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]},"article-number":"641376"}}