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Fatal malignant metastastic epithelioid angiomyolipoma presenting in a young woman: case report and review of the literature.
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PMID:  24179658     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Epithelioid angiomyolipomas (EAMLs) are rare mesenchymal tumors whose malignant variant is extremely uncommon and highly aggressive. Treatment strategies include chemo radiation, transcatheter arterial embolization and surgical resection, which has remained the mainstay treatment. Targeted therapies including mammalian target of rapamycin (mTOR) inhibitors such as Temsirolimus may offer some hope for progressive malignant EAMLs that are not amenable to other treatment modalities. We report a fatal case in a young female who presented with rapidly progressive metastatic EAML that did not respond to mTOR therapy. The literature has shown reduction in tumor burden with the use of mTOR inhibitors, but unfortunately due to the rarity of malignant EAML, a meaningful approach to treatment remains challenging.
Edward Wyluda; Giselle Baquero; Nicholas Lamparella; Catherine Abendroth; Joseph Drabick
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Publication Detail:
Type:  Journal Article     Date:  2013-09-26
Journal Detail:
Title:  Rare tumors     Volume:  5     ISSN:  2036-3605     ISO Abbreviation:  Rare Tumors     Publication Date:  2013  
Date Detail:
Created Date:  2013-11-01     Completed Date:  2013-11-01     Revised Date:  2014-01-24    
Medline Journal Info:
Nlm Unique ID:  101526926     Medline TA:  Rare Tumors     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  e46     Citation Subset:  -    
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Journal Information
Journal ID (nlm-ta): Rare Tumors
Journal ID (iso-abbrev): Rare Tumors
Journal ID (publisher-id): RT
ISSN: 2036-3605
ISSN: 2036-3613
Publisher: PAGEPress Publications, Pavia, Italy
Article Information
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©Copyright E. Wyluda et al.
Received Day: 21 Month: 5 Year: 2013
Accepted Day: 30 Month: 5 Year: 2013
Electronic publication date: Day: 26 Month: 9 Year: 2013
collection publication date: Day: 01 Month: 7 Year: 2013
Volume: 5 Issue: 3
E-location ID: e46
PubMed Id: 24179658
ID: 3804821
DOI: 10.4081/rt.2013.e46

Fatal Malignant Metastastic Epithelioid Angiomyolipoma Presenting in a Young Woman: Case Report and Review of the Literature
Edward Wyluda1
Giselle Baquero2
Nicholas Lamparella3
Catherine Abendroth4
Joseph Drabick3
1Department of Internal Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
2Department of Cardiology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
3Department of Hematology-Oncology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
4Department of Pathology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
Correspondence: Department of Internal Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania 17033-0850, USA. Tel. +1.518.810.5962-Fax: +1.717.531.5831. E-mail:
Contributions: EW primary author, GB assisted in manuscript writing and research, NL assisted in editing, CA assisted in editing, pathological review, pathology slides, JD assisted in review of manuscript.Conflict of interests: the authors declare no potential conflicts of interest.


Angiomyolipomas, including epithelioid angiomyolipoma (EAML) are a sub type of Perivascular Epithelioid Cell tumors (PEC-omas) a family of mesenchymal tumors with a strong association with tuberous sclerosis.1 The malignant variant of EAML is extremely uncommon and highly aggressive.2 Treatment strategies including chemoradiation and transcatheter arterial embolization (TAE) have demonstrated some efficacy in localized and differentiated, progressive disease. Surgical resection has remained the mainstay treatment.3 Targeted therapies including mammalian target of rapamycin (mTOR) inhibitors such as Temsirolimus may offer some hope for cases of progressive malignant EAMLs that are not amenable to surgical resection or other treatment modalities. We report a fatal case in a young female who presented with rapidly progressive metastatic EAML.

Case Report

This female patient was diagnosed on nephrectomy, at age 31, as having an epithelioid angiomyolipoma of the left kidney. Metastatic disease presented in the mediastinum 7 years later, at age 38. The tumor was characterized by nests of cells with abundant, clear to eosinophilic, polygonal cytoplasm (epithelioid features). There was marked nuclear pleomorphism with nuclear enlargement, irregularity, and eosinophilic macronucleoli. Multinucleated tumor cells were present. Histologic features of aggressive growth included mitoses and necrosis. Immunophenotyping of the original and metastatic tumors was characteristic of EAML, with positive staining for at least one melanocytic marker (Figure 1A-D).

One month prior to her last admission she presented with epigastric pain, intractable nausea and vomiting and was hospitalized for pancreatitis. Abdominal/pelvic computerized tomography scan showed in addition to pancreatitis findings, partial thrombosis of the superior mesenteric vein (SMV) with a lobulated soft tissue mass at the right cardiophrenic angle. The patient was treated for pancreatitis, stabilized and discharged home on oral anticoagulation. Repeat imaging on readmission revealed new hypodensities throughout the liver and lungs; new masses in the pancreas and uterus; enlargement of the right cardiophrenic mass; near-complete occlusion of the portal vein, IVC, and SMV; and a focal hypodensity in the right atrium suggestive of extension of a SVC thrombus (Figure 2), despite being on Warfarin with documented therapeutic INRs.

Fine needle aspiration biopsy of several lesions including the liver, pancreas, and cardio-phrenic mass all showed metastatic epithelioid angiomyolipoma. Debulking procedures to reduce tumor burden were not considered given the extensive intravascular involvement. The patient was started on temsirolimus and completed a total of 12 cycles but continued to show progression of metastatic disease. Five months later, she succumbed to the disease due to tumor burden with a complication of uncontrollable retroperitoneal bleeding.


PEComa is a family of mesenchymal tumors, with a strong association with tuberous sclerosis, which includes angiomyolipomas (AML), clear cell sugar tumors (CCST) and pulmonary lymphangioleiomyomatosis.4 A subtype of AML is the epithelioid angiomyolipoma (EAML). EAML is a rare tumor usually presenting during the fourth decade of life,5 whose malignant variant is extremely uncommon and rather aggressive. In its malignant form the most common primary site is the kidney.5 It has been reported that one third, of these primary tumors of the kidney have led to metastases and probable mortality.2

Most recently, clinicopathologic prognostic indicators have been reported. In one of the largest studies of atypical EAMLs (40 cases) Brimo et al. found that larger tumor size, older age, lymphovascular and renal vein invasion were seen more commonly in malignant EAMLs. They concluded that histological findings including an increased mitotic count (2> per 10 hpf), necrosis, atypical mitotic figures and nuclear atypia in greater than 70% of cells were predictive of malignant behavior. A tumor that displays three or more of these findings has an increased risk of malignancy.6 Our patient was found to have recurrent, metastatic disease, with large tumor burden and histologic findings including necrosis, nuclear atypia (>70%), and atypical mitotic figures, meeting 3 out of 4 of Brimo’s criteria for a bad prognosis. Also of note, pathologic features including tumor size greater than 7 cm, involvement of the renal vein and or perinephric fat tissue as well as the presence of TSC portend to poor prognosis in EAML.7

Individual cases of patients undergoing chemotherapy and or radiation treatment for malignant EAML have been reported. Doxorubicin did show a 50% reduction in tumor burden in a single individual.8 But there have been reported poor responses to dacarbazine, carboplatin, cyclophosphamide as well as dacarbazine, ifostamide and mesna and no response reported for a patient receiving radiation.9,10 There has been scant published data in regard to chemoradiation treatment likely due to the rarity of the disease as well as due to the emergence of other modes of treatment.

Treatment strategies for EAMLs are aimed at reducing tumor burden and delaying the progression of disease, they encompass chemo radiation, transcatheter arterial embolization (TAE), surgical resection and targeted therapies with mammalian target of rapamycin (mTOR) inhibitors. TAE treatments to localized tumors have shown significant reduction in tumor burden and control of bleeding.11 Lee et al. demonstrated that TAE may be used as adjunct therapy to systemic treatment in progressive, metastatic EAMLs. Radiofrequency ablation (RFA) also has been shown to decrease tumor burden with a less complicated side effect profile in renal AML.12 Surgical resection can be curative in localized disease but in metastatic or advanced disease it is performed for palliative effect only.

Therapy using Mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus and Everolimus have shown favorable responses in a few case reports with patients diagnosed with malignant EAMLs that are not amenable to surgical resection. In a report from Shitara et al., a 52 year old male with recurrent EAML was treated with mTOR inhibitor everolimus. Two month CT follow up showed marked decrease in tumor size and no progression of disease over the next 7 months.13 Along with a favorable side effect profile, Everolimus and other mtor inhibitors have at times shown a modest tumor burden reduction in the few case reports published of EAML. This was seen in which sirolimus and temsirolimus were single agents given to two different patients with EAML, resulting in overall decreased size and enhancement of malignant lesions.14 Unfortunately, for the patient reported in our case study temsirolimus had no significant impact in controlling her progression of disease.

Similarly poor responses have been documented in other patients who have received mTOR inhibitors. Higa et al. reported a poor clinical response with rapid tumor growth after initiating a patient on sirolimus.15 This result along with the poor clinical response from the patient presented in this report, lead one to postulate that inhibiting the mTOR pathway may at times only provide mild relief it at all in the progression of aggressive malignant EAML. The malignancy may feature a different pathway or is more heterogeneic in nature, possibly involving multiple genes and pathways leading to its proliferation.

Due to the rarity of EAML an overall meaningful approach to the treatment of these malignancies remains challenging. In order to advance in the treatment and overall understanding of EAML, further insight into targeted regiments, genetics and continuing reporting is needed to aid in prognosis, diagnosis and treatment of this rare and potentially fatal condition.


Reduction in tumor burden with the use of mTOR inhibitors has been demonstrated in isolated cases of malignant EAML but unfortunately due to the rarity of this entity a meaningful approach to the treatment of these tumors remain challenging. Our case represented a therapeutic challenge and did not show a favorable response to mTOR therapy with consequent mortality.

1.. Aydin H,Magi-Galluzzi C,Lane BR,et al. Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. Am J Surg PatholYear: 2009;33:289-9718852677
2.. Hornick JL,Fletcher CD.. PEComa: what do we know so far?HistopathologyYear: 2006;48:75-8216359539
3.. Park HK,Zhang S,Wong MK,Kim HL.. Clinical presentation of epithelioid angiomyolipoma. Int J UrolYear: 2007;14:21-517199855
4.. Martignoni G,Pea M,Reghellin D,et al. PEComas: the past, the present and the future. Virchows ArchYear: 2008;452:119-3218080139
5.. Mete O,van der Kwast TH.. Epithelioid angiomyolipoma: a morphologically distinct variant that mimics a variety of intraabdominal neoplasms. Arch Pathol Lab MedYear: 2011;135:665-7021526965
6.. Brimo F,Robinson B,Guo C,et al. Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg PatholYear: 2010;34:715-2220410812
7.. Nese N,Martignoni G,Fletcher CD,et al. Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: a clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification. Am J Surg PatholYear: 2011;35:161-7621263237
8.. Cibas ES,Goss GA,Kulke MH,et al. Malignant epithelioid angiomyolipoma (Sarcoma ex angiomyolipoma) of the kidney - A case report and review of the literature. Am J Surg PatholYear: 2001;25:121-611145246
9.. Ferry JA,Malt RA,Young RH.. Renal angiomyolipoma with sarcomatous transformation and pulmonary metastases. Am J Surg PatholYear: 1991;15:1083-81928559
10.. Yokoo H,Isoda K,Nakazato Y,et al. Retroperitoneal epithelioid angiomyolipoma leading to fatal outcome. Pathol IntYear: 2000;50:649-5410972864
11.. Lee SY,Hsu HH,Chen YC,et al. Embolization of renal angiomyolipomas: short-term and long-term outcomes, complications, and tumor shrinkage. Cardiovasc Intervent RadiolYear: 2009;32:1171-819572171
12.. Castle SM,Gorbatiy V,Ekwenna O,et al. Radiofrequency ablation (RFA) therapy for renal angiomyolipoma (AML): an alternative to angio-embolization and nephronsparing surgery. BJU IntYear: 2012;109:384-722176671
13.. Shitara K,Yatabe Y,Mizota A,et al. Dramatic tumor response to everolimus for malignant epithelioid angiomyolipoma. Jpn J Clin OncolYear: 2011;41:814-621415002
14.. Wolff N,Kabbani W,Bradley T,et al. Sirolimus and temsirolimus for epithelioid angiomyolipoma. J Clin OncolYear: 2010;28:e65-820048172
15.. Higa F,Uchihara T,Haranaga S,et al. Malignant epithelioid angiomyolipoma in the kidney and liver of a patient with pulmonary lymphangioleiomyomatosis: lack of response to sirolimus. Intern MedYear: 2009;48:1821-519834275

Article Categories:
  • Case Report

Keywords: Key words malignant epithelioid angiomyolipomas, targeted therapy, perivascular epithelioid cell tumors.

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