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Year : 2012  |  Volume : 1  |  Issue : 4  |  Page : 207-209

Perivascular epithelioid cell tumors: Recent advances

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois-60611, USA

Date of Web Publication27-Dec-2012

Correspondence Address:
William B Laskin
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois-60611
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2277-8632.105103

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How to cite this article:
Laskin WB. Perivascular epithelioid cell tumors: Recent advances. J NTR Univ Health Sci 2012;1:207-9

How to cite this URL:
Laskin WB. Perivascular epithelioid cell tumors: Recent advances. J NTR Univ Health Sci [serial online] 2012 [cited 2020 Sep 19];1:207-9. Available from: http://www.jdrntruhs.org/text.asp?2012/1/4/207/105103

Perivascular epithelioid cell tumors, or PEComas, are uncommon mesenchymal neoplasms found in virtually all body sites that are composed of a morphologically distinctive epithelioid cell with the potential for dual expression of myogenic and melanocytic protein markers. The prototypic PEComa, the angiomyolipoma (AML) of the kidney, was first described and then later associated with the tuberous sclerosis complex in the early 1900s. [1] Later, lymphangioleiomyomatosis (LAM) [2] and the clear cell "sugar" tumor (CCST) of the lung [3] were delineated as distinct clinicopathologic entities with ties to the tuberous sclerosis complex. [4],[5] However, these aforementioned tumors were not proven morphologically related entities until Pea, et al. in 1991 [6] identified a peculiar HMB-45 immunoexpressing epithelioid cell often arranged around vessels common to both AML and CCST and, later, this "perivascular epithelioid cell" was also described in LAM. [7] Although not having a counterpart in normal tissue, this unique cell is histologically characterized by its polygonal shape, well-defined cell borders, clear to granular eosinophilic cytoplasm, centrally located round to oval nucleus, and small nucleolus, and serves to unite AML, LAM, and CCST as members of the PEComa family of tumors. [8] More recently, the morphologic spectrum and anatomic distribution of PEComa has expanded with the rightful inclusion of the monomorphic epithelioid AML of kidney [9] and liver, [10] the purely spindled clear cell myomelanocytic tumor first described in the falciform ligament/ligamentum teres of the liver, [11] and soft tissue and gynecologic tract tumors with features of clear cell myomelanocytic tumor, CCST of lung, or epithelioid AML. [12] Tumors exhibiting immunomorphologic features of PEComa but arising in "non-classical" sites are often referred to as PEComa, not otherwise specified (PEComa, NOS). [13]

Heightened recognition of PEComa among pathologists and focused research on molecular pathways key to its pathogenesis, identifying pathologic factors related to aggressive behavior, and treatment options have led to a steady rise in the number of published articles pertaining to the lesion. Since 1993, 1713 articles referencing PEComa/perivascular cell tumor or neoplasm have appeared in the English language literature (PubMed) with almost 60% published over the past 7 years. The recent spate of PEComas reported in unconventional sites has resulted in a decrease in the percentage of tumors arising in the gynecologic tract, which represents one of the most common locations for PEComas, NOS, [12] from approximately 40% in older literature to 24% documented in a recent comprehensive study. [14] Still, a number of questions regarding PEComa persist: (1) what is the complete morphological range and immunohistochemical profile of the tumor, (2) what is the cell of origin, (3) what factors impact on prognosis, and (4) what is the best treatment option available for aggressively behaving lesions.

The paper by Matkowskyj, et al., [15] addresses the first question and illustrates just some of the morphologic and immunohistochemical trappings exhibited by PEComa that can lead to misdiagnosis. In general, the plasticity of the perivascular epithelioid cell results in PEComas composed strictly of eosinophilic epithelioid cells simulating carcinoma (epithelioid AML), spindled cells with a smooth muscle morphotype resembling bonafide smooth muscle tumors (spindle cell-predominant AML), clear epithelioid (CCST) or spindled (clear cell myomelanocytic tumor) cells, and tumors composed almost entirely of heavily lipidized cells mimicking well-differentiated liposarcoma (fat-predominant AML). In addition, PEComas arising in the retroperitoneum, including kidney and pararenal soft tissue, and the gynecologic tract often exhibit varying degrees of stromal fibrosis/sclerosis altering the typical growth patterns of conventional PEComa [16],[17] as evidenced in the cases presented by Matkowskyj, et al. [15] Without the light microscopic appreciation of the quality of the cytoplasm, its tendency to concentrate around the nucleus, and the perivascular orientation of the cells at least focally, the nested arrangement of epithelioid cells identified in some sclerosing/fibrosing PEComas could result in a misdiagnosis of paraganglioma, neuroendocrine carcinoma, Xp11-translocation renal cell carcinoma, clear cell sarcoma, or even alveolar soft-part sarcoma. The characteristic myomelanocytic immunophenotype of PEComa with HMB-45 and Melan-A representing the two most sensitive melanocytic markers, [12] generally allows for ready diagnosis. However, three caveats regarding its diagnosis need mentioning. First, Folpe, et al. [12] documented keratin immunoexpression in approximately 13% of soft tissue and gynecologic PEComas but, unlike in carcinoma, its expression was usually focal and not associated with highly atypical cells. Second, the same study reported S-100 protein in approximately 33% of PEComa, NOS, but, in contrast to clear cell sarcoma, all the S-100 protein-expressing PEComas coexpressed muscle markers. The third caveat, exemplified in case 3, [15] is that nearly 33% of sporadic PEComas demonstrate nuclear TFE3 immunoexpression. [18] According to Argani, et al., [18] this subtype of PEComa generally arises in younger aged patients, exhibits epithelioid morphology, and usually lacks myogenic marker expression. These clinicopathologic features heightening its resemblance to Xp11-translocation renal tumors and alveolar soft-part sarcoma. Compounding the problem further is that some Xp11-translocation renal cell carcinomas express HBM-45 and Melan-A. [19] Besides the characteristic immunoprofile of PEComa, the greater nuclear atypia exhibited by alveolar soft-part sarcoma and the papillary growth pattern and psammomatous calcifications observed in Xp11-translocation renal carcinomas help to separate these mimics from PEComa.

Papers like the one offered by Matkowskyj, et al., [15] further heighten our awareness of variations in histology and clinical presentation of PEComa and hopefully will encourage pathologists to report unusual examples of the lesion as well as all salient pathological parameters potentially affecting the tumor's prognosis. Such reporting will ultimately lead to a more comprehensive understanding of the pathobiology of the tumor and allow for more accurate retrospective analyses of factors impacting behavior and treatment effect. Illustrating this point is a recent study by Bleeker, et al. [14] that analyzed clinicopathologic data from 234 examples of PEComa, NOS, extracted from the literature. After multivariant analysis of 93 surgically excised tumors with adequate clinical data, this group found that a modified version of Folpe's histologic criteria for determining malignant potential of PEComa, NOS [12] using tumor size of 5 cm or greater and a mitotic count of 2 or more mitoses per 50 high-powered fields was significantly associated with recurrence after surgical excision. However, the authors pointed out that the limited database available to them precludes confident use of their stratification scheme. Additionally, their critical evaluation of the treatment strategies culled from the literature demonstrated that neoadjuvant and adjuvant chemo-/radiation therapy have little efficacy in the nonsurgical management of PEComa, NOS.

Our quest for a more comprehensive understanding of the morphological spectrum, pathobiologic behavior, and molecular profile of PEComa will hopefully help us tailor more effective treatment options, especially for PEComas exhibiting potential for aggressive behavior. Currently, our understanding of the importance of the mTOR pathway in the pathogenesis of PEComa has led to clinical studies evaluating the use of mTOR pathway inhibitors in the nonsurgical management of PEComa with some encouraging results. [20],[21]

  References Top

1.Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: Pathology and pathogenesis. Hum Pathol 2010;41:1-15.  Back to cited text no. 1
2.Frack MD, Simon L, Dawson BH. The lymphangiomyomatosis syndrome. Cancer 1968;22:428-37.  Back to cited text no. 2
3.Liebow AA, Castleman B. Benign clear cell ("sugar") tumors of the lung. Yale J Biol Med 1971;43:213-22.  Back to cited text no. 3
4.Valensi QJ. Pulmonary lymphangiomyoma, a probable form fruste of tuberous sclerosis. A case report and survey of the literature. Am Rev Respir Dis 1973;108:1411-5.  Back to cited text no. 4
5.Monteforte Jr WJ, Kohnen PW. Angiomyolipomas in a case of lymphangiomyomatosis syndrome: Relationships to tuberous sclerosis. Cancer 1974;34:3177-321.  Back to cited text no. 5
6.Pea M, Bonetti F, Zamboni G, Martignoni G, Fiore-Donati L, Doglioni C. Clear cell tumor and angiomyolipoma. Am J Surg Pathol 1991;15:199-202.  Back to cited text no. 6
7.Bonetti F, Pea M, Martignoni G, Zamboni G, Iuzzolino P. Cellular heterogeneity in lymphangiomyomatosis of the lung. Hum Pathol 1991;22:727-8.  Back to cited text no. 7
8.Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol 1992;16:307-8.  Back to cited text no. 8
9.Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: A report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 1997;21:1123-30.  Back to cited text no. 9
10.Tsui WM, Colombari R, Portmann BC, Bonetti F, Thung SN, Ferrell LD, et al. Hepatic angiomyolipoma: A clinicopathologic study of 30 cases and delineation of unusual morphologic variants. Am J Surg Pathol 1999;23:34-48.  Back to cited text no. 10
11.Folpe AL, Goodman ZD, Ishak KG, Paulino AF, Taboada EM, Meehan SA, et al. Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: A novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults. Am J Surg Pathol 2000;24:1239-46.  Back to cited text no. 11
12.Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW, et al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin. A clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29:1558-75.  Back to cited text no. 12
13.Fadare O, Parkash Y, Yilmaz Y, Mariappan MR, Ma L, Hileeto D, et al. Perivascular epithelioid cell tumor (PEComas) of the uterine cervix associated with intraabdominal "PEComastosis": A clinicopathological study with comparative genomic hybridization analysis. World J Surg Oncol 2004;2:35.  Back to cited text no. 13
14.Bleeker JS, Quevedo JF, Folpe AL. "Malignant" perivascular epithelioid cell neoplasm: risk stratification and treatment strategies. Sarcoma 2012;2012:541626.  Back to cited text no. 14
15.Matkowskyj KA, Chen ZE, Rao MS, Yang G. Perivascular epithelioid cell tumors (PEComas): Our institutional experience with several interesting cases and a brief review of the literature. J NTR Univ Health Sci 2012 [In Press].  Back to cited text no. 15
16.Hornick JL, Fletcher CD. Sclerosing PEComa: Clinicopathologic analysis of a distinctive variant with a predilection for the retroperitoneum Am J Surg Pathol 2008;32:493-501.  Back to cited text no. 16
17.Yamada Y, Yamamoto H, Ohishi Y, Nishiyama K, Fukuhara M, Saitou T, et al. Sclerosing variant of perivascular epithelioid cell tumor in the female genital organs. Pathol Int 2011;61:768-72.  Back to cited text no. 17
18.Argani P, Aulmann S, Ilei PB, Netto GJ, Ro J, Cho HY, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010;34:1396-406.  Back to cited text no. 18
19.Argani P, Aulmann S, Karanjawala Z, Fraser RB, Ladanyi M, Rodriguez MM. Melanotic Xp11 translocation renal cancers: A distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J Surg Pathol 2009;33:609-19.  Back to cited text no. 19
20.Italiano A, Delcambre C, Hostein I, Cazeau AL, Marty M, Avril A, et al. Treatment with the mTOR inhibitor temsirolimus in patients with malignant perivascular epithelioid cell tumors (PEComas). Ann Oncol 2010;21:1135-7.  Back to cited text no. 20
21.Wagner AJ, Malinowska-Kolodziej I, Morgan JA, Qin W, Fletcher CD, Vena N, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: Targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 2010;28:835-40.  Back to cited text no. 21


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