The potential of emerging new therapeutics for the treatment of perivascular epithelioid cell tumors (PEComa)

ABSTRACT

Introduction: Perivascular epithelioid cell tumor (PEComa) constitutes a family of rare mesenchymal soft-tissue tumors. These tumors pose a significant diagnostic challenge, given their cytomorphology and characteristic co-expression of both melanocytic and myogenic markers. While most PEComas show benign behavior, a subset of PEComas can act malignantly. Historically, cytotoxic chemotherapy used in other soft-tissue sarcomas has shown little benefit. However, a growing understanding of the role of aberrant mTOR pathway activation in these tumors has yielded multiple reports of durable tumor responses and clinical benefit with mTOR inhibitors such as sirolimus, temsirolimus, and everolimus.

Areas covered: We describe the histopathology, molecular features and differential diagnosis of the PEComa family and review available data on treatment strategies for localized and advanced PEComa. A literature search was performed using PubMed, American Society of Clinical Oncology, and ClinicalTrials.gov websites.

Expert opinion: mTOR inhibitors are emerging as the standard approach to the management of advanced PEComa. Results of the clinical trial for advanced PEComa with ABI-009, a nanoparticle albumin-bound mTOR inhibitor, will provide the first prospective data of mTOR inhibition in PEComa, and may establish a relationship between genotype and outcome.

KEYWORDS:

• mTOR complex pathway
• mTOR pathway inhibitors
• Perivascular epithelioid cell tumor
• therapeutic option

Article highlights

• PEComas are a family of rare mesenchymal tumors and include lymphangioleiomyomatosis, angiomyolipoma, clear-cell ‘sugar’ tumor of the lung, and PEComa (not otherwise specified).

• PEComas are characterized by co-expression of myogenic and melanocytic markers. A subset of PEComas harbor gene-rearrangements of TFE3.

• PEComas usually show benign behavior and do not recur following complete resection. However, a subset of PEComas can have aggressive local behavior and metastasize to distant organs.

• PEComas frequently harbor alterations in the tumor suppressor genes TSC1 or TSC2, resulting in overactivation of the mTORC1 complex.

• Retrospective case series in patients with advanced PEComa treated with mTOR inhibitors (sirolimus, temsirolimus, or everolimus) have demonstrated durable tumor responses and clinical benefit. mTOR inhibitors are emerging as the standard approach to management of metastatic PEComa.

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Declaration of interest

AJW has served as a consultant for Eli Lilly, Loxo, and Five Prime Therapeutics, and has received research support to his institution from AADi, Eli Lilly, Daiichi-Sankyo, Plexxikon, Karyopharm, and Five Prime Therapeutics. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.