TFE3-rearranged PEComa with hepatic and pulmonary involvement: diagnostic challenges and resistance to mTOR-targeted therapy

Abstract

Background

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of epithelioid cells that co-express melanocytic and smooth muscle markers. They can arise in various anatomic sites, most commonly the uterus, retroperitoneum, gastrointestinal tract, and liver. While most PEComas are sporadic and associated with TSC1/TSC2 mutations leading to mTOR pathway activation, a distinct molecular subset harbors TFE3 gene rearrangements, often exhibiting more aggressive clinical behavior. Given their rarity, the diagnosis and management of PEComas remain challenging and largely unstandardized.

Case presentation

We report the case of a 37-year-old woman with no significant medical history who presented with fatigue, unintentional weight loss, and vomiting. Imaging revealed a large hepatic mass and pulmonary nodules. Histopathological and immunohistochemical evaluation confirmed a diagnosis of TFE3-rearranged PEComa involving the liver and left upper lung lobe. The patient underwent right partial hepatectomy with complete resection of the hepatic lesion. Subsequent disease progression was noted in the lung, lymph nodes, and bone despite treatment with an mTOR inhibitor.

Conclusion

TFE3-rearranged PEComas represent a rare and aggressive molecular subset with limited therapeutic options. This case demonstrates resistance to mTOR inhibition, highlighting the critical importance of molecular subtyping to distinguish TFE3-rearranged from TSC1/TSC2-mutant disease and guide individualized management. Expanded molecular profiling is essential to refine treatment strategies for this uncommon entity.

Introduction

Perivascular epithelioid cell tumors (PEComas) represent a rare and heterogeneous family of mesenchymal neoplasms characterized by distinctive morphologic and immunophenotypic features, specifically the presence of epithelioid cells arranged around blood vessels and co-expressing melanocytic and smooth muscle markers such as HMB-45, Melan-A, and smooth muscle actin (SMA) (Folpe et al. 2005). PEComas compromise a broad clinicopathologic spectrum that includes angiomyolipoma, lymphangioleiomyomatosis, clear cell “sugar” tumor of the lung, and a group of histologically similar tumors arising in soft tissue and visceral organs collectively termed “PEComa–not otherwise specified” (PEComa-NOS).

These tumors can virtually occur in any anatomic location, with the uterus, retroperitoneum, gastrointestinal tract, liver, and kidneys being among the most frequently reported sites (Martignoni et al. 2008). Although most PEComas follow a benign clinical course, a subset exhibits locally aggressive or metastatic behavior, particularly those with atypical histological features such as large size, nuclear atypia, high mitotic rate, necrosis, or vascular invasion.

At the molecular level, PEComas are broadly divided into two subgroups based on their genetic background. The first, and more common, is associated with tuberous sclerosis complex (TSC1 or TSC2) mutations, leading to activation of the mammalian target of rapamycin (mTOR) signaling pathway, which underlies the rationale for using mTOR inhibitors such as everolimus as the treatment of choice. The second, more recently characterized subgroup, harbors TFE3 gene rearrangements resulting in overexpression of the transcription factor E3 (TFE3) and defining a distinct molecular subset with unique histologic and clinical behavior. TFE3-rearranged PEComas tend to occur in younger patients, lack TSC1/TSC2 alterations, and may show more aggressive biology (Argani et al. 2010).

Given their rarity, diagnostic challenges, and variable clinical outcomes, the literature on PEComas remains largely limited to case reports and small series. Herein, we present a rare case of TFE3-rearranged PEComa with synchronous hepatic and pulmonary involvement, complicated by an initial diagnostic misclassification and multi-organ progression despite mTOR inhibition in a resource-limited setting, and discuss the diagnostic and therapeutic implications.

Case report

At initial presentation (Month 0), a 37-year-old woman with no significant past medical history presented with progressive fatigue, unintentional weight loss, and recurrent vomiting over the course of one year. She was referred to our institution for further evaluation and continuity of care.

Initial imaging with contrast-enhanced computed tomography (CT) of the chest revealed a 2.8 × 2.3 cm left upper lobe (LUL) pulmonary nodule, a 1.2 cm nodule along the right hemidiaphragm, and an ill-defined hepatic lesion (Fig. 1). A subsequent positron emission tomography–computed tomography (PET-CT) one month later revealed low-grade uptake in the LUL pulmonary nodule (SUVmax 2.3), and a large hypermetabolic hepatic lesion involving segments VI and VII measuring 9.2 × 8.3 cm (Fig. 1).

Fig. 1.

Imaging at presentation and first follow-up

Magnetic resonance imaging (MRI) of the abdomen at Month 1, identified a right hepatic lesion measuring 12 × 11 cm, involving segments V, VI, VII, and VIII, with compression and narrowing of the inferior vena cava. The radiologic differential diagnosis included ruptured hepatic adenoma, atypical hepatocellular carcinoma, fibrolamellar carcinoma, and hepatic carcinoid. A core needle biopsy of the hepatic lesion was performed at an outside institution. The pathology report was signed out as hepatocellular adenoma; however, the specimen was negative for all standard hepatocytic markers, including cytokeratin, HepPar-1, AFP, glypican, vimentin, CD10, carbonic anhydrase, S100, and CD163.

A follow-up CT of the chest, abdomen, and pelvis at Month 6 showed interval progression with enlargement of the hepatic mass to 19 × 14 cm, increase in the size of the LUL pulmonary lesion to 2.3 × 2.7 cm, and persistence of the right lower lobe nodule (1 × 0.7 cm) (Fig. 1). A CT-guided core biopsy of the LUL lesion at Month 6 revealed an epithelioid neoplasm positive for TFE3, Melan-A, and HMB-45, but negative for Pax-8, SMA, calretinin, PLAP, and SOX10. The negativity for SOX10 was particularly helpful in excluding metastatic melanoma, which can also express HMB-45 and Melan-A. These findings were diagnostic of a TFE3-rearranged PEComa (Fig. 2).

Fig. 2.

Histopathological and Immunohistochemical Features of Lung TFE3-Rearranged PEComa

A repeat PET-CT at Month 7, demonstrated interval increase in size and uptake of the LUL pulmonary mass and the hepatic lesion centered in segment VII (SUVmax 5.9, previously 3.8), with new FDG-avid left inguinal and popliteal lymphadenopathy (Fig. 3).

Fig. 3.

Disease Progression on PET-CT. A 20x view of the H&E section showing nests of epithelioid cells with mild nuclear atypia and moderately abundant focally clear cytoplasm., (B) Melan A at 20x showing diffuse cytoplasmic staining., c SMA displays weak focal cytoplasmic staining as shown in this 20x photo., D Diffuse and strong nuclear staining for TFE-3 in this 20x field

Pathology review at our institution confirmed the diagnosis of TFE3-rearranged PEComa in the lung biopsy. Review of the prior liver block was inconclusive; given the discordance between the outside pathology report and findings on review, a repeat liver biopsy was performed. This confirmed a perivascular epithelioid cell tumor with an immunophenotype consistent with TFE3 rearrangement (Melan-A+, HMB-45+, TFE3+, SOX10−).

The case was presented and reviewed in the multidisciplinary gastrointestinal tumor board, and surgical resection of the hepatic lesion was recommended as the initial approach. The patient underwent right partial hepatectomy at Month 8. Histopathology revealed a 25 cm PEComa with negative surgical margins. Immunohistochemical staining showed diffuse positivity for Melan-A and TFE3, focal weak SMA expression, and negativity for cytokeratin, S100, and SOX10, confirming the diagnosis of TFE3-rearranged PEComa (Fig. 4).

Fig. 4.

Hepatectomy specimen showing tumor infiltrating the liver parenchyma

Postoperatively, the case was re-evaluated in the tumor board, and given the multifocality of the disease, systemic therapy was considered. A follow-up PET-CT scan at Month 10 revealed progression, with an increase in the size and metabolic activity of the LUL pulmonary lesion and newly enlarged left external iliac, inguinal, and lower limb lymph nodes (Fig. 3). However, no residual or recurrent hepatic disease was detected.

Following multidisciplinary discussion, systemic therapy was initiated with everolimus, an mTOR inhibitor, based on available evidence supporting its use in advanced or metastatic PEComa. The patient received therapy for three months (Month 13–Month 16). However, a follow-up PET-CT at Month 16, revealed only a mild decrease in the size and uptake of the LUL mass, with the development of new FDG-avid consolidations in the left upper and lower lobes and progression of necrotic left external iliac, inguinal, and popliteal lymphadenopathy. Additionally, new FDG-avid lytic lesions were identified in the left distal femur, consistent with osseous metastases (Fig. 5).

Fig. 5.

Progression after therapy

These findings indicated disease progression despite mTOR inhibition. Given the unavailability of nab-sirolimus, the current standard of care for malignant PEComa in Lebanon, the patient was advised to discontinue everolimus and initiate anthracycline-based chemotherapy as a last resort. Supportive management was provided for symptomatic control. Unfortunately, the patient was subsequently lost to follow-up.

Discussion

PEComas are uncommon mesenchymal neoplasms characterized by distinctive epithelioid cells that co-express melanocytic (HMB-45 and/or Melan-A) and smooth muscle markers (actin, desmin). The PEComa family compromise several entities, including angiomyolipoma (AML), typically arising in the liver or kidneys and frequently associated with tuberous sclerosis complex (TSC), lymphangioleiomyomatosis (LAM), and clear cell “sugar” and clear cell myomelanocytic tumors, among others. These tumors are extremely rare and mostly described in case reports and small series. They predominantly affect women in their fourth and fifth decades of life.

PEComas may occur in virtually any organ, reflecting the widespread distribution of perivascular epithelioid cells. The kidneys are the most frequent site, notably angiomyolipoma [4–5], followed by the female genital tract, where they can be mistaken for uterine leiomyosarcomas, as described by Kertowidjojo and Bennett (Kertowidjojo and Bennett 2022). They may also develop in the lungs (Acharya et al. 2024), liver, and retroperitoneum (Marinho et al. 2022), and have been reported in the orbit (Lin et al. 2016), pancreas (Zhang et al. 2017), bladder (Chan et al. 2011), heart (Kaur and Pillai 2024), and skin (Cohen and Kurzrock 2022).

The pathogenesis of PEComas remains ambiguous but is primarily linked to aberrations in the mammalian target of rapamycin (mTOR) signaling pathway. Most PEComas exhibit somatic inactivating mutations in TSC1 or TSC2, genes encoding the hamartin and tuberin proteins, respectively, which together form a complex that inhibits mTOR complex 1 (mTORC1). Loss of function of these genes results in constitutive mTORC1 activation, promoting uncontrolled cellular proliferation and tumorigenesis (Kenerson et al. 2007). A distinct subset of PEComas, however, harbors rearrangements in the TFE3 gene (Schmiester et al. 2021). The TFE3 gene belongs to the MiT/TFE family of transcription factors comprising MITF, TFEB, and TFEC, which regulate lysosome biogenesis, autophagy, and cellular metabolism (Goding and Arnheiter 2019). Gagnon et al. further found that alterations in TP53 and ATRX genes may contribute to the aggressive clinical behavior seen in renal angiomyolipomas (Gagnon et al. 2024).

Histologic diagnosis is often challenging because PEComas can exhibit epithelioid and spindle morphology with clear or granular cytoplasm arranged in nests or trabeculae. Cytoplasm frequently contains glycogen confirmed by PAS staining. On immunohistochemistry, PEComas demonstrate dual myogenic and melanocytic differentiation, which can overlap with leiomyosarcoma or metastatic melanoma. In a seminal series of 26 patients with non-AML and non-LAM PEComas, Folpe et al. reported expression of smooth muscle actin in 80% of cases, desmin in 36%, HMB-45 in 91%, Melan-A in 72%, and MITF in 50% (Folpe et al. 2005). Importantly, PEComas are also negative for SOX10, a marker expressed in melanoma and malignant peripheral nerve sheath tumors; SOX10 negativity in the appropriate morphologic context therefore supports PEComa over these melanocytic mimics, as was the case in our patient’s lung biopsy.

Determining the prognosis of PEComa is difficult due to the rarity of the disease and their variable clinical course. Folpe et al. proposed a classification into “benign,” “uncertain malignant potential,” and “malignant” categories based on tumor size (> 8 cm, the strongest predictor of recurrence or metastasis), mitotic activity (> 1/50 HPF), and necrosis. To build on to this classification, Nese et al. later analyzed 41 patients with pure epithelioid renal PEComas and identified five adverse clinicopathologic parameters associated with progression: (1) association with TSC or AML, (2) metastasis at diagnosis, (3) tumor size > 7 cm, (4) extrarenal extension or renal vein involvement, and (5) carcinoma-like growth pattern. Patients with < 2 adverse features had a 15% progression risk (benign), 2–3 features a 64% risk (intermediate), and > 3 features an 80% risk (high-risk/malignant) (Li et al. 2012).

Most hepatic PEComas are noted to be solitary and arising from the right lobe. The right-lobe predilection may reflect its larger volume and greater cellular population predisposing to tumorigenesis. Clinically, hepatic PEComas are frequently asymptomatic and detected incidentally, but may present with right upper quadrant or epigastric discomfort, abdominal fullness, or nonspecific systemic symptoms such as fatigue and weight loss consistent with our patient’s presentation. Because of their nonspecific imaging findings, hepatic PEComas can mimic hepatocellular carcinoma, adenoma, or metastases. Definitive diagnosis thus depends on histopathologic and immunohistochemical confirmation. The present case illustrates an important diagnostic pitfall. The initial hepatic biopsy at an outside institution was signed out as hepatocellular adenoma despite the complete absence of hepatocytic markers (HepPar-1, cytokeratin, CD10), which is entirely incompatible with that diagnosis. When an “adenoma” is entirely negative for all hepatocytic markers, an alternative diagnosis, including PEComa, must be actively considered and the biopsy repeated or reviewed at a center with expertise in rare mesenchymal tumors.

Radiologically, imaging features vary with tumor size, vascularity, and fat content. On PET-CT, FDG uptake is variable, reflecting metabolic heterogeneity, benign lesions may show low uptake, whereas malignant ones display intense uptake. Features suggesting malignancy include large size (> 5 cm), necrosis, hemorrhage, invasion of adjacent structures, and metastases.

Therapeutically, complete surgical resection remains the cornerstone of management and offers the best chance for long-term survival [19–20]. PEComas are generally resistant to conventional chemotherapy and radiotherapy, which makes systemic management particularly challenging. Chemotherapy regimens such as anthracycline- or gemcitabine-based combinations yield limited efficacy, with median progression-free survival (PFS) of about 3 months (Bourgmayer et al. 2021).

Given their molecular basis, targeting the mTOR pathway represents the most rational systemic approach. In a retrospective study, mTOR inhibitors achieved an overall response rate of 41% and a PFS of 9 months, compared with lower response rates to gemcitabine- (20%) and anthracycline-based (13%) regimens (Świtaj et al. 2021). Sirolimus is the most widely studied agent, though temsirolimus, everolimus, and nab-sirolimus (albumin-bound intravenous sirolimus) have also shown efficacy. Patients harboring TSC2 mutations respond better to sirolimus-based therapies than those with TSC1 mutations (Chen et al. 2016, Czarnecka et al. 2023). Sirolimus has also proven effective in related entities such as LAM and extrapulmonary LAM (Sobiborowicz et al. 2021). However, patients with TFE3-rearranged PEComas consistently show resistance to mTOR inhibitors. This is mechanistically explained by the distinct oncogenic pathway in this subset: TFE3 gene fusions drive tumor growth through overexpression of TFE3 transcription factor activity, a member of the MiT/TFE family, without engaging the TSC1/TSC2–mTORC1 axis. Because mTOR inhibitors act by suppressing mTORC1 hyperactivation downstream of TSC1/TSC2 loss, they have no relevant molecular target in TFE3-rearranged tumors. The clinical course of our patient including rapid multi-site progression despite three months of everolimus directly illustrates this lack of pathway overlap [24–25].

For mTOR-resistant disease, other strategies have been explored. VEGFR inhibitors such as bevacizumab, pazopanib, and sorafenib have shown modest activity, achieving a median PFS of 5.4 months (Liapi et al. 2021, Sanfilippo et al. 2019, Xu et al. 2020). Combination therapy with mTOR inhibitors and anti-estrogen agents has also shown promise (Baselga et al. 2012, Baselga et al. 2009, Boulay et al. 2005). Because estrogen and mTORC1 share regulatory crosstalk, exemestane plus sirolimus was evaluated in a small series of seven female patients with advanced PEComa who had progressed on mTOR therapy; 86% achieved disease control, with a median PFS of 7 months and median response duration of 11.1 months (Sanfilippo et al. 2020).

High PD-L1 expression has been documented in some PEComa specimens, providing a rationale for immunotherapy. In preclinical TSC-deficient mouse models, PD-1 and combined PD-1/CTLA-4 blockade demonstrated tumor regression. Clinically, Lattanzi et al. reported a near-complete response after two years of nivolumab in a patient with malignant epithelioid angiomyolipoma refractory to mTOR inhibition (Lattanzi et al. 2018).

Beyond immunotherapy, nab-sirolimus represents another promising strategy for overcoming mTOR inhibitor resistance. As demonstrated in the AMPECT trial (Wagner et al. 2021), the albumin-bound formulation achieves increased intratumoral drug uptake and more thorough mTOR pathway suppression compared with oral everolimus, translating into a confirmed 39% objective response rate with durable disease control. Notably, even patients who progressed on everolimus have shown substantial radiographic regression on nab-sirolimus, as documented by Kopparthy et al. (Kopparthy and Murphy 2021), emphasizing its potential in aggressive, high-grade PEComas.

Evidence on the use of radiotherapy remains conflicting. Most studies suggest inherent radio-resistance due to mTOR-mediated mechanisms (Nagata et al. 2010), though concurrent mTOR inhibition may enhance radiosensitivity (Willers et al. 2021). One case reported successful neoadjuvant stereotactic body radiation therapy (SBRT) facilitating resection of an unresectable hepatic PEComa.

In summary, this case adds to the limited but growing literature on TFE3-rearranged PEComa, a molecularly distinct subset characterized by aggressive clinical behavior and inherent resistance to mTOR-directed therapy. The case is notable for its synchronous hepatic and pulmonary presentation, the diagnostic delay introduced by an initial sampling error misclassified as hepatocellular adenoma, and the documentation of rapid multi-site progression (lung, lymph nodes, bone) despite everolimus in a resource-constrained setting. These features collectively reinforce the critical importance of molecular subtyping, and where feasible, FISH or NGS confirmation to identify TFE3-rearranged disease early, avoid ineffective mTOR inhibition, and guide transition to alternative strategies such as nab-sirolimus, anti-estrogen combinations, or immunotherapy.

Limitations

This case has several limitations. Molecular confirmation via FISH or NGS was not performed, as these tests were financially inaccessible to the patient; the diagnosis therefore rests on TFE3 immunohistochemistry in conjunction with the characteristic immunophenotype. Additionally, the initial hepatic biopsy was non-diagnostic due to a sampling error, contributing to diagnostic delay.

Author contributions

S.C. and T.D. contributed equally to this work and were involved in data collection, literature review, and drafting of the manuscript. M.E.T. assisted in manuscript writing and critical revision. G.F. contributed to clinical data acquisition. N.J. performed the histopathological analysis and provided the pathology interpretation. H.I.A. supervised the project, contributed to study conception and design, and critically revised the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript.

Funding

The authors state that they did not receive any financial assistance, grants, or other support while preparing this manuscript.

Data availability

All data generated or analyzed during this study are included in this published article. Additional details are available from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

The present study complies with the internationally accepted ethical standards. According to local regulations, this study did not require Institutional Review Board approval or consent to participate.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.