Liver Transplantation After Prolonged Nab-Sirolimus Therapy for Unresectable Hepatic Perivascular Epithelioid Cell Tumor With Bilobar Involvement

ABSTRACT

Primary hepatic perivascular epithelioid cell tumor (PEComa) is rare, and management of unresectable disease is not established. A 47-year-old woman had an 8-cm central hepatic PEComa bridging both lobes with tuberous sclerosis complex 2 alterations. She received albumin-bound sirolimus for 26 months with modest size reduction but durable stability, enabling listing with a nonstandard model for end-stage liver disease exception. She underwent right trisegment orthotopic liver transplantation, and the explant showed a well-circumscribed PEComa without vascular invasion or additional lesions. This case highlights prolonged nab-sirolimus as a bridge to transplantation in selected patients with favorable tumor biology.

INTRODUCTION

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms with perivascular epithelioid cell morphology and coexpression of melanocytic and smooth muscle markers.^1,2 A 2025 systematic review of primary hepatic PEComa identified 281 adult cases (145 studies) and reported liver transplantation in only 1 patient (0.4%).³ Imaging is often nondiagnostic; lesions commonly show arterial hyperenhancement and can mimic hepatocellular carcinoma or hepatic adenoma.^3–9 Nab-sirolimus is approved for adults with locally advanced unresectable or metastatic malignant PEComa and provides a systemic option when curative resection is not feasible.^10,11 We report an unresectable bilobar hepatic PEComa treated with prolonged nab-sirolimus as bridging therapy to orthotopic liver transplantation (OLT).

CASE REPORT

A 47-year-old woman with microscopic hematuria underwent a computed tomography (CT) urogram that incidentally demonstrated an 8-cm central hepatic mass. She had no chronic liver disease. Three months later, magnetic resonance imaging (MRI) confirmed a segment 8 lesion bridging the left and right lobes measuring 7.3 cm × 6.0 cm without cirrhosis or extrahepatic disease and was initially interpreted as adenoma. Alpha-fetoprotein and carbohydrate antigen 19-9 were normal.

Six months after MRI, ultrasound again confirmed a heterogeneous mass. Ultrasound-guided core biopsy demonstrated epithelioid cells with eosinophilic cytoplasm and prominent vessels (Figure 1). Immunohistochemistry was diffusely positive for HMB-45 and smooth muscle actin (Figure 1) and positive for Melan-A and TFE3 (not shown), with focal desmin positivity. Next-generation sequencing identified 2 pathogenic tuberous sclerosis complex 2 (TSC2) variants (p.G654fs and c.25445+1G>A).

Figure 1.

Histopathology of hepatic perivascular epithelioid cell tumor. (A) Core biopsy shows epithelioid cells with prominent vasculature (hematoxylin and eosin, ×40). Immunohistochemistry demonstrates diffuse positivity for (B) HMB-45 and (C) smooth muscle actin (×40). (D) Explant shows tumor in close proximity to hepatic vein without vascular invasion (hematoxylin and eosin, ×40).

Two months after biopsy, multidisciplinary tumor board deemed resection infeasible because the mass crossed the midline, involved segments 7, 8, and 4A, and abutted major hepatic veins and the retrohepatic inferior vena cava. Systemic therapy with nab-sirolimus (FYARRO; Aadi Bioscience, Pacific Palisades, CA) was initiated. At cycle 3, CT showed mild reduction, and after 6 cycles, maximal diameter decreased by 28%. Nab-sirolimus was continued for 36 cycles over 26 months.

Approximately 1 year after cycle 3 (cycle 18), CT revealed 2 subcentimeter arterially enhancing foci (7.8 and 9.0 mm) near the dominant mass. These remained unchanged for ∼18 months and were managed as indeterminate nodules; biopsy was not pursued given size and prolonged stability. The dominant tumor remained stable but unresectable.

Because laboratory model for end-stage liver disease (MELD) score remained low despite ongoing risk of tumor progression and lack of alternative curative options, the transplant program pursued a nonstandard MELD exception pathway with documentation of biopsy-proven diagnosis, sustained disease control on systemic therapy, and absence of extrahepatic spread. The exception was approved after review by the National Liver Review Board.¹²

After 36 cycles (approximately 3 years after index presentation), nab-sirolimus was held 7 months before transplant to reduce wound-healing risk. Pretransplant CT demonstrated stable disease with the dominant lesion measuring 6.7 cm × 4.1 cm × 5.3 cm without new hepatic or extrahepatic lesions (Figure 2). She underwent deceased-donor right trisegment OLT. To optimize oncologic clearance, the retrohepatic inferior vena cava and hepatic veins were resected en bloc with caval replacement.

Figure 2.

Contrast-enhanced computed tomography demonstrates a centrally located hepatic mass bridging the left and right lobes. (A) Axial arterial phase image shows arterial hyperenhancement (arrows). (B) Delayed phase axial image shows persistent enhancement/near isoattenuation.

Explant evaluation revealed a well-circumscribed 8.0 cm × 7.5 cm × 4.0-cm mass. No additional lesions corresponding to the subcentimeter arterially enhancing foci were identified. Microscopy demonstrated epithelioid cells with prominent vasculature without vascular invasion, necrosis, or increased mitotic activity (Figure 1). Background liver showed no fibrosis.

Post-transplant immunosuppression consists of tacrolimus and sirolimus. At 3-month follow-up, she has stable graft function and no radiographic recurrence.

DISCUSSION

Hepatic PEComas share the characteristic histologic and immunophenotypic profile of PEComas, with epithelioid cells arranged around a vascular network and coexpression of melanocytic and smooth-muscle markers.^1–3,6 Despite its size, this tumor lacked necrosis or vascular invasion, showed no increased mitotic activity, and lacked marked cytologic atypia, meeting only one Folpe worrisome feature (size >5 cm) and supporting uncertain malignant potential (intermediate risk).^13,14

Tuberous sclerosis complex 1 and 2 (TSC1/TSC2) alterations with mechanistic target of rapamycin (mTOR) pathway activation are recognized drivers in conventional PEComas and justify mTOR inhibition.^1,2 Nab-sirolimus is FDA-approved for malignant PEComa and has produced durable responses; other mTOR inhibitors and neoadjuvant sirolimus have also shown benefit.^10,11,15,16 In this patient, nab-sirolimus yielded long-term stability rather than major shrinkage.

Analogous to hepatocellular carcinoma (HCC) downstaging, sustained stability without extrahepatic spread served as a surrogate for favorable biology. In HCC, bridging/downstaging uses response and a defined period of radiographic stability as a test of time to select lower-recurrence tumors beyond standard criteria.¹⁷ Although PEComa lacks standardized radiographic downstaging criteria, applying a similar biology-based selection principle may help identify candidates who can benefit from transplantation.

The 2 subcentimeter enhancing foci remained stable for 18 months without extrahepatic spread and were not identified on explant, supporting indeterminate nodules rather than uncontrolled multifocal disease. A fusion-defined subset with TFE3 rearrangements may lack TSC2 alterations; here, TFE3 immunoreactivity coexisted with pathogenic TSC2 variants, and staining alone does not establish rearrangement.^18,19

For localized hepatic PEComa, resection is preferred, but very large, centrally located, or vascularly involved tumors may be unresectable by hepatectomy.^3,4,6–8 In this case, the bilobar central mass abutted major hepatic veins and portal inflow, making conventional resection prohibitive and ex vivo resection with autotransplantation high risk. Reports of bridging an anatomically unresectable hepatic PEComa to OLT with prolonged nab-sirolimus remain exceedingly limited.^3,20

Because MELD reflects hepatic dysfunction rather than tumor-related waitlist risk, nonstandard MELD exceptions may be needed for unresectable liver-confined neoplasms in patients with preserved liver function.¹² Stable disease on targeted therapy plus favorable histology and multidisciplinary review may justify listing even without dramatic radiographic response.

PEComa should remain in the differential diagnosis for large hypervascular hepatic lesions mimicking adenoma or hepatocellular carcinoma, and early molecular profiling may identify TSC1/TSC2 alterations supporting mTOR inhibition and refining risk.^1–3,6,9 Peritransplant mTOR planning is important: nab-sirolimus was held preoperatively to mitigate wound-healing complications, and maintenance tacrolimus plus sirolimus was used post-transplant to maintain mTOR inhibition, offering theoretical antineoplastic benefit in mTOR-activated tumors.^1,2 Although evidence remains limited, this case illustrates how integrating tumor biology with transplant strategy can support individualized decision-making for rare hepatic neoplasms.

DISCLOSURES

Author contributions: Study concept and design: AJ Cruz, JA Kahn. Drafting of the manuscript: AJ Cruz, D. Russell, JA Kahn. All authors participated in data acquisition and analysis, critical revision of the manuscript and approved the final version to be submitted. JA Kahn is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

ABBREVIATIONS:

CT

computed tomography

FDA

U.S. Food and Drug Administration

HCC

hepatocellular carcinoma

HMB-45

human melanoma black 45

MELD

model for end-stage liver disease

MRI

magnetic resonance imaging

mTOR

mechanistic target of rapamycin

OLT

orthotopic liver transplantation

PEComa

perivascular epithelioid cell tumor

TFE3

transcription factor E3

TSC1

tuberous sclerosis complex 1

TSC2

tuberous sclerosis complex 2