Angiomyolipoma (AML) is a rare mesenchymal tumor that most frequently occurs in the kidney and was first described in the literature in 1951. In 1992, Bonetti et al. introduced the concept of the perivascular epithelioid cell, providing new insights into the histogenesis of AML (1). However, its primary hepatic counterpart, specifically classified as the epithelioid variant (hepatic epithelioid angiomyolipoma, HEAML), is exceedingly uncommon. Current reports on HEAML remain limited both domestically and internationally, with the majority presented as isolated case reports. Epithelioid angiomyolipoma was first formally recognized as a distinct entity in the 2004 WHO Classification of Renal Tumours (2). According to the current WHO Classification of Digestive System Tumors (5th edition, 2019), hepatic angiomyolipoma belongs to the perivascular epithelioid cell neoplasm (PEComa) family and is categorized as Angiomyolipoma, Angiomyolipoma of uncertain malignant potential, or Malignant PEComa based on histological features (3). The term “epithelioid angiomyolipoma” (EAML) continues to be used to describe tumors with predominant epithelioid morphology. Hepatic epithelioid angiomyolipoma (HEAML) is a rare mesenchymal neoplasm with potential for malignant behavior.

Owing to the absence of characteristic clinical manifestations and non-specific features on conventional imaging, the preoperative diagnosis of HEAML is challenging and associated with a high misdiagnosis rate. It is often misidentified as other hepatic tumors, such as hepatocellular carcinoma (HCC), focal nodular hyperplasia (FNH), or hepatic adenoma. This study was designed to test the hypothesis that the clinicopathological and imaging features of HEAML are non-specific, leading to a high rate of preoperative misdiagnosis. By retrospectively analyzing the clinical data of 27 HEAML patients from our institution—including their imaging presentations, pathological characteristics, and management processes—we aim to summarize its clinicopathological features and provide insights to facilitate more accurate diagnosis and optimized treatment strategies.

Primary hepatic epithelioid angiomyolipoma (HEAML) is a rare mesenchymal tumor belonging to the perivascular epithelioid cell tumor (PEComa) family, a group of neoplasms that also includes angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), and clear cell sugar tumor (CCST) of the lung (4). The nomenclature for hepatic PEComa family tumors has evolved since epithelioid angiomyolipoma was first recognized in renal tumors. The current WHO classification employs a risk-stratified approach, categorizing these tumors based on histological features rather than solely on morphological subtyping. While the term “epithelioid angiomyolipoma” remains widely used in clinical practice, current evidence emphasizes comprehensive histopathological assessment for accurate risk prediction. Although initially considered benign, a growing body of evidence now recognizes that HEAML, particularly the epithelioid-predominant variant, possesses malignant potential, creating significant diagnostic and therapeutic challenges (5, 6). Our study, which presents a series of pathologically confirmed HEAML cases, corroborates these findings and highlights the non-specific clinicopathological features that often lead to preoperative misdiagnosis, most commonly as hepatocellular carcinoma (HCC) (7, 8).

Epidemiological studies on hepatic epithelioid angiomyolipoma (HEMAL) indicate that this tumor is rare among all hepatic neoplasms, with a low annual incidence. It exhibits a significant gender predilection, with females accounting for 75–85% of cases, resulting in a male-to-female incidence ratio of approximately 1:4 (9). In the present study, the proportion of female patients reached 88.9% (24/27), further corroborating this characteristic. This disparity is hypothesized to be associated with fluctuations in estrogen levels, which may also explain the predilection of this disease for women of childbearing age (10). Existing literature reports that the age of onset for patients with hepatic angiomyolipoma primarily clusters between 30 and 50 years, with a mean age of 42 years (9, 11). Although the age distribution in our cohort was broad (range: 17–75 years), it was predominantly concentrated within the 34–52-year age range, with a mean age of 44.18 ± 13.15 years. This age distribution aligns with previous reports. HEMAL typically lacks specific clinical manifestations. A substantial majority of patients are asymptomatic, with the tumor often being discovered incidentally during imaging examinations performed for routine health check-ups or other reasons. Among symptomatic patients, a smaller subset may present with non-specific symptoms such as right upper quadrant discomfort, abdominal distension, and anorexia, which are generally attributable to the mass effect of the tumor (12). Additionally, approximately 10% of patients may have concurrent systemic diseases such as tuberous sclerosis complex, suggesting a potential link to genetic background and immune dysregulation. This association underscores the importance of vigilance for potential comorbidities during clinical evaluation (13). In our cohort of 27 HEMAL patients, 81.4% (22/27) were asymptomatic, while only 18.5% (5/27) exhibited various degrees of non-specific symptoms like abdominal pain and distension, consistent with prior reports. Overall, the non-specific clinical presentation and absence of characteristic abdominal signs contribute to the diagnostic challenge of HEMAL, resulting in high rates of misdiagnosis and missed diagnosis (14). No specific tumor markers have been definitively linked to HEMAL. In this study, only a minority of patients exhibited mild abnormalities in tumor markers: elevated alpha-fetoprotein (AFP) was observed in 1 case, elevated carbohydrate antigen 125 (CA125) in 1 case, elevated carbohydrate antigen 19–9 (CA19-9) in 1 case, and elevated protein induced by vitamin K absence or antagonist-II (PIVKA-II) in 1 case. Other common hepatic tumor markers, such as carcinoembryonic antigen (CEA), showed no significant abnormalities. With the exception of one patient who exhibited a doubling of PIVKA-II levels, all other observed marker elevations were mild to moderate and did not reach the typically extreme levels seen in hepatocellular carcinoma or cholangiocarcinoma. No concurrent diseases that could explain these marker elevations were present in these patients. Although these elevations somewhat complicated preoperative assessment, they were not considered diagnostic due to their non-diagnostic levels and atypical imaging findings, and thus were not used as definitive diagnostic criteria.

Preoperative diagnosis remains a significant hurdle due to non-specific imaging features. HEAML often mimics other hypervascular liver tumors, especially HCC. On contrast-enhanced imaging, HEAML typically shows marked arterial enhancement with subsequent washout, a pattern highly characteristic of HCC (15, 16). While the presence of intratumoral fat is a strong indicator of angiomyolipoma, it is frequently absent in epithelioid-predominant variants (lipid-poor AML), further complicating the diagnosis (17). Advanced imaging techniques, such as gadoxetic acid-enhanced MRI and contrast-enhanced ultrasound (CEUS), may offer additional clues but often fail to provide a definitive distinction from HCC or other entities like focal nodular hyperplasia (FNH) and hepatic adenoma (16, 18, 19). A substantially correct preoperative diagnosis was established by imaging in merely one case (3.6%) in this study, with the remaining cases being misdiagnosed or indeterminate. Consequently, a definitive diagnosis frequently relies on postoperative histopathology.

The histological features of hepatic epithelioid angiomyolipoma (HEAML) constitute the cornerstone of its pathological diagnosis. The typical presentation is characterized by triphasic differentiation, with the tumor tissue composed of three components: abnormal blood vessels, epithelioid smooth muscle cells, and adipocytes (20). On histological sections, HEAML typically exhibits polygonal epithelioid cells with abundant eosinophilic cytoplasm and prominent nucleoli, reflecting their metabolically active biological nature (21). In the present study, pathological sections from all 27 patients demonstrated this classical epithelioid cell morphology, consistent with previous literature. Notably, malignant HEAML may also present with specific histological variations. Luo Rongkui et al., in their clinicopathological analysis of 182 HEAML patients, summarized that features such as tumor size ≥ 10 cm, multifocal lesions, tumor invasion of the portal area, tumor necrosis, intravascular tumor thrombi, and the presence of tumor giant cells within the lesion may be closely associated with tumor recurrence or metastasis. Immunohistochemistry is the cornerstone of a definitive HEAML diagnosis. The diagnosis is confirmed by the characteristic co-expression of myoid markers (e.g., Smooth Muscle Actin, SMA) and melanocytic markers (HMB-45 and Melan-A) (22, 23). Our study confirmed consistent positivity for HMB-45 and/or Melan-A in all cases, aligning with reports that these are the most sensitive and specific markers for the PEComa family. This immunoprofile is critical for the differential diagnosis, particularly in distinguishing HEAML from its primary mimic, HCC, which is consistently negative for these melanocytic markers (24). The combined use of HMB-45 and Melan-A approaches 100% sensitivity for renal AMLs and is recommended in the workup of any suspected PEComa (23).

The core challenge of HEAML lies in its potential for aggressive behavior (25). This malignant potential is not merely a theoretical concern; a large literature review by Liu et al. (5) documented a recurrence or metastasis rate of approximately 10%, a notable figure for a tumor once considered benign. This malignant potential is underscored by specific histopathological features. Recent studies have proposed quantitative risk stratification systems incorporating multiple histopathological parameters to better predict clinical outcomes. The Folpe criteria, originally developed for extra-renal PEComas, provide a framework for risk stratification (26). Malignant PEComas are defined by the presence of two or more worrisome features, including large tumor size (> 5 cm), high mitotic rate, necrosis, and vascular invasion. In our series, several cases exhibited features such as necrosis and high nuclear grade, reinforcing the notion that HEAML is not uniformly benign and requires careful pathological assessment and long-term surveillance (27). The epithelioid component itself is a key factor; tumors composed predominantly of epithelioid cells are more likely to exhibit aggressive behavior compared to classic triphasic angiomyolipomas (28). The diagnostic criteria for HEAML vary in the literature, with epithelioid cell cutoffs ranging from 10 to ≥ 80% (29). Recent studies suggest that higher thresholds (≥ 80% epithelioid cells with minimal adipose tissue) may better correlate with malignant potential (30).

The understanding of the malignant potential of hepatic epithelioid angiomyolipoma (HEAML) has evolved beyond clinicopathological observations, progressively delving into the interplay among its cellular origins, molecular regulation, and tumor microenvironment. A hallmark feature of HEAML is its strong expression of melanocytic markers, such as HMB-45 and Melan-A, suggesting a probable origin from perivascular epithelioid cells (PECs). PECs are characterized by their bidirectional differentiation potential, giving rise to both smooth muscle and melanocytic lineages, which provides a theoretical basis for the potential malignant transformation observed in HEAML (5). At the molecular level, Studies have shown that a significant subset of PEComas harbor inactivating mutations in the TSC1 or TSC2 tumor suppressor genes (31). These mutations lead to the constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway, a key regulator of cell growth and proliferation (32). This understanding provides a strong rationale for the use of mTOR inhibitors, such as sirolimus and everolimus, in managing advanced, unresectable, or metastatic PEComas. Several studies have demonstrated the clinical activity and efficacy of these agents, establishing them as a standard of care in the systemic treatment of malignant PEComas (33). Furthermore, the malignant progression of HEAML is often accompanied by increased genomic instability. In addition to the aforementioned TSC gene mutations, multiple studies have demonstrated that abnormal expression of the P53 protein may be associated with the potential malignant behavior of HEAML (34), suggesting that its malignant transformation may involve the synergistic dysregulation of multiple pathways. Although accumulating evidence indicates a propensity for malignant transformation, well-defined diagnostic criteria for malignancy have yet to be established, posing challenges for clinical risk assessment. To address this diagnostic ambiguity, Folpe et al. (26) introduced in 2005 a three-tiered classification system (“benign,” “uncertain malignant potential,” and “malignant”) for perivascular epithelioid cell tumors (PEComas), based on a constellation of histopathological features. Key prognostic parameters in this system include tumor size exceeding 5 cm, infiltrative growth pattern, significant nuclear atypia, the presence of tumor necrosis, vascular invasion, and a mitotic index of ≥ 1 per 50 high-power fields (HPF). This provides an important framework for morphological evaluation. The malignant potential of HEAML is a biological process driven by cellular origin characteristics and specific molecular genetic events, ultimately manifesting as a series of identifiable histopathological features. A systematic assessment must go beyond mere morphological description and progress toward an integrated pathological diagnostic model that incorporates immunohistochemistry, proliferative activity, and key molecular markers. This approach enables more precise risk prediction and individualized management. In the future, multi-omics research holds promise for further elucidating the key driving mechanisms of malignant transformation and discovering novel therapeutic targets.

Given the malignant potential, surgical resection is the mainstay of treatment for localized HEAML (35, 36). Complete surgical excision offers the only potential for cure and is recommended for resectable tumors, especially if they are large, symptomatic, or if malignancy cannot be excluded (35). For patients with unresectable or metastatic disease, mTOR inhibitors are the primary systemic therapy option (32, 33). The prognosis after treatment appears to be heterogeneous. Despite successful resection, the risk of recurrence and metastasis necessitates long-term postoperative follow-up. Studies have reported metastases occurring months to years after initial surgery, emphasizing the need for vigilant surveillance (27, 35). The findings from a large 26-case series by Zhang et al. showed an excellent prognosis with no recurrence or metastasis after a median follow-up of 62.5 months, suggesting that complete resection can be highly effective (37). However, this contrasts with other reports documenting a clear risk of disease progression, highlighting the variable natural history of HEAML and reinforcing the importance of vigilant follow-up.

Despite the contributions of this study, several limitations should be noted. First, as a single-center retrospective analysis, the findings are inevitably susceptible to selection bias and information bias. All included cases were derived from a tertiary medical center, which may have resulted in the overrepresentation of patients with more complex conditions or those requiring surgical intervention. Consequently, the sample may not fully reflect the true disease spectrum of all HEAML patients in the broader community, particularly those who are asymptomatic and do not seek medical care. Second, given the rarity of hepatic HEAML, the present study involved a small sample size from a single institution, which may limit the generalizability of the results. Further investigations with larger, multicenter cohorts are necessary to obtain more robust evidence. Finally, due to the retrospective nature of this study, follow-up duration and protocols were not standardized. Although surgical resection demonstrated favorable short-term outcomes, the lack of long-term, uniformly collected follow-up data constrains our ability to accurately evaluate the risks of late recurrence and metastasis, as well as the true prognostic value of markers such as Ki-67. Future research should adopt prospective, multicenter designs and establish long-term follow-up registries to address these limitations.

Hepatic epithelioid angiomyolipoma (HEAML) is a rare entity whose non-specific clinical and radiological features present a significant diagnostic challenge. This study of 27 pathologically confirmed cases quantitatively underscores this challenge, revealing a preoperative diagnostic accuracy of only 3.7%, with frequent misdiagnosis as hepatocellular carcinoma. Our findings confirm that the definitive diagnosis relies on histopathology, with the consistent co-expression of HMB-45 and Melan-A being the key diagnostic feature.

Based on these findings, we conclude that a high index of suspicion for HEAML is clinically warranted for any hypervascular liver lesion, particularly in female patients without a background of chronic liver disease. Given the unreliability of imaging for definitive characterization, early consideration of percutaneous biopsy should be integrated into the diagnostic algorithm for such atypical cases. As complete surgical resection remains the standard of care due to the tumor’s malignant potential, this heightened clinical awareness is crucial for guiding appropriate management and avoiding potentially incorrect therapeutic pathways.