Materials and methods
This retrospective study adhered to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics committee of our hospital. Given the retrospective nature of the research, the requirement for informed consent was waived.
Patients
A retrospective analysis was performed on 4 patients with hepatic PEComa who were confirmed by surgical resection and biopsy at our hospital between November 2017 and August 2024. The inclusion criteria were as follows: all patients had complete clinical data, including blood biochemical analyses, tumor marker assessments, hepatitis virology evaluations, abdominal imaging studies, as well as pathological and immunohistochemical examinations. The exclusion criterion was incomplete imaging and clinical data.
Imaging and pathological examination
The CT scan was performed using a Philips Brilliance 64 iCT scanner. The scanning parameters were set as follows: tube voltage at 120 kV, tube current ranging from 200 to 400 mA, slice thickness and spacing of 1.0 mm, pitch between 0.984 and 1.375, and a rotation speed of 0.5 seconds per rotation. For the enhanced CT scan, a nonionic contrast agent, iodine hexylide (350 mg I/ml), was administered at a volume of 100–120 ml. The arterial phase was acquired approximately 35 seconds after injection, the portal phase around 70 seconds, and the delayed phase about 120 seconds. The scanning range covered from the apex of the diaphragm to the inferior border of the pubic symphysis.
The MR examination utilized a Siemens 3.0T MRI scanner with an 8-channel abdominal coil. The patient was placed in a supine position, and the scanning range extended from the diaphragm to the inferior margin of the liver. The contrast agents used were Gd-EOB-DTPA or Gd-DTPA, injected into the antecubital vein of the arm at a flow rate of 1.0 ml/s, with a dose of 0.025 mmol/kg. Subsequently, an equal volume of saline solution was injected at the same flow rate to flush the line. For both non-contrast and dynamic contrast-enhanced imaging, axial liver volume acceleration scans were conducted with a repetition time (TR) of 2.8 ms, an echo time (TE) of 1.2 - 1.3 ms, a flip angle of 20°, a field of view (FOV) of 380.0 mm × 380.0 mm, a slice thickness of 5 mm, and a slice gap of 1 mm. The contrast agent was administered at 20 seconds, 55 seconds, 2–5 minutes, and 20 minutes to define the arterial phase, portal vein phase, transitional phase, biliary phase, and hepatic phase, respectively.
All surgical specimens and biopsy tissues obtained from the patients underwent routine pathological examination and immunohistochemical staining.
Imaging analysis
Two experienced radiologists, who were blinded to the pathological results, jointly evaluated all imaging data. In case of any discrepancies, a consensus was reached through joint discussion. The evaluation included the lesion’s location, morphology, size, density/signal characteristics, enhancement pattern, and its relationship with adjacent vascular structures.
Discussion
PEComas are rare mesenchymal tumors, first described by Bonetti et al. in 1992 (4). They are characterized by a unique composition of vascular perivascular epithelioid cells with diverse morphological and immunohistochemical features. The PEComa family encompasses angiomyolipoma (AML), clear cell sugar tumor of the lung (CCST), lymphangioleiomyoma/lymphangioleiomyomatosis (LAM), and a group of immunohistochemically similar tumors, including primary extrapulmonary sugar tumor, clear-cell myomelanocytic tumor (CCMMT) of the falciform ligament/ligamentum teres, abdominopelvic sarcoma of PECs, and PEComa arising in various soft tissue and visceral sites (5, 6). PEComas can occur in many anatomical locations, but they predominantly arise in the uterus, retroperitoneum, abdominopelvic region, and gastrointestinal tract. Hepatic PEComas, in particular, are extremely rare (7).
Hepatic PEComa predominantly affects middle-aged women (8) and usually presents without distinctive clinical symptoms or signs, often being incidentally detected during routine physical examinations (9). Larger tumors may cause abdominal pain due to compression of adjacent tissues or result in rupture and hemorrhage. Unlike HCC, this condition is not associated with hepatitis or liver cirrhosis, and tumor markers are typically negative (8, 10). The cases in our study align well with these characteristics. All patients were female, with a median age of 55 years. One case was detected during a routine physical examination, another during an abdominal CT scan for vulvar cancer, one patient presented with right upper abdominal discomfort, and the last reported fatigue and weight loss. Hepatitis virus markers were negative in all cases; while two cases showed mild elevations in CA125 levels, other tumor markers remained within normal ranges.
Histologically, hepatic PEComa is mainly composed of proliferating epithelioid and spindle cells. The tumor cells are polygonal, with translucent cytoplasm containing eosinophilic particles, and thick-walled blood vessels are observable within the tumors. Epithelioid cells are radially arranged around these thick-walled blood vessels, and feather-like collagen fibers can be identified (11). Immunohistochemically, PEComa tumor cells exhibit features of perivascular epithelioid cell differentiation, similar to melanocytes, neuroendocrine cells, and smooth muscle cells. They commonly test positive for HMB-45, Melan-A, and SMA (11–13). Tumors with a predominantly epithelial composition tend to express melanocyte markers, whereas those with a spindle-shaped morphology often show myogenic cell markers (SMA is common, Desmin is less so) and lack hepatic markers such as Hep and LFABP. Among these, HMB-45 is the most sensitive diagnostic marker for PEComa. In our study, all four cases were positive for HMB-45 (+/++), Melan-A (+), and SMA (+/++), consistent with previous reports. Notably, the malignant liver PEComa case showed a Ki67 expression level exceeding 70%, significantly higher than the other three cases. Ki67, a protein involved in cell proliferation and expressed in all active cell cycle phases except G0, is located exclusively in the nuclei of proliferating cells. Its expression level is closely correlated with tumor grade and biological behavior (14). The Ki67 expression rate serves as a key indicator of early tumor cell proliferation, and as tumor cells continue to divide, increased Ki67 expression reflects higher pathological grades and malignancy (15).
The imaging characteristics of hepatic PEComa vary depending on the heterogeneity of tissue components (10), and neither CT nor MRI shows high specificity for diagnosis (3, 16, 17). On CT, it typically appears as a low or mildly hypodense mass; on MRI, it shows a slightly hypointense signal on T1-weighted images (T1WI), a mildly hyperintense signal on T2-weighted images (T2WI), and high signal intensity on diffusion-weighted imaging (DWI), usually with well-defined margins (18). The presence of fat within a hepatic lesion is a notable feature, strongly suggesting a diagnosis of hepatic PEComa (19). MRI is more sensitive than CT in detecting fat components, especially with the aid of fat suppression techniques (20). However, the fat content in tumors can range from 10% to 90% (21), and for tumors with low fat content, both CT and MRI may fail to clearly demonstrate this feature, posing diagnostic challenges. In our four cases, all had minimal fat content, and no obvious fat components were detected on CT or MRI. Three cases showed homogeneous density/signal, while the malignant case exhibited heterogeneous density with extensive areas of low-density necrosis.
The CT and MR enhancement patterns of hepatic PEComa share common features, characterized by intense arterial phase enhancement and thickened vessels within and around the lesion (16, 17), sometimes accompanied by peripheral draining veins (21). Gao X et al. (22) reported two enhancement patterns, “fast in and fast out” and “fast in and slow out”, in 11 cases of hepatic PEComa. Nie P et al. (17) described four enhancement patterns in 22 cases: arterial phase enhancement with rapid washout (n= 9), arterial phase enhancement with slow washout (n= 7), arterial phase enhancement with persistent late-phase enhancement (n= 4), and unspecified heterogeneous enhancement (n= 2). Literature also indicates that hepatic PEComa shows low signal intensity during the hepatobiliary phase, which corresponds to its pathological features (23). In our study, all four hepatic PEComa cases had abundant vascularity and prominent arterial phase enhancement. Two cases showed vascularity both at the periphery and within the tumor. One case showed early visualization of the middle hepatic vein during the arterial phase, suggesting the presence of a hepatic arteriovenous fistula. Two cases showed high arterial phase enhancement with rapid portal phase washout, and one of these lesions exhibited a “pseudo-capsule” effect. Two cases had high arterial phase enhancement with slow washout, and one case showed low signal intensity during the hepatobiliary phase.
Although most hepatic PEComas are benign, 4% to 10% of cases are malignant (24). Folpe et al. (25) first proposed diagnostic criteria for potentially malignant PEComas, including tumor size >5cm, infiltration of surrounding tissues, vascular invasion, high nuclear grade, high cellularity, necrosis, and a mitotic figure >1/50 high power field. Based on these criteria, PEComas are classified into three categories: (1) malignant (meeting two or more of the above criteria); (2) benign (meeting none of the criteria); and (3) with malignant potential (characterized by a tumor maximum diameter > 5 cm or nuclear hyperplasia) (26). In our study, cases 1 and 2 were classified as benign. Case 3, with the largest lesion diameter of 5.2 cm, significant atypia in several tumor cells, and individual nuclear divisions, was diagnosed as PEComa with malignant potential, after three months of interventional treatment, follow-up showed no significant tumor growth. Case 4 was diagnosed as malignant hepatic PEComa, which met the above malignant diagnostic criteria, during the three-month postoperative follow-up, the number and size of the liver lesions in this patient increased, which confirmed ntrahepatic metastasis of PEComa.
The differential diagnosis of hepatic PEComa is relatively straightforward when fat tissue is present in the lesion, increasing the likelihood of diagnosing it as either hepatic PEComa or angiomyolipoma (AML) (21, 27). However, the absence of fat makes preoperative diagnosis difficult, often leading to misdiagnosis as HCC, HCA, or FNH. Misdiagnosis as primary HCC is the most common (28). In our cohort, three cases were misdiagnosed as HCC, and one as a metastatic tumor. HCC predominantly affects males, is often associated with a history of hepatitis B or C and liver cirrhosis, and typically shows elevated AFP levels. It exhibits intense arterial phase enhancement followed by rapid washout in the portal and delayed phases, and hepatic portal vein thrombus formation is common. HCA mainly occurs in young women, often related to the use of contraceptive pills or steroid medications, and frequently presents with intra-tumoral hemorrhage and necrosis. FNH more common in middle-aged and younger women, lacks a capsule, shows rapid inflow enhancement with gradual outflow enhancement, may have central star-shaped scars with delayed enhancement, and lesions usually show equal or slightly increased signal intensity in the hepatobiliary phase.
Surgical resection is the preferred and effective treatment for primary hepatic PEComa (29). However, due to the limited number of retrospective case studies, a standardized treatment protocol has not been established. Sanfilippo R et al. (30) suggested that mTOR inhibitors may be effective for advanced or metastatic PEComa patients, while Kirste S et al. (31) proposed stereotactic body radiation therapy as a potential treatment option. Guan H et al. (32) also reported promising clinical outcomes with interventional therapy. In our study, two cases underwent surgical resection, one case was successfully treated with interventional therapy, and one case was diagnosed by biopsy without subsequent specific treatment.
Our study has several limitations. First, as a retrospective study, it was subject to selection and reporting biases. Second, the sample size was small, with only four cases from a single center. Future multi-center studies with larger sample sizes are needed to further validate our findings.
In conclusion, hepatic PEComa is a rare tumor that predominantly affects middle-aged women and lacks typical clinical manifestations. Laboratory tests usually do not reveal specific abnormalities. Although CT and MRI play a role in preoperative diagnosis, due to the tumor’s multi-directional differentiation, misdiagnosis rates remain high. When a lesion shows marked arterial phase enhancement with thickened and tortuous vessels, and there are no specific findings in the clinical history and laboratory tests, hepatic PEComa should be considered. A definitive diagnosis ultimately relies on pathological and immunohistochemical examinations.