Introduction

Perivascular epithelioid cell tumors (PEComas) are very rare mesenchymal neoplasms composed of perivascular epithelioid cells expressing both smooth muscle and melanocytic markers. They can arise in various sites, including angiomyolipomas, clear cell tumors of the lung, and lymphangioleimyomas. Among extrarenal locations, the genital tract is the most prevalent, constituting approximately 25% of all PEComas, with the uterine corpus being the predominant site [1, 2].

On the basis of histological criteria, the 2020 World Health Organization (WHO) classification define PEComa with uncertain malignant potential as a tumor presenting less than three worrisome pathologic features including the tumor size, necrosis, vascular invasion, and mitotic count [3, 4].

Owing to the scarce number of reported cases in literature, standard diagnostic and management procedure have not been well established and remain challenging. The lack of information emphasizes the necessity of multicentric research, a global PEComa registry, and case series reporting standards to improve clinical and pathological data.

Ongoing research is essential to better understand their pathogenesis and guide treatment strategies.

CASE presentation

We present the case of a 38 year-old north African non-smoking woman referred to our clinic with a diagnosis of uterine PEComa of uncertain malignant potential. There were no significant personal or family medical histories. Married for 5 years, the patient experienced primary infertility. An ultrasound examination performed in a local hospital revealed an intra-cavity polypoid mass that was misdiagnosed as a subserous myoma. No further imaging was thereby carried out.

She underwent abdominal myomectomy with resection of the uterine polyp. Final histopathological analysis reported the polypoid mass as mesenchymal epithelioid cell neoplasm. The tumor cells showed abundant focally eosinophilic or granular cytoplasm with centrally located round or oval nuclei associated with a stromal hyalinization. The mitotic index was less than 1/50 high power field (HPF), no necrosis nor vascular invasion were noted. (Fig.1). Immunohistochemistry showed positive staining for Desmin, Cadesmon, and Human Melanoma Black45 (HMB45) (Figure 2). The tumor cells tested negative for MelanA and inhibin. The tumor’s size, very low mitotic activity, and absence of vascular invasion and necrotic areas supported the diagnosis of uterine PEComa with uncertain malignant potential. The patient was then referred to our clinic.

Fig. 1
figure 1

Conventional perivascular epithelioid cell tumor (perivascular epithelioid cell tumor): a nests and sheets of tumors cells surrounded by delicate thin-walled vessels (hematoxylin and eosin × 200), b noncohesive epithelioid cells with clear to eosinophilic granular cytoplasm and slightly atypical, finely nucleolated nuclei (hematoxylin and eosin × 400).

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Fig. 2
figure 2

Immunohistochemical staining. Tumor cells express: a human melanoma black 45 (×200), b desmin (×200) and c cadesmon (×100)

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Postoperative enhanced magnetic resonance imaging (MRI) was requested to guide and direct subsequent management, which revealed postoperative changes without an evolving tumor process.

Given the patient’s expressed desire for fertility preservation, we have chosen a conservative treatment approach. The patient has been regularly monitored for 6 months now with a clinical examination and MRI every 3 months. She is currently in good health, showing no signs of local, regional, or distant recurrence.

Discussion

Perivascular epithelioid cell tumors (PEComas) are a group of tumors characterized by epithelioid cells displaying abundant clear to eosinophilic cytoplasm and immunoreactivity to human melanoma black 45 (HMB45). According to the World Health Organization (WHO), the PEComa family encompasses angiomyolipoma (AML), clear cell sugar tumor of the lung (CCST), lymphangioleiomyomatosis (LAM), clear cell myomelanocytic tumor (CCMMT), and uncommon clear cell tumors found in the pancreas, rectum, serosa, uterus, vulva, thigh, and heart [5]. The gynecologic tract is the most frequently affected site, with the uterus accounting for the majority of cases [5].

Several algorithms have been developed to predict the malignant potential of these tumors. Initially, Folpe et al. [6] and Schoolmeester et al. [7] assessed a series of gynecologic and soft tissue PEComas on the basis of various histologic characteristics. They defined three categories according to the number of high-risk criteria present, which included tumor size equal to or greater than 5 cm, infiltrative growth pattern, high nuclear grade cellularity, mitotic rate > 1/50 high-power field (HPF), tumor cell necrosis, and vascular invasion. Tumors exhibiting a single high-risk criterion are categorized as having uncertain malignant potential.

Several years later, Bennett [8] suggested eliminating the benign category after a case previously categorized as benign recurred. Consequently, the criteria for diagnosing malignant PEComa were redefined to require the presence of at least three features.

This classification was acknowledged by the WHO classification in 2020. The present case was categorized as a uterine PEComa with uncertain malignant potential due to the absence of any histological worrisome features [8].

To date, approximately 100 cases of uterine PEComas have been reported in the English literature [9]. The mean age of patients was around 40 years [10], although it can be observed in all age groups.

The clinical presentation of this entity is typically nonspecific, often involving symptoms, such as abdominal pain, uterine bleeding, or incidental discovery, on imaging for small, asymptomatic lesions, as in our case. Hemoperitoneum and/or uterine rupture are uncommon presentations, particularly during pregnancy [11].

The radiographic appearance of uterine PEComa can vary, presenting as a large heterogeneous mass or as a small benign smooth cell neoplasm, which is often mistaken for a uterine fibroid. In a literature review, Giannella et al. [12] studied 11 scientific articles referring to the ultrasound appearance of uterine PEComa, encompassing 19 patients. They defined certain imaging characteristics that could be helpful in suspecting malignancy, including central necrosis, irregular margins, a high color Doppler score, and heterogeneous echogenicity. However, the positive predictive value of these traits is modest, as they may also be present in benign lesions [13]. Magnetic resonance imaging (MRI) findings are also nonspecific, with reported appearances being diverse [2]. Uterine PEComa may present as a well-defined heterogeneous mass, either single or multiple, with irregular or lobulated shapes.

Therefore, accurately characterizing PEComa before surgery solely on the basis of imaging features remains challenging. Mass excision is the cornerstone of diagnosis and treatment for these lesions. In our case, the patient underwent resection of the polypoid lesion, with no radical treatment planned owing to the patient’s urgent desire for fertility preservation.

In gross examination, uterine PEComas typically present as well-circumscribed lesions, occasionally appearing polypoid or pedunculated [8]. Morphologically, the cells are characterized by clear to eosinophilic and granular cytoplasm, with centrally located, round to oval nuclei. Immunohistochemistry plays a crucial role in confirming the diagnosis. Perivascular epithelioid cells are typically positive for melanocytic markers, such as HMB-45 and melan-A, as well as smooth muscle markers, including smooth muscle actin, desmin, h-caldesmon, pan-muscle actin, muscle myosin, and calponin [8].

From a molecular perspective, 9–10% of these tumors are associated with tuberous sclerosis [6]. However, even in sporadic cases, the most common genetic alterations involve the loss of heterozygosity of the TSC2 gene located at 16p13.3, or less commonly, TSC1 at 9q34. A small subset of PEComas exhibits rearrangement of the TFE3 gene [14]. [15].

The differential diagnosis of uterine PEComa includes all mesenchymal neoplasms presenting with epithelioid features, such as endometrial stromal sarcoma, clear cell sarcoma, epithelioid smooth muscle neoplasm, and gastrointestinal stromal tumors. Morphological features and immunohistochemistry play a crucial role in establishing an accurate diagnosis [8]. Cathepsin K was originally used in the differential diagnosis of renal cell carcinoma and epithelioid angiomyolipoma, but its use has major limitations in the distinction between PEComa and smooth muscle tumors [8]. Next-generation sequencing is recommended to evaluate for TSC alterations/TFE3 fusions that seems to be characteristic for uterine Pecomas [15].

Owing to their rarity, there is no consensus on the treatment of gynecological PEComas; nonetheless, total surgical excision with a tumor-free margin and without morcellation is the gold standard treatment regardless of the histological grade [10]. For malignant PEComas limited to the uterine cavity, total hysterectomy with or without bilateral salpingo-oophorectomy is considered the optimal treatment [10]. Conversely, fertility-sparing approaches may be considered for patients with a desire to preserve fertility.

Nevertheless, the oncological outcomes of patients with PEComa who undergo conservative surgery with a fertility-sparing approach remain unknown owing to limited data.

The role of chemotherapy in the management of PEComas remains unclear. However, treatment with mammalian target of rapamycin inhibitors (mTOR inhibitors), which inhibit a kinase causing suppression of T cell proliferation, has been explored in patients with advanced-stage disease, showing promising results. These studies have demonstrated better overall response rates and disease-free survival compared owing other tested agents [16]. [17].

Additionally, antiestrogens may be combined with targeted therapy for tumors with positive hormonal receptors, leading to improvements in disease burden [17].

Prognosis for uterine PEComas remains incompletely understood due to the rarity of the disease and limited data available. In a review by Lui and colleagues [13], follow-up data of 64 out of 82 patients diagnosed with uterine PEComa were presented. After a median follow-up of 19 months, 70% were alive with no signs of recurrence, 16.2% died of the disease, and the remaining were alive with the disease. Follow-up data were available for 68 out of the 82 patients [13].

Additionally, 12 cases of uterine PEComa were reported between 2018 and 2020, with clinical status known for 9 of these cases: 8 were disease-free after a median interval of 22 months (range, 3 to 71 months), while one patient died of the disease 10 months after surgery [2, 11, 18, 19].

In summary, owing to the absence of established treatment or follow-up consensus for this rare neoplasm, emphasis should be placed on the necessity of long-term follow-up. It is crucial to recognize that treatment planning requires a multidisciplinary effort.

Conclusion

PEComas are uncommon mesenchymal neoplasms of the female genital system, most frequently found in the uterus.

Preoperative diagnosis poses a challenge, often requiring pathologic evaluation of the patient’s sample after surgery and immunohistochemistry. Indeed, there is no imaging technique capable of distinguishing these lesions from other benign or malignant gynecological tumors.

Surgery with negative margins remains the cornerstone of treatment, and fertility-sparing approaches may be considered, balancing the risk with the need for vigilant follow-up.

Treatment strategy should be a multi-disciplinary decision involving oncologists, surgeons, radiologists, and pathologists. Further studies are necessary to establish treatment guidelines and analyze survival and recurrence rates accurately.