Uterine Perivascular Epithelioid Cell Tumors (PEComas) represent a distinctive yet infrequent pathological entity, posing ongoing diagnostic and therapeutic challenges for medical practitioners. Predominantly, these cases have been identified post-hysterectomy, initially presumed benign. Preoperative radiological discernment proves arduous owing to the absence of defining PEComa- specific radiographic markers, thereby complicating differentiation from benign uterine leiomyomas or malignant sarcomas, compounded by the rarity of such occurrences.

Clinically, uterine PEComas often mimic the presentation of benign leiomyomas, with patients commonly presenting with vaginal bleeding, nonspecific abdominal discomfort, or, less frequently, palpable abdominal masses, occasionally remaining asymptomatic. Radiologically, these tumors typically exhibit characteristics akin to other benign uterine lesions. Ultrasonography typically reveals solid masses with heterogeneous echotexture devoid of cystic regions or notable vascularity on Doppler examination.

A retrospective study conducted by Tan et al. [4] scrutinized 32 PEComa cases post-pathological diagnosis, correlating findings with preoperative CT or MRI scans. Dynamic imaging modalities revealed tumors predominantly of low density or hypointensity on T1-weighted imaging, contrasting with hyperintensity on T2, with some presenting isodensity with fat tissue. Typically, tumors manifested well-defined margins and exhibited uniform shapes, ranging in diameter from 1.5 to 18 cm. Most notably, these lesions demonstrated heterogeneous and significant enhancement during arterial and venous phases, often appearing slightly hyperdense on delayed CT imaging, albeit with some instances (6 out of 32 cases) showcasing delayed enhancement. Despite the distinct imaging characteristics elucidated in the literature, distinguishing PEComas from other uterine neoplasms, both benign and malignant, remains a formidable task, exacerbated by the rarity of these tumors, further complicating preoperative diagnostic endeavors.

Controversy persists in academic literature about the necessity of histological verification of uterine PEComas prior to surgery. Although successfully attempting to distinguish these neoplasms from other pathologic entities like leiomyosarcomas by using preoperative biopsies and immunohistochemical stainings, the diagnostic difficulties remain. In addition, the occurrence of uterine PEComas is relatively rare; thus, the cost-effectiveness concerns regarding routine biopsies in uterine processes should be considered. Therefore, an assessment of the diagnostic approach regarding both diagnostic performance and applicability is needed for the clinical care of such sparse malignancies.

One of the major obstacles in the diagnosis of uterine PEComas involves determination of their malignant potential. Different scoring models have been used to categorize the features of these tumors according to their class. Folpe et al. described a scoring system of benign, UMP, and malignant nuclear atypia which are deemed worrisome histologically. These defined features include tumor diameter/size ≥ 5cm, infiltrating border, high nuclear grade cellularity, mitosis rate per 50 HPF and necrosis or vascular invasion [2].

Uterine PEComas are typically sharply delimited lesions on imaging that might represent other benign or malignant lesions of the uterus including leiomyomas or sarcomas. Anderson et al. [5] opined that despite MRI and CT imaging, no imaging characteristic is unique to PEComa. As with most tumors, histopathological examination is the gold standard investigation demonstrating epithelioid cells with a clear to eosinophilic cytoplasm and a characteristic immunophenotype that comprises HMB-45 and SMA [6]. Nevertheless, according to Dubé et al. [7], various marker patterns may result in false diagnoses and, therefore, it becomes necessary to perform multiple tests as well as multiple biopsies whenever possible in complicated cases.

PEComas can be clinically indolent and have localized manifestations of Sturge-Weber syndrome or are aggressively malignant with metastatic capabilities. Historical osteology risk factors, including those reported by Folpe et al. [2], stem from test elements including tumor size, MIB-1, and necrosis. However, the existing data indicate that these criteria do not fully address the heterogeneity of PEComas. For example, Sanfilippo et al. [8] showed that there were cases with low risk factors and metastases in some patients hence underlining some of the existing models’ drawbacks.

Newer studies are trying to improve the methods of risk assessment. Recent data suggest that molecular markers including TSC1/TSC2 mutations should be included in prognostic models because of their correlation with the activation of the mTOR pathway. Lyle et al. [9] observed that TFE3-altered PEComas may be a molecularly different subtype regarding its prognosis. Subsequently, there is a call to continue similar research so as to confirm the conclusions made above and apply molecular analytics into formal clinical practice.

Schoolmeester et al. [10], using the Folpe criteria, applied the scoring system to 16 gynecological tract PEComas and suggested a new scoring system with a threshold of four or more features suggestive of malignancy. These changes allowed an increased discrimination in terms of positive and negative predictive values for likelihood of subsequent malignant behavior but caused no change in the overall sensitivity of the tests. On the other hand, Bleeker et al. [11] recommended a more stringent risk stratification system by retaining size ≥ 5 cm as well as high mitotic activity, because these were the only two histopathological characteristics that in their opinion, were predictive of recurrence.

A retrospective analysis compared the performance of the original Folpe criteria with a modified version it, in which a tumor with a single ‘suspicious’ feature such as a maximum of size more than 5 cm, infiltrative borders, lymphovascular invasion or mitotic rate exceeding 1/50 HPF would be classified as benign. Indeed, the modified Folpe criteria exhibited higher sensitivities and negative predictive values than the Schoolmeester criteria. Nonetheless, the tumors defined as malignant by the strict criteria of the Schoolmeester classification were found to have a tendency for early recurrence. Based on these observations, until more extensive cohorts are available, the modified Folpe criteria should be first used for tumor classification [1].

In our above-mentioned case of malignant PEComa the tumor was described as TFE3-altered. In particular, during the last several years, about twenty cases of TFE3 translocation related PEComas have been described in various anatomic locations including renal, bladder, colonic, pelvic soft tissue, ovarian, vaginal, and uterine PEComas. Notably, activation of the mTOR pathway may not always be a contributory factor in these specific tumors. This observation has major relevance for the patient’s suitability for clinical trials of mTOR pathway inhibitors [1].

In cases like the current one where a more aggressive biology is expected, particularly when systemic treatment is required, mutation analysis for prospective mTOR changes is warranted. In general, such broad molecular profiling not only helps to individualize treatment and enhance the outcome of therapy of TFE3-altered PEComas, but also can be useful for successful preliminary diagnostic tests.

The treatment of uterine PEComas also continues to be a therapeutic challenge in both approaches. Lack of sufficient cases makes it still challenging to develop a clear definition of an acceptable standard of care in patients with gynecological PEComas. Currently, surgical resection remains the sole option for the management of this disorder. In any case, it is predominantly performed as a total hysterectomy, with or without BSO, which has larger support in practice. For cases of PEComas that show spread or localization in the uterine cervix or malignant potential, radical hysterectomy with bilateral salpingo- oophorectomy should be considered [12]. This additional surgery is expected to help remove more suspicious tissue or tumor volume because of higher disease prevalence which may lead to local recurrence or metastasis. However, the best therapeutic strategy for managing uterine PEComas remains a question mark that calls for interdisciplinary cooperation and the enhancement of existing therapeutic strategies. Transabdominal hysterectomy is by far the most often adopted procedure. Some surgical techniques, including myomectomy, have been described in this setting; however, Fang et al. [13] suggested that fertility-sparing approaches should be avoided if the tumor exhibits high-risk criteria because of the possible recurrence.

mTOR inhibitors that include sirolimus and everolimus have been used for the treatment of PEComa with TSC mutations [8]. These targeted agents work on the fact that the existence of the tumor is dependent on the mTOR signaling pathway. However, the role of mTOR inhibitors in TFE3-altered PEComas is still questionable because such tumors may not be as dependent upon mTOR signaling as mTOR inhibitors were initially believed to be. In some patients with high-grade or metastatic lesions, Adriamycin, ifosfamide and carboplatin have been used in different schedules, and efficacy varies widely [14].

Radiotherapy has also been used for local control in malignancies that are unsuitable for resection, although the utility is questionable. Similarly, Seidman et al. stated that the extent of radio sensitivity in PEComas is not absolute that is why the use of that modality should be patient specific depending on the features of the tumor and the preferences of the patient [6].

Progress in the field of molecular pathology increased our knowledge about the PEComas. Indeed, the identification of TSC1/TSC2 gene mutation and TFE3 rearrangement not only improves diagnostic accuracy but also provides therapeutic targets [8]. However, due to the low incidence of uterine PEComas, the applicability of these data is questionable, which underlines the imperativeness of cooperation.

Wang et al. [14] indicated that further registries should be encouraged to focus on the clinical, pathological, and molecular profile of PEComas. They could help create guidelines that draw from research results and advance clinical investigations concerning new therapeutic instruments.