Perivascular Epithelioid Cell Tumor of the Uterus with Ovarian Involvement: A Case Report and Review of the Literature

Background

Perivascular epithelioid cell tumors (PEComas) are a rare group of mesenchymal neoplasms composed of epithelioid cells, in a perivascular distribution, that express both melanocytic and smooth muscle markers and contain eosinophilic to clear granular cytoplasm. PEComas can occur at any anatomic site and include angiomyolipomas, lymphangioleiomyomatosis, clear cell “sugar” tumors of the lung, and PEComa not otherwise specified [1–5].

In the female genital tract, the uterus is the most common location for PEComas, with 78 reported cases to date [6]. Ovarian PEComas are exceptionally rare, with only 1 reported primary case [7] and 6 reports of PEComa metastatic to the ovaries [8–13]. Four of these 6 metastatic cases were associated with tuberous sclerosis and had multiorgan involvement including the ovary [8–11]. Of the 2 remaining cases that were not associated with tuberous sclerosis, one reported a jejunal PEComa with metastasis to the pelvic wall and ovary [12] and the other described a primary uterine PEComa with involvement of the ovary [13]. Here, we report the second published case of a primary uterine PEComa with involvement of the left ovary in a 61-year-old woman.

Case Report

A 61-year-old Caucasian woman presented with a 3-month history of a firm, nontender enlargement of the abdomen and a palpable abdominal mass in the absence of other gastrointestinal or genitourinary symptoms. At the time of her annual examination, 7 months previously, she had no symptoms and no palpable mass. The patient had no history of tuberous sclerosis. Her past medical history included leiomyomas with endometrial ablation at age 47. Her family history was significant for a mother with breast cancer diagnosed at age 59. Physical examination showed a firm, irregular, and enlarged uterus. A pelvic ultrasound identified a 10.5×9×12 cm mass adjacent to the superior aspect of the uterus, and computed tomography (CT) of the pelvis characterized the mass as complex, cystic, and with septations. Serologic evaluation, including a complete blood count, comprehensive metabolic panel, and CA-125 study, was remarkable only for a mild anemia with a hemoglobin of 11.6 g/dL.

The patient underwent hysterectomy and bilateral salpingooophorectomy. Macroscopic examination of the uterus showed a 10.7×10.5×10.2 cm solid, tan-brown mass in the fundus. The mass was partially filled with blood-tinged fluid and was coarsely trabeculated. No gross abnormalities of the fallopian tubes or ovaries were noted. The intraoperative diagnosis was determined to be a low-grade spindle-cell mesenchymal lesion. A follow-up positron emission tomography/CT scan, performed approximately 6 months after tumor resection, was negative for tumor recurrence and metastatic disease.

On microscopic examination, the uterine tumor was densely cellular, with epithelioid cells arranged in fascicles. Moderate nuclear atypia was also present with 1 to 2 mitotic figures per 10 high-power field (HPF). The tumor was biphasic in nature and without necrosis. Some cells contained a clear-granular cytoplasm, whereas others had an eosinophilic cytoplasm. A vascular network was also evident, with cells arranged radially around blood vessels. Many intranuclear pseudoinclusions were also present (Figure 1). The tumor exhibited pushing borders into the myometrium. Tumor cells of the same morphology were also present in the left ovary (Figure 1).

Immunohistochemistry indicated that tumor cells were caldesmon, smooth muscle actin (SMA), and desmin positive (diffuse, Figure 1), as well as focally positive for melanoma-associated antigen (HMB-45). Tumor cells were cytokeratin AE1/AE3, CD10, Melan-A, and S-100 negative.

Discussion

In this study, we report a case of a uterine PEComa with left ovarian involvement in the absence of systemic disease associated with tuberous sclerosis. The patient had minimal symptoms and was found to have a uterine mass by CT scan. The tumor was characterized by epithelioid cell morphology, with cells radiating around a delicate capillary network and possessing a clear to eosinophilic cytoplasm. Cells with spider cell-like morphology and cells containing intranuclear pseudoinclusions were also identified. Tumor cells exhibited moderate atypia, including variability in size and shape, and frequent prominent nucleoli. Immunohistochemistry revealed expression of the melanocytic marker HMB-45 and the smooth muscle markers SMA, desmin, and caldesmon. These morphologic features and the immunohistochemical staining pattern supported a diagnosis of PEComa.

In the only other reported case of primary uterine PEComa with ovarian involvement, the patient had vaginal bleeding and was found to have a large uterine mass by CT scan [11]. The mass was significantly larger than in the current case, measuring 30×27×18 cm in comparison with 10.7×10.5×10.2 cm. On microscopic examination, tumor cells displayed similar morphology to cells in the tumor of the current case (Table 1). The tumor was also composed of epithelioid cells containing clear to eosinophilic cytoplasm and arranged in fascicules. Immunohistochemistry was similar as well, with cells showing positive reactivity to both melanocytic and smooth muscle markers including HMB-45, SMA, and caldesmon [11].

The term perivascular epithelioid cell tumor was introduced in 1992 [14] and in 2002 the World Health Organization defined PEComas as mesenchymal tumors composed of perivascular epithelioid cells that express both melanocytic and smooth muscle markers [15]. The origin of PEComas is unknown, but it has been hypothesized that these tumors arise from neural crest stem cells and possess the ability to differentiate into both myoid and melanocytic cells [6,16]. To date, there have been 78 reported cases of uterine PEComas, the most common site in the female genital tract.

PEComas express both melanocytic and smooth muscle markers. In a recent review HMB-45 was found to be the most common melanocytic marker of uterine PEComas, with positive results in 99% (77/78) of reported cases [6]. Additionally, SMA was determined to be the most common smooth muscle marker, with positive results in 80% (53/68) of uterine PEComas. In the current case, the tumor was focally positive for HMB-45 and diffusely positive for SMA.

When considering a mesenchymal neoplasm of the uterus, leiomyosarcoma, endometrial stromal sarcoma (ESS), and PEComas must all be considered. Distinguishing among these can be challenging and requires both morphologic and immunohistochemical evidence for diagnosis (Table 2). Morphologic features such as the identification of a capillary network are of particular importance in distinguishing between mesenchymal neoplasms. Leiomyosarcomas lack a capillary network, and although a capillary network is often present in ESS, the capillaries lack the radial appearance of epithelioid cells characteristic of PEComas [17]. Although PEComas are most commonly positive for melanocytic markers, cases of both leiomyosarcoma and ESS tumors expressing HMB-45 have been reported [18,19]. However, the absence of CD10 expression can provide evidence against ESS, which has been shown to express CD10 in 96% of cases. In contrast, CD10 expression is rare in both PEComas and leiomyosarcomas [6,18,20,21].

The age of patients affected by uterine PEComas varies widely from 9 to 79, with an average age of 45 [6]. Presenting symptoms are often vague and include postmenopausal or abnormal bleeding and abdominal pain. In the current case, the only presenting symptom was a palpable abdominal mass. Although PEComas are often benign, there have been reported cases of malignant tumors. To distinguish between benign and malignant uterine PEComas, the Folpe criteria are often used [22]. According to the Folpe criteria, a tumor is considered malignant if it contains at least 2 worrisome features, defined as size of at least 5 cm, high nuclear grade and cellularity, a mitotic rate of at least 1 per 50 HPF and necrosis or vascular invasion. In 2015, a modification of the Folpe criteria was proposed, defining malignant tumors as those containing any necrosis or at least 1 worrisome feature, defined as an invasive edge, size of at least 5 cm, a mitotic rate of at least 2 to 3 per 50 HPF, and lymphovascular invasion [6].

In the current case, we determined the PEComa to be of aggressive potential because moderate nuclear atypia was present, the size was greater than 5 cm, and the mitotic rate was greater than 1 mitotic figure per HPF, thus fulfilling both the Folpe and the modified Folpe criteria. The left ovarian metastasis also supported a diagnosis of malignancy. The most common sites of metastasis of PEComas are lung, followed by liver, lymph nodes, and peritoneum [23]. In contrast, PEComa metastasis to the ovaries is rare, with only 6 reported cases, the majority of which have been associated with multiorgan involvement in the context of tuberous sclerosis [8–13]. To our knowledge, this is only the second reported case of a primary uterine PEComa with ovarian involvement in the absence of tuberous sclerosis. The clinical consequences of ovarian involvement are still unknown. In the current case, the patient underwent resection of all gross disease by total hysterectomy and bilateral salpingo-oophorectomy; however, recurrence may still be a possibility.

There is no established treatment protocol for uterine PEComas. Hysterectomy is the current treatment of choice, but long-term outcomes remain unclear. As a result, close follow-up is necessary for all patients diagnosed with PEComas and is especially important for those diagnosed with PEComas of malignant potential.

Conclusions

PEComas are a rare group of neoplasms that are difficult to differentiate from other mesenchymal tumors. Careful examination of morphologic features and immunohistochemistry are necessary for accurate diagnosis. Of PEComas occurring in the female genital tract, the uterus is the most common location; involvement of the ovaries is quite rare. No established therapy protocol exists, and additional research is needed to determine the best treatment for these neoplasms.