Gynecologic Pathology

Malignant Perivascular Epithelioid Cell Tumor (PEComa)

Teri A. Longacre
Stanford University
Stanford CA

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Case History:
A 38 year old woman with lower abdominal pain and uterine mass.

Slide 1
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Figure 1
Low magnification of uterine mass.

Figure 2
Irregular nesting of epithelioid cells

Figure 3
Mitotically inactive, uniform nuclei with central nucleoli

Figure 4
Epithelioid cells with eosinophilic, granular cytoplasm

Malignant Perivascular Epithelioid Cell Tumor (PEComa)

Perivascular epithelioid tumor (PEComa) is a rare epithelioid mesenchymal tumor in the female genital tract that is composed of histologically and immunohistologically distinctive perivascular epithelioid cells [4]. The PEComa family of tumors, initially advanced by Bonetti et al and now codified by the WHO includes clear cell "sugar" tumor of lung, angiomyolipoma, and lymphangioleiomyomatosis (LAM) [2, 4]. Despite the rarity of these tumors, PEComas of the gynecologic tract account for almost 40% of all cases [5, 20]. Most occur in the uterus, with smaller numbers of PEComas reported to arise in the uterine cervix, vagina, and pelvic soft tissues. The uterine tumors are 0.5 to 13 cm in size (mean, 3.5 cm) and usually single, although several additional, smaller PEComas are occasionally identified at the time of hysterectomy. Most occur in perimenopausal women (mean, 51 years), but the age range of reported cases is 19 to 79 years. In some patients with uterine PEComas, additional perivascular aggregates of HMB-45-positive epithelioid cells are seen in the adjacent ovary, pelvic tissue and lymph nodes ("PEComatosis") [3, 10, 12]. A subset of PEComa, angiomyolipoma, and lymphangioleiomyomatosis is associated with tuberous sclerosis complex, although this appears to be less common for the tumors that arise in the gynecologic tract [1, 5, 6, 12, 20].

The histologic features of PEComa vary from a predominantly spindled morphology with cells arranged in short fascicles and cell nests to a predominantly epithelioid morphology arranged in a nested or sheet-like pattern [5, 20]. A prominent intrinsic vasculature is almost always present, ranging from an extensive, arborizing capillary network to thick-walled, often hyalinized larger caliber vessels. Hyalinization of the adjacent mesenchymal tissue has also been described [14] The constituent cells are clear to slightly eosinophilic with granular cytoplasm and are often arranged in a radial fashion around blood vessels. Nuclear atypia may be present, but the nuclei in most cases are ovoid and normochromic with small nucleoli. Multinucleated cells and cells with so-called "spider cell" morphology giant cells with a central eosinophilic zone surrounded by a peripheral clear zone - may be seen in 69% and 35% of cases, respectively [5]. Mitotic activity varies considerably, ranging from 0 MF/50 HPF to 50 MF/50 HPF, with most cases exhibiting 0 MF/50 HPF [5, 20].

All PEComas express at least one melanocytic marker, with HMB-45 most frequently expressed (92%), followed by Melan-A (72%), and MiTF (50%) [5]. Almost one-third of cases also stain positively with S100 in a nuclear and cytoplasmic pattern; however, most of the desmin-positive reported cases do not exhibit typical smooth muscle histology. Coexpression of smooth muscle actin and melanocytic markers is quite common. Up to 80% of PEComas will stain positive for smooth muscle actin, while desmin and caldesmon expression are less common, particularly in uterine PEComas. Rarely, PEComas may also express CD117 and cytokeratin, usually in a focal pattern [5]. However, CD34 has not been reported in these tumors.

Folpe et al have classified PEComas into "benign," "uncertain malignant potential," and "malignant" categories based on tumor size (> 5 cm); infiltrative margins; high grade nuclear atypia and cellularity; mitotic index (> 1 MF/50 HPF); necrosis; and vascular invasion [5]. PEComas with nuclear pleomorphism and/or multinucleated giant cells only or size > 5 cm are "of uncertain malignant potential," while PEComas with two or more worrisome features are considered to be "malignant" or at "high risk for aggressive behavior". Clinically aggressive tumors typically spread to the lungs, although local recurrences, bone metastases, and rarely, lymph node metastases have also been reported.

Differential Diagnosis:
The differential diagnosis of epithelioid cell tumors in the gynecologic tract includes: epithelioid smooth muscle tumor, endometrial stromal tumor, melanoma/clear cell sarcoma, carcinoma, placental-site trophoblastic tumor, and gastrointestinal stromal tumor (GIST) secondarily involving the uterus.

Smooth muscle tumors are the most common tumor in the differential diagnosis of PEComa in the gynecologic tract [8, 9, 15]. Epithelioid smooth muscle tumors contain cells that are predominantly rounded with eosinophilic or clear cytoplasm; they may be practically indistinguishable from PEComas and are often only recognized on routine histology by the presence of more typical spindled areas with the characteristic morphology of smooth muscle (e.g., blunt-ended "cigar-shaped" nuclei, diffusely eosinophilic and fibrillar cytoplasm, elongated spindled cells) [7]. Both uterine PEComas and smooth muscle neoplasms contain thick-walled blood vessels, but the rich vascular capillary network in PEComa is not a characteristic of uterine smooth muscle tumors. Multinucleated giant cells and so-called "spider cell" histology, when present are other features that are more typical of PEComa than the usual epithelioid uterine smooth muscle tumor [5]. In most instances, however, the distinction may be difficult. Since conventional benign and malignant smooth muscle neoplasms may rarely express HMB-45 [16, 17, 18, 19], and PEComas may rarely express desmin and caldesmon, it is likely that the two types of tumors represent a morphologic continuum of uterine mesenchymal differentiation [20]. However, because of the potential association with tumors in the tuberous sclerosis complex and the more uncertain clinical behavior of PEComa, the distinction between the two tumors should probably be made until more information is known about these unusual neoplasms. In general, any epithelioid mesenchymal neoplasm in the uterus with clear or eosinophilic pale granular cytoplasm should be evaluated by a panel of markers that includes HMB-45, Melan-A, desmin, caldesmon, and smooth muscle actin. CD10 should also be included in those problematic cases in which stromal differentiation is also a consideration (see below).

The rich vascular capillary network and tongue-like growth pattern of some PEComas may mimic endometrial stromal sarcoma, particularly when the latter tumors exhibit a more epithelioid or luteinized histology [12]. The thick-walled vessels and occasional cleft-like spaces, which are not characteristic of endometrial stromal tumors, serve to distinguish PEComa. The distinction is also based on strong, diffuse expression of CD10 in endometrial stromal cell neoplasms on the one hand and HMB-45 and Melan-A expression in PEComa on the other. CD10 expression may be seen in PEComa, but it is usually focal. In addition, almost all low-grade endometrial stromal tumors express estrogen receptor and progesterone receptor.

Melanoma and clear cell sarcoma are more frequently confused with soft tissue PEComas, particularly those that feature a mixed epithelioid and spindle cell morphology. In most instances, melanoma and clear cell sarcoma can be distinguished from PEComa by the presence of strong and diffuse S100 expression. On occasion, clear cell sarcoma may express only HMB-45 and in these instances, identification of the t(12;22)(q13;q13)(EWS;ATF1) gene fusion will confirm the diagnosis [5]. The presence of smooth muscle actin in epithelioid PEComa is also useful in this differential diagnosis, but since spindle cell melanomas may exhibit significant actin expression, the use of this marker to distinguish a PEComa with spindle cell morphology form a spindled cell melanoma should be interpreted with caution [11].

Epithelioid PEComa can be confused with a variety of epithelial neoplasms such as undifferentiated carcinoma, clear cell carcinoma, and metastatic lobular carcinoma of the breast, particularly when present in a small biopsy specimen. Although a rare PEComa may express cytokeratin, diffuse keratin expression has not been observed in PEComa and EMA expression is typically absent.

Placental site trophoblastic tumor is also strongly cytokeratin positive, but negative for HMB-45 and Melan-A. This tumor occurs during the reproductive years and is typically diagnosed in curettage specimens obtained for a suspected missed abortion. Additional markers, such as hPL, Mel-CAM, and inhibin help confirm the diagnosis of placental site trophoblastic tumor [13].

Gastrointestinal stromal tumors (GIST) may secondarily involve the gynecologic tract. Like PEComa, GIST may exhibit spindled, epithelioid and mixed epithelioid and spindled cell morphology. However, the vascular pattern in PEComa is usually more pronounced than in the typical GIST. Since some PEComas may express CD117, HMB45, Melan-A (both positive in PEComa) and CD34 (often positive in GIST) are the most useful markers in this differential diagnosis.

Take Home Message:
  • Uterine epithelioid neoplasms require a wide differential diagnosis that includes mesenchymal, epithelial, and melanocytic tumors.

  • The significance of HMB-45 expression in uterine smooth muscle tumors with usual morphology is uncertain, but uterine mesenchymal tumors with epithelioid morphology should be evaluated for the presence of HMB-45, since at least some of these tumors will fall into the category of PEComa.

  • PEComas with two or more of the following features are considered to be malignant or at high risk for aggressive behavior: size > 5 cm, infiltrative margins, tumor cell necrosis, mitotic index > 1mf/50 hpf, vascular invasion, and high nuclear grade or cellularity.

  • PEComas with nuclear pleomorphism and/or multinucleated giant cells only or size > 5 cm are considered to be of uncertain malignant potential.

  • PEComas that are < 5 cm, cytologically low grade, mitotically inactive (< 1mf/50hpf), and noninfiltrative, with no necrosis or vascular invasion appear to be clinically benign.

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