Perivascular epithelioid cell tumor of the uterus: report of three cases

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The family of PEComa includes angio-myolipoma (AML), clear cell “sugar” tumors of the lung (CCST), lymphangioleiomyomatosis (LAM), clear cell myomelanocytic tumor of the falciform/ligamentum teres (CCMT), and clear cell tumors of the pancreas, rectum, peritoneum, uterine, vagina, thigh, and heart. They are very rare besides AML, CCST, and LAM.1 To our knowledge, only 84 cases of PEComa have been reported, 30 of them occurred in the uterus.2,3 Here we report 3 cases of uterine PEComa and discuss its pathological features and differential diagnosis. CASE REPORT Medical history Case 1 On September 2001, a 40-year-old woman presented with a distended abdomen and irregular uterine bleeding for three months was admitted to our hospital. Ultrasonography revealed a subserosal tumor sized 3.5 cm×2.5 cm×2.0 cm in the uterus. Case 2 On February 2002, a 33-year-old woman complaining of distended abdomen and irregular uterine bleeding was admitted to our hospital. She had a subserosal tumor in the uterus sized 7.7 cm × 6.5 cm × 5.5 cm, which was revealed 2 years ago by ultrasonography. On admission, physical examination showed that the uterus was enlarged, ultrasonography found that the tumor had increased in size to 8.5 cm × 4.3 cm × 6.4 cm. The laboratory findings including CA199, CA125, and CEA were normal. Case 3 On May 2003, a 44-year-old woman complaining of irregular uterine bleeding for half a year was admitted into our hospital. Gynecological examination found that the uterus was enlarged. Ultrasonography revealed a tumor sized 5.5 cm × 5.0 cm × 4.5 cm in the uterine wall. Pathological examinations In all of the 3 patients, a diagnosis of uterine leiomyoma was made and hysterectomy was performed. After the operation, gross examination showed that the cut surface of the tumor was brown-reddish with elasticity, well demarcated but not capsulated. In the Case 2, there was a 2.0 cm×2.0 cm×1.5 cm cyst in the center of the tumor. Histological examination showed that the tumor cells were round or polygonal (Cases 1 and 3), or spindle or epithelioid (Case 2) with abundant clear or pale eosinophilic and granular cytoplasm. The nuclei were round or oval, small but prominent. (Fig. 1) The mitotic index was low (<1/50 HPF). The tumor cells were arranged in sheets or nests around the vascular network, which had scattered thick wall (Fig. 2). In the Case 2, spindle cells were arranged in palisades around the tumor with infiltrating growth pattern.Fig. 1.: In the Case 1, light microscopy showing that the tumor cells were round or polygonal with abundant clear or pale eosinophilic and granular cytoplasm. The nuclei were small and center located (H&E, original magnification ×200). Fig. 2. In the Case 2, light microscopy showing that the tumor cells were round or polygonal, arranged in sheets or nests around the vascular network which had scattered thick wall (H&E, original magnification× 100). Fig. 3. In the Case 3, the tumor was strongly positive for HMB45 (Immunostaining, original magnification×400). Fig. 4. In the Case 3, melanin pigment was observed in the cytoplasm (Electron microscopy, original magnification×20000).Immunohistochemically, the tumor cells were strongly positive for HMB45 (Fig. 3), but negative for SMA, actin, S-100 protein, CD34, CD117, desmin, CD10, CK, and EMA in the Cases 1 and 3; and were strongly positive for HMB45, diffusely positive for SMA and actin, and negative for S-100 protein, CD34, CD117, desmin, CD10, CK, and EMA in the Case 2. In the Case 3, electron microscopy found that the tumor cells were polygonal with large nuclei with chromatin that tended to be marginate, and the membrane can be observed. The cell organelles were blurred for the sample was fixed in formalin. Melanin pigment was observed in some cytoplasm (Fig. 4). DISCUSSION The “perivascular epithelioid cell” (PEC) was first addressed by Bonetti and colleagues in 1992,4 according to its morphological and immunohistochemical features. Subsequently, they further proposed that the diseases with the same phenotype, including CCST, CAM, LAM as a panel of entity.5 And then, in 1996, “PEComa” was proposed by Zamboni and colleagues.6 PEComa is defined as a mesenchymal tumor composed of perivascular epithelioid cells with definite morphological and immunohistochemical features (WHO, 2002). The age of the patients with the disease ranged from 17 to 79 years with a median age of 54.7 Most of them had abnormal uterine bleeding and mass or pain at the lower abdomen, which was similar with the symptoms and signs of other uterine tumors. Thus the patients with PEComa were often diagnosed with uterine leiomyoma before operation. In some cases, the tumor may be complicated with tuberous sclerosis complex.8–10 Vang and colleagues9 suggested that the uterine PEComa has two subgroups (groups A and B) according to the number of the tumor cells with clear cytoplasm, the presence of a prominent tongue-like growth pattern, and the proportion of the cells expressing HMB-45 and muscle markers. Both epithelioid smooth muscle tumors and PEComa are parts of a continuous histological spectrum. The group A PEComa is at one end of the spectrum and the epithelioid smooth muscle tumors at the other end; while group B PEComa shares the features of the both ends and had an uncertain relationship to smooth muscle tumors. They suggested that all the uterine epithelioid tumors should be stained with HMB45. In our patients, the Cases 1 and 3 belong to group A PEComa, and their symptoms of uterine bleeding and pain were located at the lower abdomen; the tumor cells were round, polygonal with abundant clear or pale eosinophilic and granular cytoplasm. Melanin pigment was observed in some cytoplasm in the Case 1. The Case 2 seemed to belong to the group B, although she aged 33 that was younger than that reported by Vang (from 47 to 58).9 The tumor cells were spindle or epithelioid, with abundant clear or pale eosinophilic and granular cytoplasm. The spindle cells arranged in palisades were observable, and infiltrating growth pattern could be seen around the tumor. The principle characteristics of perivascular epithelioid cells are immunoprofiles of HMB45 (+). Vang and colleagues9 proposed that the PEComa cells are strongly positive for HMB45, and diffusely positive for SMA and actin. However, the results of immunohistochemistry in our three cases were not fully accordant with it but were more similar to those reported in some other literatures.3,11 Heretofore, the relation between Vang’s classification of PEComa and the prognosis of the tumor is still uncertain.11–13It was said that the tumor cells could be positive for CD117, desmin, EMA, CD10 in a few cases,11,12,14,15 however, the three cases were all negative for CK, EMA, CD34, CD117, CD10, desmin, and S-100 protein. Only in one case, the CGH and DNA of the tumor was studied showing a balanced chromosomal profile and diploid nuclei, respectively.13 But the analysis failed to show the EWS/ATF-1 fusion transcript from the t(12;22) characteristic of clear cell sarcoma. Since PEComa has no distinctive symptoms and signs, the diagnosis should depend on pathological examinations. As previously noted, differentiation between epithelioid smooth muscle tumor and group B PEComa is extremely difficult. Endometrial stromal sarcoma can be ruled out because it has no perivascular concentric proliferation and is positive for HMB45. Group A PEComa has a tongue-like growth pattern and can be different from endometrial stromal sarcoma with a variety of endometrium stromal cells by staining with CD10. Besides, PEComa should also be differentiated with clear cell sarcoma, paragangliomas, transferred renal clear cell carcinoma, epithelioid malignant peripheral nerve sheath tumor, and metastatic malignant melanoma. The biological behavior of PEComa is hard to be defined. Some of the patient showed metastasis, recurrence or even postoperational death in one or two years.8,14Folpe and colleagues2 proposed that the disease could be classified into three subgroups, including the benign, uncertain malignant potential, and malignant. The benign tumor has no worrisome features (e.g. diameter of the tumor ≤5 cm, non-infiltrative, non-high nuclear grade and cellularity, mitotic rate≤1/50 HPF), while uncertain malignant potential tumor shows pleomorphrous or multinucleated giant cells only, or sized over 5 cm in diameter only. Some cases of PEComa with metastasis or causing death have been reported.5,9–11 Though the tumor sized over 5 cm in diameter and had infiltration in the Case 1, and necrosis in the Case 2, the common characteristic in our three cases was a short of cellularity and mitotic rate≤1/50 HPF. There was no recurrence or metastasis during follow-up (16 months, 32 months and 52 months, for the Cases 1 to 3 respectively). We think that the biological behavior of PEComa mainly depends on heteromorphism and mitotic rate; close follow-up is necessary for the patients; total abdominal hysterectomy and bilateral salpingo-oophorectomy are suggested; and radiotherapy and chemotherapy as adjunct treatments might be helpful.8,9