PEComas have been defined by the World Health Organization as “a member of a family of mesenchymal neoplasms composed of perivascular epithelioid cells (PECs) that express melanocytic and smooth muscle markers” [5]. PEComas arise most frequently in the uterine corpus and less commonly in the cervix. However, the diagnosis of PEcoma by cervical cytology is much rarer. So far, only two cases of cervix PEComa diagnosed by conventional cervical smear have been reported. Our case was the first reported cervix PEComa diagnosed by a liquid-based cytology test. Compared with conventional cervical smear, liquid-based cytology test has the characteristics of clear background, distinct cell structure, and uniform distribution. It is difficult to diagnose based on a conventional smear alone. Since the characteristic perivascular arrangement cannot be discerned in cytologic smears, the application of a panel of immunocytochemical markers on cell blocks is likely to suggest a diagnosis of PEComa [6], especially in unusual sites like the cervix. Fortunately, in our case, the cytological features were consistent with the later biopsies.
The cytologic features of this patient were similar to those reported in the previous studies, but there are also some differences. The similarities are the tumor cells had an epithelioid morphology, appeared relatively uniform and discohesive, with characteristically abundant clear or granular eosinophilic cytoplasm, spindle cells or multinucleated giant cells in previously reported cases are not found in our case. Instead, our case contains a large number of melanin pigments in the cytoplasm, which is easy to be confused with MM. The tumor in the previously reported cases was initially diagnosed as a possible high-grade glandular lesion with a more specific diagnosis of clear cell carcinoma, and the other was reported as a tentative diagnosis of low-grade sarcoma. The final diagnosis of all cervix PEComa is based on the results of the biopsy. In our case, the tumor was initially considered as a MM because of the infrequent presence of spindle cells and a large number of melanin pigments in the cytoplasm. We did not include uterine sarcomas in the differential diagnosis. Combined with the results of cell blocks, IHC, subsequent colposcopic biopsy, and FISH, we finally diagnosed PEComa.
The differential diagnoses by cytology include: 1. Malignant melanoma (MM): Tumor cells are typically pleomorphic, with discrete distribution ranging from round, oval, spindle-shaped, contained large nuclei, coarsely clumped, irregularly distributed chromatin prominent nucleoli. Additionally, binucleation and intranuclear pseudoinclusions may be identified. The cytoplasm is well defined with or without cytoplasmic melanin pigment. The background is dirty, necrotic, inflammatory, or hemorrhagic because of tumor diathesis [7]. IHC can be useful for differentiating these lesions. PEComa is positive for myoid markers and negative for S-100 protein expression in contrast to MM. Controversial cases can be identified by FISH. 2. Reactive endocervical cells: The nuclei of reactive cervical glandular cells show a variable increase in nuclear size, with prominent nucleoli and uniform finely stippled chromatin, and rare intracytoplasmic polymorphonuclear leukocytes are seen; Moreover, they are not as loosely cohesive as PEComa cells and are columnar in appearance. 3. Clear cell carcinoma (CCC): Although cytologically, there are some overlaps between CCC and PEComa, the nuclear pleomorphism of CCC is striking. It often contains prominent nuclei that can be hyperchromatic and pleomorphic and project into the glandular lumen to form hobnail cells. On IHC, CCC expresses epithelial markers (AE1/AE3 and EMA), and does not show the “myomelanocytic” phenotype of PEComa. 4. Endometrial or ovarian adenocarcinoma: Three-dimensional groups and clusters or papillary configurations are more common in endometrial or ovarian adenocarcinoma cells, and the nuclear atypia is more obvious, including nuclear hyperchromasia and pleomorphism. These features are uncommon in PEComa. 5. Alveolar soft part sarcoma (ASPS): ASPS is also rare in the cervix, but the cytological morphology and immunohistochemical features of PEComa and ASPS can sometimes be similar. Similar with PEComa, some ASPS also express TFE3 [8]. However, ASPS exhibits smooth muscle markers, such as SMA but is invariably negative for melanocytes marekers [9].
Although most PEComas harbor loss-of-function TSC1/TSC2 mutations, a small subset of PEComas shows rearrangement of the TFE3 gene [10]. Recently, it was suggested that TFE3 translocation-associated PEComas of the gynecologic tract represent a distinct form of this tumor. Morphological features of these tumors include alveolar or nested growth, predominant epithelioid component, low nuclear atypia, and rare mitoses, showing Strong expression of HMB-45 and TFE3, focal or absent for melanA and smooth muscle markers [8]. In our case, FISH confirmed TFE3 gene rearrangement. Both morphology and immunophenotype of the tumor were also consistent with those TFE3 translocation-associated PEComas described previously. Immunocytochemical staining were positive for HMB45, TFE3, focally positive for Melan-A, while negative for muscle markers.
Because of the rarity of cervix PEComa, there are no standardized guidelines for treatment. Complete surgical resection with a tumor-free margin is usually considered to be the standard treatment [11]. Chemotherapy and radiotherapy have not yielded conclusive results [10]. Some histologic features associated with the aggressive behaviour of uterine PEComa, including Tumor size＞5cm, high nuclear grade, ＞1 mitosis/50 HPF, necrosis, and vascular invasion were absent in our case. The tumor displayed no evidence of malignancy. She underwent total hysterectomy with bilateral salpingo-oophorectomy and was followed up for two years without any evidence disease progression.
In conclusion, this is the third such case of PEComa of the cervix reported in English literature. The cytologic characteristics of the tumor may provide sufficient clues for diagnosing a PEComa, including loosely cohesive, epithelioid morphology with abundant clear cytoplasm or eosinophilic cytoplasm, low-grade nuclear atypia, cytoplasmic melanin pigment. The pathologist should be familiar with these cytological features, combined with results of other detection methods, can achieve the definitive diagnosis of PEComa.