Perivascular epithelioid cell tumour and investigation of genetic susceptibility

Discussion

PEComas are a rare group of mesenchymal neoplasms with about 100 cases reported in the literature.3 The origin of PEComas is unknown, but it has been hypothesised that these tumour cells show differentiation towards neural crest-derived perivascular epithelioid cells, and display dual myoid and melanocytic differentiation4–6 as they express both melanocytic and myogenic markers.2 Nearly a quarter of all PEComas are reported arising from the female genital tract, most commonly the uterus followed by the cervix.7 When considering a mesenchymal neoplasm of the uterus, leiomyosarcoma, endometrial stromal sarcoma and PEComas must all be considered4 for their overlapping morphological and immunohistochemical features.3 Preoperative diagnosis is not straightforward because neither clinical presentation nor imaging modalities are specific. Patients are on average in their mid-40s,7 and symptoms vary between abdominal and pelvic pain, pelvic mass, uterine prolapse, vaginal bleeding and incidental.3 On imaging, PEComa is usually a circumscribed mass lesion containing solid and cystic components, seldom involving the adjacent organs or structures.7 Avid enhancement is found in the solid components, and areas of high T1 signal intensity internally represent haemorrhagic or proteinaceous fluid content.8–10

Although the majority of the PEComas are benign lesions,11 most studies recommend complete surgical resection with a tumour-free margin.12 They can occasionally show malignant potential and rarely behave in an overtly neoplastic fashion. A review of the literature demonstrates no optimal treatment strategy, with no consensus established regarding adjuvant therapy, further emphasising the need for multidisciplinary care.

PEComas are conventionally composed of epithelioid and/or spindle-shaped cells with clear to eosinophilic granular cytoplasm. Epithelioid cells are arranged in dyscohesive nests surrounded by delicate thin-walled vessels and/or in sheets, whereas spindled cells often form fascicles. Other features include radial/perivascular distribution of tumour cells, multinucleated cells, cells with lipid-rich or rhabdoid cytoplasm and stromal hyalinisation (if extensive, the tumour may be called sclerosing PEComa).13

PEComas essentially express HMB45, melan-A and smooth muscle markers (SMA, Desmin and h-caldesmon), with variable intensity and extent. Among the melanocytic markers, HMB45 is the most sensitive, being positive in nearly all tumours, whereas melan-A is more specific, being positive (sometimes focally) in at least half of the tumours. No muscle marker is more frequently positive than the others.13

To distinguish between benign and malignant uterine PEComas, a number of worrisome histological features have been proposed.3 11 12 PEComas tend to be malignant potential or malignant if they are ≥5 cm in size, reveal high-grade atypia (excluding degenerative atypia), mitoses >1/50 HPF, necrosis and contain lymphovascular invasion. These features are predictive of outcome in patients with PEComa and are summarised in table 1.2 3 11 12 This patient’s histopathology showed an average of 2 mitoses per 50 HPF (2/50 HPF) and many nuclei also showed high-grade cytological atypia and multinucleated tumour giant cells; therefore, the collective view was to call this PEComa with malignant features. In addition, 20 out of 50 cells showed a TFE3 rearrangement supporting the diagnosis of PEComa.

PEComas also represent a few alternative tumourigenic pathways, with known germline and somatic mutations including TSC inactivation, an autosomal dominant disease due to loss of TSC1 or TSC2 genes2 (located on chromosomes 9q34 and 16p13, respectively) and a small subset carrying TFE3 gene translocations.2 Besides these associations, very little is still known about the molecular phenotype of uterine PEComas.3 One comprehensive genomic study in 2015 evaluated 38 PEComas from varying anatomical locations, and novel RAD51B gene rearrangements were identified in 3 out of 11 (8%) uterine PEComas.14 While no germline gene variants have been identified in our patient’s analysis, her personal and family history still raises the possibility of genetic susceptibility. TFE3 translocation-associated PEComas have uniform epithelioid cells with either purely clear or clear to eosinophilic cytoplasm and nested, alveolar, or solid architecture. They are diffusely positive for TFE3, HMB45 and cathepsin K, with focal to absent melan-A. Smooth muscle marker expression varies but is often weak to negative.13

TSC1/TSC2 genes are involved in the regulation of the phosphatidylinositol 3-kinases/AKT/mammalian target of rapamycin (mTOR) signalling pathway,1 which is one of the most commonly activated signalling pathways in cancer, leading to cell proliferation, survival and differentiation, opening a new perspective in clinical research.15 The pathophysiology of aberrant mTOR signalling offers a strong rationale to target this pathway and similar mTOR inhibitors, such as sirolimus or everolimus, have shown promising therapeutic activity in PEComas of different sites.6 16 17 The prognosis is usually favourable, with most of the patients reported in the studies remaining free of disease during their follow-up.7