Introduction

Perivascular epithelioid cell tumours (PEComa)s are rare mesenchymal neoplasms composed of undifferentiated cells which usually express both melanocytic and myogenic markers [1].

The course of the disease is not well understood, as there are just over 100 cases of uterine PEComas been reported in the literature. Specific management protocols not standardized and there is sparsity of data on use of adjuvant therapy for PEComa.

The uterus and retroperitoneal structures are common site of origin which can present with postmenopausal bleeding for these. They remain part of the differential diagnosis of abnormal uterine bleeding [2, 3].

These present a diagnostic dilemma, especially histologically. Characteristic histological features include perivascular arrangement, epithelioid or spindle cells often identified in sheets or strands, while the intervening stroma could be normal [4, 5].

Throughout the literature, tumours often display markers commonly seen in melanoma and smooth muscle such as HMB 45 Melan-A, MiTF, cathepsin K [4, 6] and less so desmin and actin [3]. An absence of cytokeratin and protein S-100 can help differentiate from melanomas and other smooth muscle tumours [7].

Specific histopathological criteria further stratify the tumours into benign, tumours with uncertain malignant potential and malignant (Table 1) [4, 5, 8, 9].

Table 1 Histological Criteria of PECOMA
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There are currently no definitive radiological diagnostic criteria for PEComa.

PEComas often appears as a defined mass on cross-sectional imaging [10]. Tan et al. also suggested importance of CT and MRI in demonstrating PEComa tumours that were of low density on T1-weighted imaging (WI) and hyperintense on T2WI, with some being isodense with fat. The tumours usually had well-defined borders and were of a regular shape; however, ultimately PEComas may be indistinguishable from atypical fibroids or other forms of uterine tumours [10].

Surgery remains the mainstay of treatment [4]. Although some reports that have revealed beneficial effect, PEComas are considered resistant to chemotherapy and role of chemotherapy is yet to be identified [11, 12].

There is scope for further evaluation of new adjuvant treatment options such as use of mTOR inhibitors.

In Pecoma, there is over activity in the mTOR pathway. There might be a potential role of mTOR inhibitors as adjuvant treatment in selected cases. Pecoma tumours which have less mTOR overactivity, this option might not be an effective treatment modality. This offers a new option for women with diagnosis of PECOMA in specific cases [7, 11].

Case Presentation

Case 1

A 65-year-old woman presented with postmenopausal bleeding as the only symptom. She had normal BMI, one previous vaginal delivery and no history of hormone replacement therapy. Transvaginal scan showed thickened endometrium and hysteroscopy was performed, the histopathology showed perivascular epithelioid cell tumour (PEComa). Mitotic figures were scarce. MIB-1 staining showed approximately 1% of cells in cycle. There is diffuse strong expression with Melan-A and HMB-45 and patchy expression with Desmin and Calponin. Immunoprofile and histopathology features both were entirely consistent with the PEComa.

On MRI, a well-circumscribed lobulated soft-tissue mass was seen within the lower segment and endometrial thickness was measuring 24 mm. There was inner myometrial invasion which did not reach the deep margin.

Patient was discussed in the multidisciplinary meeting and decision was made for total laparoscopic hysterectomy with bilateral salpingo-oopherectomy and was performed without complications. The patient made a good post-operative recovery and was discharged home day after the surgery.

Figure 1 depicts histology revealing a 17 mm polypoid and friable tumour mass with a necrotic centre and cream lobules invading through the superficial myometrium and extending into the outer 50% of the myometrium, with 5.5 mm serosal clearance. There was no significant cytological atypia, increased mitotic activity or tumour cell necrosis and no lympho-vascular invasion. The tumour was staged as pT1N0M0. Decision for routine oncology surveillance with no adjuvant treatment was made by the multidisciplinary team, patient remains well four year since the treatment.

Fig. 1
figure 1

Histopathology of the case 1

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Case 2

This is a case of 64-year-old woman presented with postmenopausal bleeding as the only symptom. She was obese with BMI of 38 kg/m2, with a history of 3 vaginal deliveries, no hormone replacement therapy use and had history of epilepsy.

Ultrasound scan demonstrated a thickened endometrium hysteroscopy and endometrial biopsy was performed.

The endometrial biopsy showed mitotic figures conspicuous along with atypical forms(> 10/ 1 HPF). On immunohistochemistry, the tumour was positive for p16, CD 117, SMA, ER and melanocytic markers (Melan-A and HMB 45).

The overall histological features along with immunoprofile were consistent with a malignant PEComa (perivascular epithelioid cell tumour).

Staging CT and MRI was done (Fig. 2). MRI showed an irregular aggressive mass centred on the left lateral myometrium with possible early encroachment through the left lateral uterine serosa. Pelvic nodes were suspicious of metastasis but there was no other pelvic metastatic disease.

Fig. 2
figure 2

Large, irregular soft tissue mass centred on the left lateral myometrium measuring 6cmx 6.7 × 6.4 cm. This appears to at least involve, if not possibly extend through the uterine serosa. Medially there is extension into the lower endometrial cavity. The mass demonstrates enhancement with restricted diffusion, as well as areas of presumed necrosis with areas of mild T1 hyperintensity, in keeping with haemorrhage or proteinaceous material

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After multi-disciplinary meeting, patient underwent explorative laparotomy with surgical staging. Intra-operative findings of parametrial involvement on the left side with close proximity to the ureter, lead to upstaging of the disease. Macroscopic clearance of the disease was completed.

The final histopathological report described malignant PEComa of the uterus, 8 cm in diameter, extending beyond the uterus and involving the left parametrial/uterovesical soft tissue, with vascular invasion.

Microscopically, tumour was characterized by epithelioid and spindle-shaped tumour cells, arranged in highly cellular sheets, nests separated by vascular channels, and short fascicles, with high-grade nuclear atypia, prominent nucleoli, occasional tumour giant cells and either clear or eosinophilic cytoplasm. Mitoses, including atypical forms, were identified with a mitotic count of up to 21/10 hpf. There was extensive tumour necrosis and the tumour shows an irregular infiltrative border with surrounding myometrium. Vascular invasion is seen.

Immunoprofile showed positive expressions of SMA, Melan-A, HMB45, ER and PR (focally and weakly positive), negative for desmin, CD10, WT1, DOG-1.

Histopathological examination of the right fallopian tube, revealed high-grade serous carcinoma of the right fallopian tube, showing early invasion of the mesosalpinx without involvement of the ovaries, left fallopian tube or cervix by either tumour with no lymph nodes involvement.

After discussion in multidisciplinary meeting final staging agreed for malignant PEComa was pT2N0M0 and for tubal high-grade serous carcinoma as pT2N0M0. (Fig. 3)

Fig. 3
figure 3

Histopathology of Case 2

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The sarcoma team was consulted for further management, advised for ongoing surveillance with no further treatment.

During post-operative follow-up after 41 days, patient reported new vaginal bleeding, on examination revealed a friable, polyp-like lesion arising from the right side of the vaginal wall associated with contact bleeding. Histopathological examination of the lesion revealed infiltrative malignant perivascular epithelioid cell tumour (PEComa), thus suggesting early recurrence. CT scan showed metastatic lung lesions. The patient underwent video assisted thoracoscopic surgery (VATS) procedure for lung lesion. Histopathology was reported as foci of metastatic PECOMA with clear margins. Patient was referred to regional sarcoma centre and received.

Chemotherapy with sirolimus (mTOR inhibitor) and nab-sirolimus (nanoparticle albumin-bound mTOR inhibitor). Unfortunately patient died 17 months after the diagnosis.

Discussion

We present two cases of PEComa of the uterus with different spectrum of histology from benign to metastatic malignant disease.

Both the patients presented with postmenopausal bleeding only. Both patients had histological and immunohistochemical findings consistent with uterine PEComa.

Both the patients’ histology demonstrated strong diffuse positivity for HMB 45 and Melan-A. Immunohistochemical diagnosis could be challenging, as in case 1 patchy expression of desmin was noted and SMA negative whereas in case 2 desmin was negative while SMA was positive.

Imaging demonstrated a well-circumscribed large intra-cavity mass in both cases. This is a non-specific finding as with large intra-cavity masses it may be soft tissue tumours, PEComa being part of the differential diagnosis.

Both patients underwent surgery, case 1 had good post-operative recovery and had been well under surveillance without adjuvant treatment. The second patient had an early recurrence and metastasis and was administered adjuvant treatment with mTOR inhibitors, died after 17 months of diagnosis. This exemplifies the diagnostic challenges and risk stratification of PEComa and the need for further clinical trails and assessment of adjuvant treatment with the aim of improving outcome in high risk patients.

Most of the PEComas are benign tumour which get treated with completed surgical resection and remain well without any adjuvant treatment like our first case. However, set of PEComas are malignant exhibiting local invasion, recurrence or distant metastasis, commonly in lungs as in our second case. For such selected cases adjuvant chemotherapy in selected cases mTOR inhibitor chemotherapy is being used reluctantly as there were no clear benefits noted.

Conclusion

This illustrates natural history of a rare uterine tumour(PEComa) and management in rare presentations with aggressive tumours. The management can be challenging requiring multidisciplinary approach. There is lack of how to manage recurrence of PEComa not salvaged by surgery. Recent advances in chemotherapy have allowed the trial of new drugs to treat recurrence but their benefits are debatable. Further evidence is needed to evaluate the treatment of aggressive tumours.