Malignant perivascular epitheloid cell tumour (PEComa) of the lung - a rare entity.

Malignant Perivascular Epitheloid Cell Tumour (PEComa) of the lung is very rare, with only six cases reported in literature. This case presented with a large mass originating from right upper lobe of the lung with dilemma in its histopathological diagnosis and management. Postoperative histopathology after a right upper and middle lobectomy describes a tumour with an alveolar/nested pattern of growth and epitheloid morphology with expression of TFE-3 and diagnosed as PEComa. After 6 months the patient had a local recurrence inside the thorax & chest wall.This case qualifies it as a rare type of malignant PEComa with younger age of presentation, aggressive clinical behaviour & malignant histological features along with TFE3 positivity on immunohistochemistry. This case is probably the first of its kind with the largest reported size involving two lobes of the lung. ©2017 Chakrabarti A. et al., published by De Gruyter.

Introduction

Perivascular epithelioid cell (PEC) tumours are a rare group of mesenchymal tumours, with an abundance of periodic acid Schiff (PAS)-positive glycogen. These tumours are mostly seen in the gastrointestinal tract and pelvic organs and are mostly benign [1].

Owing to its rarity, the World Health Organization (WHO) defines a perivascular epithelioid cell (PEComa) tumour as a “mesenchymal tumour composed of histologically and immunohistochemically distinctive perivascular epithelioid cells”.

The lung is an uncommon location for PEC tumour, which is otherwise commonly seen in the gastrointestinal tract and pelvic organs. Pulmonary PEC tumours also are mostly benign [2], with malignancy being very rare [3].

The diagnostic challenge arises from the silent and indolent course of this tumour, which is otherwise asymptomatic in most cases, with hemoptysis in only a few of them. Our case stands out in being a primary pulmonary PEComa with malignant characteristics, and adding to its rarity is the fact that the tumour showed a TFE (transcription factor 3) positivity. The complex characteristic and rare nature of the tumour accounted for a dilemma in diagnosis and management.

Case report

A 36-year-old nonsmoker, nonalcoholic, nondiabetic male presented with right-sided chest pain for 2 months and a history of hemoptysis. Chest X-ray revealed right upper zone haziness. The contrast-enhanced computed tomography (CECT) of the thorax showed large encapsulated heterogeneously enhancing mass in right paratracheal region indenting right upper lobe and lobar bronchi. It measured 86×78 mm, with a sharp defined margin and no obvious invasion or enlarged mediastinal nodes. Lung fields were otherwise normal. Further, a positron emission tomography (PET)/CT scan suggested an active primary disease in the large necrotic mass in the right upper lobe of the lung with mediastinal invasion, and diffuse bone marrow uptake metastatic involvement. The fine-needle aspiration cytology (FNAC) was consistent with non-small cell lung cancer (NSCLC). True-cut biopsy of the same lesion suggested TFE-3-positive alveolar soft-part sarcoma.

Presurgical workup indicated leukocytosis to the tune of >50,000/mm3 with neutrophilic predominance. All other parameters were within normal limits.

Surgery was decided in a multidisciplinary team meeting. Right thoracotomy was done and a solid mass originating from the right upper lobe extending into the right middle lobe was found. A right upper and middle lobectomy was performed. The postresection mass measured 18×13 cm in size. The postoperative course was uneventful. On first postoperative day, leukocytosis plummeted to 12,000/mm3.

Tissue was sent for histopathology, and the microscopy describes a tumour with an alveolar/nested pattern of growth and epitheloid morphology. Focally, the tumour cells had spindled morphology and were arranged in fascicles. A major portion was necrotic. The tumour cells expressed TFE-3, desmin (focal), and smooth muscle actin (SMA; focal) and were negative for cytokeratin, epithelial membrane antigen (EMA), CD68, HMB-45, Melan-A, S100 protein, myogenin, and microphthalmia transcription factor (MiTF). It was diagnosed to be a PEComa.

At 6 months postoperation, the patient came back with a heaviness in the right thorax. The CT scan of the thorax showed lung mass extending into the lower part of the neck up to the posterior paravertebral soft tissue with erosion of upper ribs and metastatic lesion in the right head of the humerus. The patient was sent to a medical oncologist for further management (Figure 1).

Pictures showing pre operative CT , histology, IHC, operative specimen and post operative recurrence.

(A) CT scan of thorax showing mass in the right hemithorax. (B) Resected mass. (C) TFE3 positivity in immunohistochemistry of resected mass. (D) HMB-45 positivity in immunohistochemistry of resected mass. (E) Slice of CT scan of thorax at 6 months follow-up showing recurrent mass in right hemithorax. (F) Swelling in the back and base of the neck at 6 months follow-up showing patients’ back scar from earlier operation.

Comments and discussion

After an extensive search, we could only find six relevant cases in the literature (Table 1) of malignant PEC tumours of the lung. Unlike mesenchymal tumours that express positivity for HMB-45, our case is rare in the sense that this case had TFE3 positivity and HMB-45 negativity.

Table 1:

Relevant literature on malignant pecoma of the lung.

Author	Demographics	CT scan findings	Treatment	Immunohistochemistry marker	Remarks
Ye et al. [4]	50/F	4 cm round and well-circumscribed mass in RLL	Right lower lobectomy with mediastinal LN clearance	HMB-45, PNL2, A013	Negative for vimentin, AE1/AE3, and CAM2.5
Parfitt et al. [5]	53/F	5.4 cm mass in RUL with multiple lung nodules, 4.8 cm left adrenal mass, temporal lobe mass	Could not be operated		Brain metastasis after several months
Yan et al. [6]	78/F	3 cm coin lesion on chest radiograph	Surgical resection		No recurrence
Lim et al. [1]	63/M	12 cm well-circumscribed mass in LLL with nodules in both lungs	Left lower lobectomy	S100 and SMA	Appeared to be arising from LLL bronchus with dense pleural attachment; initially VATS attempted but converted to open; not positive for HMB-45
Liang et al. [7]	63/M	6.7×9.8 cm large mass with moderate heterogeneous enhancement in the anterior and middle mediastinum and with well-defined margins	Surgical excision of the mass	Vimentin, HMB-45, Melan-A, and Ki67	Pan-cytokeratin, EMA, and S100
Sambo [8]	40/M	7 cm centrally located mass in the left lower lobe of the lung with an endobronchial lesion	Given the location of the tumour and to achieve a negative margin of surgical resection, a left pneumonectomy was performed	Negative for S100, HMB-45, CD31, SMA, calponin, and desmin immunostatin	Final pathology yielded a poorly differentiated malignant epithelioid and spindle cell neoplasm, consistent with malignant PEComa

PEC is a type of cell present in a constellation of tumours viz. angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), clear-cell sugar tumour (CCST), clear-cell myomelanocytic tumour of falciform ligament, and clear-cell tumour of other anatomical sites.

LAM is a rare tumour, the pulmonary equivalent of AML commonly affecting premenopausal women. It consists of a nodular, often widespread, and bilateral interstitial proliferation of smooth muscle cells positive for HMB-45, actin, and desmin. They cannot alter their immunophenotype like PEComa alternating between muscular and epithelioid components, neither do they express a wide range of melanocytic markers. The spindle-shaped cells are usually arranged around thin-walled, branching vascular channels. LAM is usually sporadic, with occasional association with tuberous sclerosis complex (TSC) [3].

CCST was originally described in the lung [9]. It is a rare and benign neoplasm composed of uniform round-to-polygonal epithelioid cells, with a clear or eosinophilic cytoplasm and well-defined borders. Tumour cells are surrounded by prominent and thin-walled vascular channels. CCST has a nested pattern similar to PEC tumour. It is also observed that adipocytic cells are seen between the nesting in a few cases of CCST [9]. Tumour cells are positive for HMB-45 like most mesenchymal tumours (unlike in our case, which is HMB-45 negative) [10], [11], [12]. In the vast majority of cases, it is a sporadic tumour with very occasional association with TSC.

PECs stand out from other mesenchymal tumours because they can modulate their morphology and immunophenotype. They can have more muscular feature with a stronger positivity for actin compared to HMB-45 or more epithelioid features with stronger positivity for HMB-45 and mild reaction to actin [3]. PEC also expresses melanocytic markers, such as gp100 protein [monoclonal antibody (mAb) HMB-45], Melan-A, tyrosinase, and MiTF, and muscle markers, such as SMA, pan-muscle actin, muscle myosin, and calponin. Thirty percent of PEComas express desmin, which does not guarantee a true smooth muscle origin [13]. Also, it has recently been appreciated that approximately 30% of PEComas express S100 protein, and this too does not necessarily imply a melanocytic origin. It has been established that a subset of PEComas harbours TFE3 gene fusions (as in our case). The presenting features include younger age of presentation, absence of association with TSC, and strong (3+) immunoreactivity for TFE3. They present with malignant histological features and aggressive clinical behavior. Despite significant morphologic and immunohistochemical overlap, PEComas harbouring TFE3 gene fusions are nowadays taken as a distinctive entity [14].

Folpe et al. [13] reported a significant association between tumour size >5 cm, infiltrative growth pattern, high nuclear grade, necrosis and mitotic activity >1/50 HPF, and recurrence and/or metastasis of PEC tumours, with the tumour being malignant. In our case, the size (>5 cm in diameter), large area of necrosis, and recurrence within 6 months qualified it as a malignant PEComa. To our knowledge, an optimal treatment strategy does not exist for such an aggressive PEC tumour, although surgical resection remains the most common modality. Recently, limited studies have reported encouraging results of targeted therapy after an oral administration of mammalian target of rapamycin (mTOR) inhibitors in a metastatic retroperitoneal PEC. No consensus exists to the specific targeted therapy for this extremely rare malignant PEComa of the lung with metastasis, and a further study is required for rational usage.

There is no consensus on an optimal management strategy for such aggressive PEC tumour of the lung. However, surgical resection remains the most common and favoured modality of treatment with variable results. A few recent studies have shown encouraging results with oral mTOR targeted therapy and merit further research.

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