Presentation and management of pulmonary artery sarcoma

PAS is usually asymptomatic until vessel occlusion occurs, and as such patients normally present with signs and symptoms of advanced disease. These are often suggestive of pulmonary hypertension, heart failure or thromboembolic disease. Dyspnoea is a universal complaint, although chest pain, oedema and constitutional symptoms are also frequently reported. The radiological findings can mimic pulmonary hypertension and in many cases, inappropriate thrombolytic or anti-coagulant therapy had already been given before a diagnosis of PAS was considered. Certain features on CT pulmonary angiography could help to differentiate between these two conditions [13,14]. The role of ¹⁸F-fluorodeoxyglucose positron emission tomography in the diagnosis of PAS is still under investigation [15,16].

The prognosis for patients with PAS is generally poor, with a median OS of approximately 17 months as reported here and by others [2,3,8]. Due to the presence of pulmonary arterial occlusion and the acute symptoms associated with this, surgical resection is usually the mainstay of therapy. Surgery for PAS can include pneumonectomy, lobectomy, PEA or tumour debulking with or without pulmonary artery reconstruction, and the choice of procedure is dependent on factors such as the tumour location and distal extension. Immediate post-operative mortality rate has been previously reported to be around 13-15%, and surgical resection was nearly never R0 [3,5]. An analysis of combined series by Blackmon et al. suggested that patients who underwent an attempt at curative resection have longer OS compared to those who had incomplete resection (median OS of 36.5 vs 11 months) [2]. Since PAS arises from the vascular endothelium and is often bilateral, the aim of PEA is to remove the tumour to restore blood flow to affected regions of the lungs and to relieve the associated pulmonary hypertension. For this reason, PEA often results in significant symptom improvement although the resection margins are rarely clear and therefore the procedure is deemed non-curative. However, in the unusual event of a unilateral disease that was diagnosed early, surgical cure by pneumonectomy is a possibility provided that the patient has enough functional reserve in the remaining lung. Unfortunately this was not the case for any of our patients in the series. Even though PEA did not result in a clear survival benefit, it did provide a significant alleviation of symptoms (from NYHA class III/IV to I/II). Three of our 14 patients who underwent PEA died peri-operatively, although two of them were high-risk surgical candidates following an emergency transfer from other hospitals due to rapid cardio-respiratory deterioration.

All of the notable case series published to date have focused primarily on the surgical aspect of PAS management [3,9,10], and the role of post-operative chemo- and radio-therapy remains unclear. In the combined series by Blackmon et al., the median survival of those who had received multimodality treatment was found to be superior to those who only had single-modality therapy (median survival of 24.7 and 8.0 months, respectively), although the latter was defined as either surgery, chemotherapy or radiotherapy alone, rather than surgery with no post-operative treatment [2]. In 2013, Mussot et al. reported a relatively large surgical series of 31 patients with PAS [3]. Of these, six received neoadjuvant chemotherapy. For adjuvant treatment, 15 received chemotherapy, two had radiotherapy and one patient received both. The authors concluded that there appeared to be no statistical survival benefit in those who received adjuvant treatment compared to those who did not.

A number of peri-operative chemotherapy agents have been reported in the literature for PAS, including anthracyclines, ifosfamide, gemcitabine, taxanes, platinums and immunotherapy [2,17-20]. Anthracyclines, either alone or in combination are the most commonly-used agents, as with most soft tissue sarcomas. Chemotherapy is normally given post-operatively, although cases of improved outcome with neoadjuvant chemotherapy have been described – Linden et al. reported a patient whereby tumour downstaging with neoadjuvant doxorubicin and ifosfamide allowed a radical pneumonectomy to be performed, resulting in a 7-year disease-free survival [7,19]. In our series, a total of four patients received trimodality treatment with post-operative chemotherapy and radiotherapy. The median OS for this group of patients was 24 months compared to 8 months for those who only had surgical resection (n = 6) or post-operative chemotherapy alone (n = 1), although this was not statistically significant. All but one patient had received an anthracycline, and they tolerated it well without evidence of cardiotoxicity despite symptoms of pulmonary hypertension before PEA. For patients with inoperable, metastatic or recurrent PAS, chemotherapy with an anthracycline or its combinations are commonly administered, but others such as gemcitabine and docetaxel, cisplatin and vinorelbine, ifosfamide, as well as radiotherapy could also provide reasonable disease control [17,21-24]. In our series, PLDH, VID, cisplatin and topotecan appeared to have some activity in PAS, although disease progression occurred within months from treatment completion.

Other than chemo- and radio-therapy, a number of reports have found that repeated surgical interventions could also be associated with prolonged survival in patients with metastatic PAS [18,25,26]. This is not entirely surprising, given that surgery for limited metastatic sarcoma is well established. Indeed, we were able to achieve some degree of disease control with radiofrequency ablation for our longest surviving patient who developed lung metastases 7 years after her initial diagnosis.

An inherent shortcoming with a study of such a rare disease is the small sample size. Another limitation of our series is the lack of complete data for some patients that were discharged back to their local hospitals. We do not have information on any post-operative treatment of one patient, as well as details of palliative chemo- and/or radio-therapy of another five patients, although these were censored accordingly on their last follow-up visits in the survival analysis.

Is there a role for targeted therapy in PAS? The only targeted agent approved for use in soft tissue sarcoma at present is the tyrosine kinase inhibitor pazopanib, based on the results of the PALETTE trial [27]. Its use in PAS has not been reported – this is likely due to the rarity and aggressiveness of the disease, and its associated risk of bleeding and thrombosis that could be viewed as relative contra-indications for treatment with pazopanib. A frequent observation in the molecular analysis of intimal sarcoma is gains and amplifications in the chromosomal region of 12q13-14 and the overexpression of Mdm2, a negative regulator of p53 [28,29]. Furthermore, amplification of genes encoding for the platelet-derived growth factor receptor α (PDGFA), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4) and Gli1 (GLI1) are also commonly found [29-31]. Targeting these aberrations with small molecule inhibitors might someday prove beneficial in controlling this devastating disease.