Pulmonary artery sarcoma (PAS) stands as an exceedingly rare and inadequately studied disease, with only about 500 reported cases since its initial description in 1923 (1, 2). Often, PAS faces misdiagnosis as pulmonary embolism due to overlapping symptomatology; nevertheless, its prognosis remains highly unfavorable. Studies in the past have indicated that patients afflicted by PAS, without receiving effective treatment, exhibited a mere six-week median survival (3). Given its rarity and intricate anatomical location, the management of PAS remains a subject of controversy. Presently, treatment approaches predominantly rely on limited case series, with surgical interventions such as pulmonary endarterectomy (PEA) and pneumonectomy standing as the most efficacious options for PAS patients (4, 5).

This study aims to present a case series encompassing 20 PAS patients who underwent PEA at a tertiary referral center. The primary objective of this investigation is to shed light on the treatment modalities employed and the corresponding outcomes in the context of PAS.

Primary tumors of the pulmonary artery are exceedingly rare, with most of them being intimal sarcomas arising from the intimal layer (7). In clinical practice and published literature, PAS primarily refers to pulmonary artery intimal sarcoma. Due to its rarity and complexity, the optimal treatment approach for PAS remains uncertain (8). Complete surgical resection is the preferred treatment, but achieving complete resection is challenging due to PAS often involving bilateral pulmonary arteries and spreading along the pulmonary intima to the entire pulmonary artery system (9). The unique growth pattern of PAS, however, allows for the possibility of complete tumor removal with PEA. PEA can alleviate pulmonary embolism and pulmonary hypertension while preserving the pulmonary vascular bed, thus offering PAS patients the opportunity for further treatment.

This study presents a cohort of 20 PAS patients who underwent PEA, representing one of the largest case series in recent years. Among the 20 patients, the median age was 52 (45, 57) years, which aligns with a review of 381 patients with a median age of 52 (41, 62) years (10). While most studies have shown no significant gender difference in PAS patients (11), our center's experience showed a slight female predominance, consistent with studies conducted by Akitaka et al. and Cherry et al. (12, 13). Common symptoms observed in PAS patients included dyspnea, chest pain, cough, and hemoptysis. In some cases, fever or weight loss may also occur, which could be indicative of a distinguishing manifestation (14). Unfortunately, these non-specific symptoms often lead to misdiagnosis. Among the 20 patients, only six were initially suspected to have malignancy during their first hospitalization, while most were misdiagnosed as pulmonary thromboembolism. The median time from symptom onset to diagnosis was 3 (range: 1–8) months.

Routine laboratory tests generally did not reveal any significant abnormalities, except for elevated NSE levels in 50% of patients, which is consistent with previous studies (11). The cause of elevated NSE remains unclear, but it suggests the need to consider PAS in pulmonary embolism patients with elevated NSE levels. Moreover, patients with elevated pro-GRP levels are at high risk for neuroendocrine tumors (15), as evidenced by one patient in this series whose pathological result indicated LCNEC.

While the definitive diagnosis of PAS relies on pathology, patients presenting with symptoms associated with pulmonary embolism may suggest PAS after undergoing a series of tests. TTE is essential for evaluating patients with pulmonary embolism and may detect pulmonary hypertension or suspicious masse in the pulmonary artery, although it may not accurately distinguish between thrombus and tumor tissues in the pulmonary trunk. CTPA is the most common examination for patients with pulmonary embolism. Findings of PAS on CTPA resemble those of pulmonary embolism, presenting as nodular filling defects (16). However, Gan et al. concluded that the wall eclipsing sign on CTPA is pathognomonic of PAS (17). Additionally, CTPA and MRI can detect parenchymal invasion and intrapulmonary or mediastinal metastasis (1). Fluorodeoxyglucose PET-scan and MRI are more commonly used in the workup of suspected PAS patients. Typical MRI findings include higher heterogeneous enhancement and a grape-like appearance of pulmonary vasculature (18, 19). Furthermore, MRI can assess pulmonary valve and right ventricular outflow tract involvement, which is crucial for determining the appropriate surgical technique (20). PET-CT can differentiate PAS from pulmonary embolism based on the uptake of radiopharmaceuticals, with PAS patients showing a higher mean SUVmax (7.63 ± 2.21 in the PAS group vs. 2.31 ± 0.41 for the thrombus group) (21).

In this study, 65%, 84.2%, and 83.3% of patients who underwent CTPA, MRI, and PET-CT, respectively, were diagnosed with PAS based on typical imaging manifestations. MRI and PET-CT exhibited high accuracy, with false-negative results primarily attributed to low cellularity or the presence of fresh thrombus or other non-cellular components (22). In this series, all patients were clinically diagnosed with PAS based on multiple findings. Seven patients underwent biopsy to confirm the pathological diagnosis. The role of preoperative biopsy in PAS patients remains controversial. Some studies have reported successful pathological diagnosis through CT scan-guided transthoracic aspiration, EBUS-TBNA, and ECGF biopsy (23). Among these seven patients, two using EBUS-TBNA and three of five using ECGF were confirmed to have malignancy. However, two preoperative biopsies resulted in false negatives. Given the associated risk, preoperative biopsy is not deemed necessary for patients opting for surgery.

In clinical practice, PAS is often referred to as pulmonary artery intimal sarcoma—a unique type of soft tissue sarcoma with uncertain differentiation (1). Previous literature often described PAS with local differentiation as other types of sarcomas (24). In our study, intimal sarcoma was confirmed in 19 patients, with 8 of them displaying local differentiation. Additionally, we identified one patient with a diagnosis of LCNEC. Interestingly, this patient’s tumor grew along the lumen of the pulmonary artery without evidence of parenchymal lung invasion on imaging or nuclear medicine examination. Similar cases have been rarely reported, including a study by Estrera et al. describing LCNEC with local parenchymal lung invasion (25), and two cases of small cell carcinomas without parenchymal lung invasion (26, 27). It is plausible that these tumors may arise from neuroendocrine cells within the pulmonary artery intimal tissue. Given the similar growth pattern with intimal sarcoma and potential benefits from PEA, we have included this case in our series.

Surgical management is currently the most promising treatment for PAS, aiming to relieve clinical symptoms and prolong survival. Numerous centers have reported their experiences with surgical treatment for PAS (2, 28, 29). Patients who underwent radical resection demonstrating longer median overall compared to those with incomplete resection (36.5 vs. 11 months) (20). A review of 381 PAS patients by Bandyopadhyay et al. demonstrated significantly improved survival for patients who underwent definitive surgeries compared with partial resection (10). Currently, the two prominent surgical procedures are pneumonectomy and PEA, chosen based on the extent of tumor involvement. In the past, surgeons attempted radical resection via pneumonectomy when the tumor was confined to a unilateral pulmonary artery. However, considering that PAS are often bilateral and spread along both pulmonary arteries, even in the absence of macroscopic tumors, unilateral pneumonectomy might not be sufficient (30). PEA, which is a palliative procedure, offers the advantage of relieving pulmonary embolism and preserving the pulmonary vascular bed. For instance, Veysel et al. performed PEA for 13 PAS patients with a median survival of 18 months, and the 1 and 3 years survival rates were 60.6% and 30.3%, respectively (31). Song et al. reported 10 PAS patients who underwent PEA, with a median survival of 37.0 months (5). Mussot et al. reported a survival rate of 63%, 29%, and 22% at 1, 3, and 5 years, respectively, for patients who underwent surgery (32). Recently, Chan et al. reported an anatomic resection and replacement technique for involved pulmonary root and main pulmonary arteries, with or without PEA, leading to more adequate local control and 1, 3, 5, and 10-year survival rates of 70%, 48.8%, 41.8%, and 8.4% (2). In our center, PEA was the routine surgical technique for PAS patients, and pneumonectomy was performed when the pulmonary parenchyma was involved. The perioperative mortality in this series was 15%, which was higher than PEA performed among patients with chronic thromboembolic pulmonary hypertension but comparable to other PAS studies (2, 5). The estimated cumulative survival rates at 1 and 2 years in this series were 66.4% and 55.3%, respectively, which were comparable to most studies. However, some patients in this study had a short follow-up period, and long-term observation of patients with recurrence is necessary to accurately evaluate overall survival.

The effect of adjuvant therapies, including postoperative chemo- and radiotherapy, remains controversial. Mussot et al. reported that postoperative adjuvant therapy did not significantly improve survival for PAS (32). However, several other reports suggested that postoperative adjuvant therapy could be effective. Wong et al. studied 14 PAS patients who underwent PEA and found that those who received both postoperative chemo- and radiotherapy had longer overall survival compared to those who did not (24 vs. 8 months) (33). Similar results were found by Yin and colleagues (29). A systematic review conducted by Bandyopadhyay et al. showed that adjuvant therapy improved survival and reduced distant metastasis but did not affect local recurrence (10). The molecular genetics of PAS have recently developed rapidly, and targeted therapy is promising for PAS patients (1). For instance, tyrosine kinase inhibitors like anlotinib can target vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, thereby inhibiting tumor angiogenesis and tumor cell proliferation (34). However, there are limited targeted therapy studies for PAS (35, 36). Hideomi et al. reported two recurrent PAS cases who used pazopanib after surgery (37). One patient did not respond to pazopanib, but another patient still had a stable disease after using pazopanib for 18 months. Further evidence is needed to verify the effectiveness of targeted therapy.

Considering that PEA may be a palliative procedure for PAS, all of our patients received postoperative chemotherapy. Targeted therapy with anlotinib, or immunotherapy with sintilimab were used for 7 patients. These additional treatments significantly prolonged survival in patients with recurrent tumors, with two patients having a stable disease over 50 months after surgery. Our results showed that most of the patients undergoing PEA experienced recurrence or metastasis, but only five patients died during the follow-up period. This indicates that PEA can relieve pulmonary embolism and prevent sudden death in PAS patients, and when combined with postoperative treatment, it can prolong survival.

This study has some important limitations due to the rarity of PAS. First, it is a retrospective single-center approach, which may limit the generalizability of the findings. Second, the study only includes patients who underwent PEA, which may not represent the overall characteristics of all PAS patients. Third, the sample size is limited, and some patients had short follow-up periods, potentially affecting the accurate evaluation of overall survival for PAS patients undergoing PEA.

PAS is a rare malignancy characterized by a poor prognosis. However, our study has shown that PEA is a palliative bur effective treatment method for PAS patients. When combined with postoperative therapies such as chemotherapy and targeted therapy, it can lead to improved long-term survival outcomes. Our findings underscore the importance of early diagnosis and comprehensive treatment strategies in managing this challenging and uncommon disease. Further research and multi-center studies are warranted to validate these results and explore potential advancements in the management of PAS.