Multimodality treatment including surgery for primary pulmonary sarcoma: Size does matter

Primary pulmonary sarcoma (PPS) accounts for less than 1.1% of all pulmonary tumors. Few outcome data are reported. We evaluated outcome and prognostic factors in our series.


| INTRODUCTION
Primary pulmonary sarcoma (PPS) is a rare aggressive tumor, accounting for only 0.4% to 1.1% of all lung malignancies. 1,2 Due to its rarity, the literature is limited mostly to case reports or small retrospective case series. Surgery is the cornerstone of treatment and most studies have demonstrated a survival benefit after complete resection. [3][4][5] The role of chemotherapy in localized sarcomas is undisputed in Ewing Sarcoma, high-grade osteosarcoma, and pediatric rhabdomyosarcoma. Most sarcoma centers use chemotherapy to treat locally advanced high-grade soft tissue sarcomas (STSs) as well as STS deemed to have a high Stéphane Collaud and Theresa Stork contributed equally to this work. risk of metastatic disease and a chemotherapy-sensitive histology. [6][7][8] Staging aims at better stratifying patients' risk of death and guide therapeutic management. Until shortly, there has been no dedicated staging classification for PPS and different staging systems were used, depending on the background of the authors. Lung cancer staging system was used in three reports. 1,4,9 It was found to be well applicable to PPS and was a significant predictor for survival. 1,4 In two other studies including the largest PPS series with 365 patients, staging system for STS of trunk and extremity was used. 3,10 In the 8th edition of the AJCC (American Joint Commission on Cancer) cancer staging manual, an effort was made to emphasize the anatomic site of primary sarcoma and for the first time, a dedicated staging system was described for STS of the abdomen and thoracic visceral organs, which would be applicable for PPS. 11 To our knowledge, the reliability of this dedicated staging system has not been assessed so far. Table 1 summarizes the different staging systems available for PPS as well as their impact on overall survival.
Here, we describe our patient cohort with PPS that was surgically treated within a multimodality therapy concept. We assessed the reliability of the abdomen and thoracic visceral organ STS classification when applied to PPS, as well as the outcome and prognostic factors for survival.

| MATERIALS AND METHODS
All consecutive patients with histologically confirmed PPS who underwent resection in a curative intent in our center, from January 2002 to December 2018, were included. Lesions with both lung and chest wall invasions were considered as PPS when more than 95% of tumor volume was located in the lung. 1 Tumor resectability was evaluated by the surgeon based on preoperative imaging. Tumors involving structures such as the brachial plexus, esophagus, or heart were considered unresectable. Data were retrospectively retrieved from the patients' electronic documentation system and all follow-up centers. The study was approved by the institutional ethics committee (19-8751-BO).
Staging included computed tomography (CT) of the chest and upper abdomen, brain imaging with CT or magnetic resonance imaging (MRI), and a whole-body positron emission tomography integrated in CT (PET/CT).
Histological confirmation of malignancy was obtained preoperatively whenever possible. Treatment strategy was discussed on a case-by-case basis during our multidisciplinary tumor board conferences dedicated to thoracic oncology and/or sarcoma. When the diagnosis of PPS was known preoperatively, neoadjuvant treatment was administered with or without radiation. Restaging included CT of the chest and upper abdomen and/or PET/CT. Surgical approach and extent of lung resection were based on surgeons' evaluation of preoperative imaging. Anatomic lung resection was favored over wedge resection. Mediastinal lymph node dissection was routinely performed. Resection was defined by the pathologist as complete (R0), or microscopically (R1) or macroscopically (R2) incomplete.
PPS were staged according to the 8th edition of the AJCC cancer staging manual for lung cancer, STS of trunk and extremities as well as for STS of abdomen and thoracic visceral organs. 11 Of note, patients with complete response after induction therapy were classified as ypT0 in all three staging systems. Patients with pleural sarcomatosis were defined as T4 in the STS of the abdomen and thoracic visceral organ TNM staging system. Grading was based on the evaluation of tumor differentiation, mitotic count, and necrosis according to the French Fedeŕation Nationale de Centres de Lutte Contre le Cancer (FNCLCC) system. 12,13 Recurrence was defined as local (intrathoracic) or distant, based on follow-up imaging. Patients with incomplete resections were not defined as having recurrence until progression was observed on imaging.
T A B L E 1 Available staging systems for PPS and the impact of their variables on overall survival

| RESULTS
Thirteen patients (7 females, 54%) with PPS were surgically treated within a multimodality therapy concept during the study period in our center. Patient characteristics are summarized in Table 2. Median age at surgery was 56 years . Most of the patients had a preoperative diagnosis of sarcoma (n = 9, 69%). Median tumor size at diagnosis was 11.5 cm (1-30 cm).
Eight patients (62%) received neoadjuvant treatment. One patient had radiotherapy alone and two had combined chemoradiotherapy with a median dose of 50 Gy (range 45-66).
Chemotherapy regimen was ifosfamide/doxorubicin (n = 3), VIDE (n = 1), ifosfamide/adriblastin (n = 1), and epirubicin (n = 1). In one patient chemotherapeutic agents given were unknown. One patient with preoperative diagnosis of sarcoma did not receive induction therapy due to his advanced age. Median delay between preoperative imaging and resection was 12 days (from 3 to 41). Surgical resection required a pneumonectomy in most of the patients (n = 7, 54%). On pathologic examination, response to neoadjuvant treatment was complete in two patients. The most common histology was synovial sarcoma (n = 4, 31%). Most of the patients had high-grade (G3) sarcomas (n = 6, 46%). Complete R0 resection was achieved in 81% of patients (9/11).

| DISCUSSION
In this single-center retrospective study including 13 patients who underwent resection in a curative intent for PPS, overall survival reached 60% at 5 years. This is in line with the best results from the literature, which range from 27% to 69%. 4,14 In STS of the extremity, tumor size and grade are major determinants of overall survival. 15   with lobectomy and pneumonectomy. 10 The authors could not show a difference in distribution of predictive factors between the three groups, except for gender. Progression-free survival was not different between anatomic and nonanatomic resections (P = .34). In sarcoma, the typical mechanism of spread is local extension within the organ or within the involved cavity and hematogenous to distant sites. 18 Lymphatic spread is rare. In STS of the extremities, lymph node involvement ranges from 2% to 6%. 3,[20][21][22] In comparison, lymph node involvement may occur much more frequently in PPS. It can be as high as 16% to 25% in patients who underwent surgery with curative intent. 3,5 In another series also including patients with unresectable disease who underwent exploratory thoracotomy, 30% of patients had positive lymph nodes. 4 No correlation between histologic subtype and nodal status could be shown. 3 The reason why PPS do have more frequent lymphatic spread than extremity sarcoma is probably due to the characteristics of lung tissue. It has a very dense lymphatic vessel network compared with tissue of extremity. In the analysis of the SEER database, a trend was seen for worse survival in patients with nodal involvement in multivariate analysis while the difference was statistically significant in the univariate analysis. 3 Patients with node-negative disease had 5-year OS of 39% compared with 14% for those with node-positive disease. 3 Node involvement per se may yield to unfavorable prognosis or can just be a sign of more advanced disease. Indeed, all three patients with unresectable disease who underwent exploratory thoracotomy had histologically proven lymph node involvement in the series of Bacha et al. 4 In our work, despite routine mediastinal lymph node dissection, none of the patients had lymph node involvement. The reason is unclear but There is also a gray zone for definition interpretation of T3 (tumor invading another organ) and T4 (multifocal involvement) tumors in case of PPS. To the best of our knowledge, we defined patients with pleural sarcomatosis as having multifocal involvement or T4 tumors.
Unfortunately, from our patient cohort, we could not demonstrate any value of this new staging system in predicting death or relapse.
However, we encourage the use of this classification for the purpose of future data collection and potential refinement of a more specific thoracic organ staging algorithm in the future, including different known prognostic factors and specific thoracic anatomic relationships.
In our study, 62% of patients had induction chemo(radiation) therapy before resection. Induction therapy was administered routinely in all but one case with preoperative diagnosis of PPS. While the use of chemotherapy is undisputed in Ewing and osteosarcoma, it is more controversial in STS. However, in recent years, the clinical benefit has been more evident when selected for patients with chemotherapy-sensitive subtypes and at highest risk of metastatic disease. To this end, most centers prefer neoadjuvant treatment to interrupt treatment early in those few patients progressing on chemotherapy. 6,7,[23][24][25] Given the rarity of PPS it is not surprising that no prospective data is available. At our center, we feel that given the mostly large tumor size and proximity to vital structures, induction therapy may facilitate resection and offer earliest treatment of micrometastases.
In our series, no patient had become unresectable due to early progression under induction therapy.
Our study has the highest proportion of patients with PPS who received induction therapy before resection in a curative intent.
Despite its limited sample size, clinical factors such as tumor size, gender, and type of lung resection were found to be predictive of overall and sarcoma-specific survival. These factors, along with other known survival predictors (tumor grade, completeness of resection) should aid the clinician to determine the need for neo-or adjuvant therapy, respectively. Due to the rarity of PPS and so far the lack of collaboration between centers to elaborate common study protocols, there are still more questions related to the optimal management of PPS than concrete answers. Building an international register and improving networking would probably set optimal conditions to more uniformly manage patients with PPS, leading to increasing patient survival and quality of life.

DATA AVAILABILITY STATEMENT
The anonymized data that support the findings of this study are available on request from the corresponding author. ORCID