Radiological unilateral pleuroparenchymal fibroelastosis as a notable late complication after lung cancer surgery: incidence and perioperative associated factors

Abstract OBJECTIVES Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural-parenchymal involvement, predominantly in the upper lobes. Unilateral upper lung field pulmonary fibrosis (upper-PF) that is radiologically consistent with PPFE reportedly develops after lung cancer surgery in the operated side and presents many clinical characteristics in common with PPFE. However, the incidence and perioperative associated factors remain unclear. METHODS All consecutive patients with lung cancer resected completely from 2008 to 2016 were investigated retrospectively. Pre-/postoperative characteristics were compared between patients with and without unilateral upper-PF. Cumulative incidence curves were estimated using competing risk analysis. RESULTS Among the 587 included patients, 25 patients (4.3%) were diagnosed as unilateral upper-PF. The 3-, 5- and 10-year cumulative incidence of unilateral upper-PF was 2.3%, 3.3% and 5.3%, respectively. In multivariable analysis, male sex, presence of a pulmonary apical cap, lobar resection and low % vital capacity (%VC < 80%) were independent perioperative associated factors. The 10-year cumulative incidence was 6.3% in patients treated with lobar resection, 8.0% in male patients, 10.3% in patients with pulmonary apical cap and 14.5% in patients with low %VC. Postoperative pleural effusion at 6 months after surgery was much more common in the patients who later developed unilateral upper-PF (96.0% vs 24.2%). This pleural effusion persisted and was accompanied thereafter by pleural thickening and subpleural pulmonary fibrosis. During the clinical courses of 25 patients with unilateral upper-PF, 18 patients presented symptoms related to upper-PF and 6 patients died. CONCLUSIONS Unilateral upper-PF is an occasional but under-recognized late complication after lung cancer surgery.

More recently, upper lung field pulmonary fibrosis (upper-PF) radiologically consistent with PPFE has been reported to develop as a late complication after thoracic surgery [6,7]. Upper-85 PF lesion was limited to the operated side, but similar to PPFE in terms of radiological and clinical characteristics. Most of the patients with unilateral upper-PF presented with respiratory symptoms and developed intra-/extrathoracic aberrant air suggestive of lung parenchymal air leak during their clinical courses [8], which might be related to the progression of unilateral upper-PF [7]. The prognosis was poor with a median survival time of 49.3 months, and all 90 causes of death were respiratory diseases. Regarding respiratory complication after thoracic surgery, pneumonia is well known and can be caused by bacterial colonization of atelectatic lung [9]. Pneumonia generally occurs in the early post-operative periods and may improve with appropriate treatment. On the other hand, unilateral upper-PF occurs late after surgery [6,7] and therefore may receive less attention compared to pneumonia. Although unilateral upper-95 PF is considered an important late complication after thoracic surgery, little is known about the incidence, mechanisms and perioperative associated factors for unilateral upper-PF development after lung cancer surgery. In addition, the previous reports showed that almost all patients with unilateral upper-PF had a preoperative pulmonary apical cap in the apex of the lungs [6], and an autopsy showed findings consistent with postoperative chronic pleuritis 100 [7]. However, the effect of pulmonary apical cap and postoperative chronic pleuritis on disease development is also unclear. The purpose of this study was to determine the incidence, mechanisms and perioperative associated factors for unilateral upper-PF development.

Ethics Statement
The study protocol was approved by the ethics committee of Kanagawa Cardiovascular and Respiratory Center (KCRC-20-0052, approval date: 2021/02/24). The requirement for informed consent from individual patients was waived because it was a retrospective study.

Study participants
All consecutive patients with lung cancer who underwent complete resection between January cancer-free surgical margins, both grossly and histologically. We excluded patients with a 115 history of bilateral interstitial pneumonia; thoracic surgery, including cardiac, esophageal, and lung surgery; inflammatory lung disease, including mycobacteriosis and aspergillosis; and chemotherapy and chest radiotherapy for a previous malignancy. We also excluded patients who underwent pneumonectomy. For patients with lung cancer recurrence, we evaluated the clinical and radiological findings within the recurrence-free survival period, considering the 120 effects of treatment for recurrent cancer. Patients with early recurrence within 6 months after surgery were also excluded. For patients with metachronous multiple lung cancer, we evaluated the clinical and radiological findings until just before the start of the metachronous multiple lung cancer treatment. Patients treated for multiple lung cancers within 6 months after surgery were also excluded. 125 Eligible patients were divided into two groups based on the development of unilateral upper-PF: with unilateral upper-PF group and without unilateral upper-PF group. Upper-PF was diagnosed when radiological findings in CT matched the criteria of "definite PPFE" or "consistent with PPFE" previously reported as follows. "Definite PPFE" is defined as demonstrating pleural thickening associated with subpleural fibrosis concentrated in the upper 130 lobes, with a markedly less or absent involvement of the lower lobes. "Consistent with PPFE" is defined as pleural thickening associated with subpleural fibrosis in the upper lobes, but distribution of these changes is not concentrated in the upper lobes or there are features of [1]. These criteria were applied only for unilateral lung in the operated side. The diagnosis of upper-PF was made based on the consensus of at least two 135 board-certified chest surgeons, chest physicians, and chest radiologists.
We then reviewed the medical records of all eligible patients and compared the clinical characteristics including age, sex, smoking history, BMI, results of respiratory functional analysis, operative approach (video-assisted thoracoscopic surgery or open thoracotomy), operative procedure (lobar resection or sublobar resection), the use of polyglycolic acid (PGA) 140 sheet and fibrin glue, preoperative pulmonary apical cap and adjuvant chemotherapy between the two groups.

Operative Procedure
Lobar resection is lobectomy (removal of a single lobe) or bilobectomy (removal of two adjacent 145 lobes). Sublobar resection is wedge resection or segmentectomy. We routinely covered PGA sheet (Neoveil large size; 10.0 x 10.0cm: Gunze, Kyoto, Japan) and 3ml or 5ml of fibrin glue (Bolheal: Teijin, Tokyo, Japan or Beriplast P Combi-Set: CSL Behring, Tokyo, Japan) to the dissected hilum when we performed lobectomy, bilobectomy and segmentectomy regardless of lung parenchymal air leak. In the case of wedge resection, we covered them to the air leak 150 point only when we confirmed the presence of air leak.

Definition of pulmonary apical cap
Pulmonary apical cap is a wedge-and triangle-shaped opacity in the apex of the lung with a 155 broad pleural contact [10,11]. The length of pleural contact was reported to range from 7 mm to 6.0 cm on CT [10,11]. Therefore, we evaluated the presence or absence of preoperative pulmonary apical cap with a pleural contact of 5 mm or more on the operated side on CT.

Radiological evaluation before and after lung cancer surgery 160
In all eligible patients, thin-sliced high-resolution CT (1 mm) was routinely performed before and after lung cancer surgery. During the postoperative follow-up period, chest radiography and CT was performed alternately every 3 months for the first 5 years, and thereafter CT was performed every 6 months typically up to 10 years. All images were interpreted using Synapse (Fujifilm Medical Systems, Japan). 165

Pathological evaluation of the background of the lung specimen in the patients who developed upper-PF later
Histopathologic materials from all patients who developed unilateral upper-PF later were reviewed by a board-certified pathologist. The presence or absence of interstitial pneumonia 170 in the area distant from lung cancer was microscopically evaluated.

Pleural effusion at 6 months after lung cancer surgery
A previous report showed that an autopsy of a patient with unilateral upper-PF showed chronic pleuritis and suggested that chronic pleuritis following thoracic surgery contributes to unilateral 175 upper-PF development [7]. Because all eligible patients were routinely evaluated with CT every 6 months, we assessed the presence or absence of pleural effusion on CT at 6 months after surgery, regardless of the amount of pleural fluid.

Statistical analysis 180
Descriptive statistics were expressed as n (%) or median and range. Mann-Whitney U-test and Fisher's exact test were used to compare continuous variables and categorical variables, respectively. A competing risk method was used to estimate the cumulative incidence of unilateral upper-PF. In this study, recurrence of lung cancer, treatment for metachronous multiple lung cancer or death of other diseases before unilateral upper-PF development were 185 considered competing risk events. Patients who had not developed unilateral upper-PF and had not died were censored at the time of last follow-up. Gray's test was used to test for differences in the cumulative incidence curves. The association between unilateral upper-PF and patient characteristics at lung cancer surgery were assessed using a proportional hazards model (Fine-Gray model). Statistical significance was set at p value < 0.05. Variables with p 190 value < 0.05 in univariable analysis were considered factors potentially associated to upper-PF development and used in subsequent multivariable analysis. Statistical analyses were conducted using EZR (Saitama Medical Center, Jichii Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [12]. 195

Patient characteristics
Among the 943 patients with completely resected lung cancer, 587 patients were included. The study profile is shown in Supplementary Figure 1 Table 1. Twenty-five patients with unilateral upper-PF were significantly older (p = 0.035), more men (p = 0.004), and had a lower BMI (p = 0.014) than those without. Lobar resection was more frequently performed in patients with unilateral upper-PF than in those without (92.0% 205 vs. 73.1%, p = 0.036). The incidence of unilateral upper-PF development was 4.5% for lobectomy (19/426) and 50.0% for bilobectomy (4/8). The details of operative procedures for patients with unilateral upper-PF is shown in Table 2. Patients with unilateral upper-PF had more commonly preoperative pulmonary apical cap than those without (84.0% vs. 39.7%, p < All patients did not receive adjuvant radiotherapy. 210

Cumulative incidence of unilateral upper-PF after lung cancer surgery
The cumulative incidence of unilateral upper-PF gradually increased two years after lung cancer surgery as shown in Figure 1A. For entire population, the 3-, 5-, 10-, and 12-year cumulative incidence of unilateral upper-PF was 2.3%, 3.3%, 5.3% and 6.9%, respectively. 215

Pleural effusion at 6 months after lung cancer surgery
We investigated the presence or absence of postoperative pleural effusion at 6 months after surgery and found that pleural effusion was much more common in patients with unilateral upper-PF than in those without (96.0% vs. 24.2%, p < 0.001) ( Table 3). This trend was also 220 observed regardless of operative procedure (lobar resection and sublobar resection). Of note, pleural effusion in all patients with unilateral upper-PF persisted and was accompanied by pleural thickening and fibrosis adjacent to the pleura.

Clinical and radiological courses of patients with unilateral upper-PF 225
The median interval from lung cancer surgery to the diagnosis of unilateral upper-PF was 36.3 months (range, 4.8-121.8) ( Table 4). We carefully examined the radiological findings on CT in order to detect intra-/extrathoracic aberrant air such as subcostal and pneumothorax air.

Pathological background of lung specimens resected for lung cancer in 25 patients who later developed unilateral upper-PF
Interstitial pneumonia was pathologically observed in two patients (8.0%) despite no radiological evidence of interstitial shadow. One was usual interstitial pneumonia (UIP) and the other was indeterminate for UIP. In addition, centrilobular emphysematous change was 245 commonly observed in 18 patients (72%). The cumulative incidence curves and the details of the cumulative incidence according to perioperative associated factors were shown in Figure 1B-1E and Table 6. The 10-year cumulative incidence was 6.3% in patients treated with lobar resection, 8.0% in male patients, 260 10.3% in patients with pulmonary apical cap and 14.5% in patients with low %VC, respectively.  Although he was asymptomatic during the course, unilateral thoracic deformity apparently emerged.

Discussion
The present study identified four clinical findings. First, the incidence of unilateral upper-PF 275 development was 4.3% for all lung cancer surgery, 4.5% for lobectomy and 50.0% for bilobectomy. The cumulative incidence gradually increased after lung cancer surgery and 10year cumulative incidence was 5.3%. Second, 72% of the patients with unilateral upper-PF had some adverse events associated with the lesion. Third, pleural effusion at 6 months after surgery was much more common in patients who later developed unilateral upper-PF than 280 those who did not. Fourth, multivariable analysis revealed male sex, low %VC, lobar resection as secondary PPFE [7]. In addition, the previous study showed that almost all patients with 305 unilateral upper-PF had aberrant air emergence suggestive of lung parenchymal air leak on CT during their clinical courses [7]. Therefore, some visceral pleural disorders may contribute to the progression of unilateral upper-PF. In the present study, almost all patients who later developed unilateral upper-PF had had pleural effusion in the residual space at 6 months after surgery. The pleural effusion persisted, accompanied by pleural thickening and subpleural 310 pulmonary fibrosis. These results indicate that chronic pleuritis contributes to unilateral upper-PF development. In fact, there was a case of bilateral tuberculous pleuritis progressing to upper-lobe-predominant pulmonary fibrosis mimicking PPFE 3 years thereafter [16], which supports our hypothesis. In addition, PGA sheet and fibrin glue were used in all patients who later developed upper-PF. Because fibrin glue reportedly induced eosinophilic pleural effusion 315 after lung resection [17], PGA sheet or fibrin glue may play an important causal role for upper-PF development despite no significant difference.
. Third, chest physicians and surgeons should be aware that unilateral upper-PF development may be correlated with perioperative patient characteristics including male sex, 320 pulmonary apical cap, low %VC and lobar resection. To our knowledge, there is no definite reason for the predominance of male sex in this disease development. However, almost all patients with the above-mentioned "unilateral fibrobullous change" were male [15], which indicates that male sex is associated with disease development. With regard to low %VC and preoperative pulmonary apical cap, PPFE patients commonly have low %VC [1,3,4,18] and 325 pulmonary apical cap has the same histology as PPFE in spite of being an anatomically localized and non-progressive lesion [1,10,19]. In addition, pulmonary apical cap has been reported to be potentially caused by relative ischemia in the upper lobes and low-grade inflammation in the lung parenchyma [1,18] and be considered as a potential risk factor of PPFE [20]. Therefore, we suppose that patients with low %VC and pulmonary apical cap have 330 some potential pathophysiological factors in common with those with PPFE. Furthermore, our results also showed that lobar resection was also an associated factor for unilateral upper-PF development. Generally, lobectomy, especially bilobectomy, is a wide resection of the lung

Conclusion 345
Unilateral upper-PF is not a rare but under-recognized late complication after lung cancer surgery. This complication may be correlated with perioperative patient characteristics including male sex, low %VC, pulmonary apical cap and lobar resection.

Acknowledgement 350
We would like to thank Editage (www.editage.com) for English language editing.

Data availability statement
All relevant data are within the manuscript and its Supporting Information files.

Funding Sources
The study did not receive any funding.

Conflict of interest:
The authors have no conflicts of interest to declare. Central Image.