In this study, we retrospectively investigated the clinicopathological characteristics of patients with PPC who were surgically treated in our hospital. PPC is generally associated with a poor prognosis with a 5-year OS rate of 20–48% after surgical resection (3, 4, 8–10). In the present study, we observed a favorable long-term survival rate of 60% compared with previous studies. This is presumably attributed to the absence of locally advanced cases, such as T3 tumors extending beyond parietal pleura, which were frequently observed in previous studies (4, 9, 11). Tumor relapse tends to occur within one year of surgery (3, 4, 11, 12). Similarly, 11 of 13 relapses were observed within 6 months of surgery, and most cases were detected as distant metastases. This finding might imply that identifying such an aggressive subgroup in this entity would lead to clarify appropriate candidates for neoadjuvant or adjuvant therapy in patients with curative resection of PPC. The strategy on adjuvant chemotherapy in the current study does not seem consistent, and no patients received pre- or postoperative immune checkpoint inhibitors (ICIs). These facts made it difficult to discuss implications for neoadjuvant or adjuvant therapy in PPC.
Several factors have been reported to be determinants of poor outcomes in patients with PPC, such as lymph node metastasis, tumor size, and pleural invasion (3, 4, 8–10, 13). However, most studies were retrospective analyses with small sample sizes with the prognostic factors remaining unclear. In particular, the association between imaging findings and prognostic factors of PPC has been reported in only a few articles to date. The CT features of PPC are almost the same as those of NSCLCs, but the possibility of PPC might be suggested when a subpleural necrotic tumor is detected with peritumoral areas of ground-glass opacification and regional invasion to the chest wall or mediastinum (14). A central low-attenuation area or cavity on CT was reported to have a poor prognosis and represents tumor necrosis on histopathological specimens (15). Pathological massive coagulation necrosis indicates aggressive tumor growth, thereby contributing to poor prognosis (8). On the contrary, air bronchogram on CT was suggested to be a favorable prognostic factor, which might reflect intact intratumoral bronchi without tumor invasion (16). In addition to the cavity in the tumor, tumor size, and pleural invasion, our study showed for the first time that ringed FDG uptake on PET/CT was a significant prognostic factor of PPC. In 5 cases, the tumor had no cavity macroscopically or on CT, but revealed ringed FDG uptake on PET/CT (Figure 1a-c). The ringed uptake supposedly indicates central necrosis, which is an aggressive feature that was later confirmed histologically (Figure 1d). PET/CT might potentially detect central necrosis prior to cavity formation on CT and has important clinical implications for the prognosis of PPC.
PD-L1 on antigen-presenting cells or tumor cells, when interacting with PD-1 on T cells, negatively regulates T cell activation or immune response against tumor cells (17, 18). Accordingly, PD-L1 expression in tumors is thought to affect tumor behavior and prognosis. PD-L1 is expressed more frequently in PPCs than in NSCLCs. In a previous report, PD-L1 was expressed in 75% of PPC cases (5) but was expressed in approximately 20% of NSCLC (19) or adenocarcinoma cases (20). Similarly, in the present study, 69% of PPC cases expressed PD-L1. These studies, including the current one, used clone E1L3N and 5% as the cut-off of positivity. Younger patients (21) and parietal pleural invasion (12) were reportedly associated with higher PD-L1 expression in PPC patients. A meta-analysis of over 11,000 NSCLC patients revealed that higher expression of PD-L1 was associated with the male sex, smoking history, tumor size, and lymph node metastases but not age (22). The current study showed that PD-L1 expression was associated with smoking history but not sex, age, or tumor size. Therefore, meta-analyses or multicenter prospective studies are necessary to define the correlation between PD-L1 expression and clinicopathological features. The association between PD-L1 and prognosis remains inconclusive, although several retrospective studies have focused on PPC. This is partly due to varieties of the clone of antibodies as well as cut-off values, both of which probably have a substantial influence (21, 22). In addition, factors regarding whether or not surgical resection is indicated and whether or not ICI was available or is indicated would affect the analyses. The present study only included surgical cases with or without adjuvant chemotherapy other than ICI and did not demonstrate any prognostic impact for PD-L1 expression even though other cut-off values were applied (data not shown).
The current study has several limitations. First, our analysis was based on a very small number of patients from one institution because of the rarity of PPCs; hence, our findings are inconclusive. Second, the retrospective nature of this study may lead to the potential risk of several biases. Therefore, our results should be interpreted with consideration of these limitations, and multicenter prospective studies are needed to validate our findings.