Concise and accurate prognostic prediction models for patients with malignancy are essential for clinical decision-making and scientific research. Clinically, TNM stage is the most widely used survival predictor for cancer patients. Therefore, identifying more prognostic factors and a more individualized model will certainly improve the accuracy of clinical outcome prediction. In this study, we used the SEER database, a large-scale population-based cancer registry program, to explore the clinical characteristics of 4087 patients with LPA and identified the factors associated with distant and lymph node metastases in LPA patients. After that, we developed and validated accurate and personalized prognostic nomograms predicting 1- and 5-year OS and CSS of patients with LPA. Moreover, the nomograms demonstrated better prognostic capacity than TNM stage.
Survival outcomes of LPA patients with poor prognostic factors were undesirable, the median OS of advanced LPA patients was 20.1 months . However, the prognosis of advanced LPA patients could be improved by appropriate treatments, including chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) . The 5-year disease-free survival of LPA patients after complete surgical resection was about 90% . With the evaluation of the nomograms that generated in our study, more aggressive treatments are recommended for high-risk patients with LPA, and appropriate shortening of the follow-up interval is encouraged to detect the occurrence of endpoint events as early as possible. For example, older, unmarried, black men with sizeable tumor and advanced TNM stage are recommended for frequent follow-up and more aggressive treatments, including primary tumor resection when they meet the operational criteria.
Compared with other rare histologic subtypes of lung cancer, such as papillary adenocarcinoma  and carcinosarcoma , our results suggested the incidence of LPA was much higher. Our results indicated that female and older age were highly associated with LPA rather than ADC-NOS, which is consistent with previous studies [13,14]. In addition, some clinicopathological features of LPA patients indicate a good prognosis, including smaller tumor size, fewer separate tumor nodules, lesser pleural invasion, lower histological grade and stage. This is consistent with previous studies  and in line with the good prognosis of LPA [3,13,15]. Moreover, LPA have some characteristics differing from other histologic subtypes of invasive pulmonary ADC, such as being more common in non-smokers or light smokers, a preference for pulmonary peripheral location and be false-negative in positron-emission tomographic scan [13,16]. Clinically, asymptomatic at presentation and excessive airway secretion were more common in patients with LPA . In the genetic alteration profiles, EGFR mutations were occurred in about 50% patients with LPA, which is significantly higher than other subtypes , especially the mutations in exon 21 [17,18]. Whereas KRAS mutations were much less common that account for about 10% of LPA population . Comparing with other histologic subtypes, a lower rate of ALK rearrangement and a higher rate of RET rearrangement were reported [6,19,20].
Most studies supported that patients with LPA had desirable survival outcomes compared with other subtypes of invasive pulmonary ADC. In the treatment strategies, surgery is still the superior option for LPA patients whereas adjuvant chemotherapy including oral fluoropyrimidines and platinum-based regimens conferred no survival benefit on patients with LPA, regardless of the tumor stage at presentation [21,22]. In patients with advanced LPA, studies suggested that taxane-based chemotherapy and pemetrexed might be effective and well-tolerated in LPA [23,24]. With higher frequencies of EGFR mutations, EGFR-TKIs as first- or second-line treatment for advanced LPA demonstrated encouraging efficacy . Nevertheless, due to the lower expression level of programmed cell death-ligand 1, the efficacy of immune checkpoint inhibitors in patients with LPA may be poor [25-27]. Moreover, multiple studies suggested that a higher percentage of lepidic growth patterns were associated with a lower risk of recurrence, and the invasive component size were better predictors of survival than overall tumor diameter [16,17,28,29]. Furthermore, no recurrence was observed in any of the 18 LPA patients with maximum tumor diameter > 3 cm but the maximum diameter of the invasive area < 5 mm . Therefore, Suzuki et al.  proposed that LPA with an invasion of 5 mm or less can be regarded as minimally invasive ADC even if the tumor is larger than 3 cm in diameter. Unsurprisingly, our results suggested that primary tumor surgery was a major prognostic factors of LPA patients following the histological grade and stage. By contrast, chemotherapy was far less important to the prognosis of LPA patients. Furthermore, our results suggested that radiotherapy had no significant effect on the survival outcomes of LPA patients. Regrettably, we could not explore the prognostic significance of chemotherapy regimens, targeted therapy, immunotherapy and the diameter of the invasive area.
In the current study, we identified that age, sex, marital status, primary tumor size, pleural invasion, histological grade, TNM stage, primary tumor surgery, and chemotherapy were independently associated with OS and CSS in patients with LPA. It is of note that few patients with histological grade IV LPA were included in this study. Therefore, the nomograms we constructed to predict the survival outcomes were not suitable for patients with histological grade IV LPA. Similar to previous studies, our results suggested that treatment, tumor size and some demographic characteristics also had an impact on the prognosis of LPA patients, and we provided a statistical prediction tool that can incorporate and quantify the selected prognostic factors to estimate the survival outcome for an individual patient.
To date, it is the first time that the demographic and clinicopathological features, as well as the incidence of LPA, were elucidated based on a large-scale population-based database. Meanwhile, this is the first nomograms predicting the survival outcomes in LPA patients, which could aid in the personalized prognostic evaluation and clinical decision-making. However, there were still some limitations in our study though the nomograms demonstrated good accuracy and applicability. First, the nomograms were constructed based on the retrospective data, and the prospective validation is needed. Second, some critical information such as the diameter of the invasive area in LPA, tumor biomarkers, chemotherapy regimens, targeted therapy, molecular pathology, and genetic tests were absent in the database. Therefore, we could not analyze those variables and improve prognostic nomograms in our study. Third, the patients were almost all Americans, and the results might be different in other races. Such drawbacks are inherent to almost all retrospective population-based studies. However, the large size and the long follow-up duration of the present study compensate to a great extent and provide a comprehensive knowledge of LPA. Further prospective studies with more important information are needed for model improvement and independent validation.