Background
Pulmonary blastoma (PB) is a rare subtype of human lung tumors accounting for approximately 0.25–0.5% of primary pulmonary malignancies. There are only about a few hundreds of cases reported worldwide since the first description by Barnett and Barnard in 1945 [
1‐
3]. These tumors morphologically resembling embryonal lung structure were historically described under a uniform medical term until distinct entities were recognized [
4]. Childhood PB, also referred as pleuropulmonary blastoma (PPB) [
5], occurs almost exclusively in children and adolescents and is characterized by localized-regional evolution with some cases exhibiting more aggressive and metastasizing properties [
6,
7]. On contrast, Adult-onset PB is more common in middle-aged people and typically presents with non-specific clinical manifestations similar to lung cancer. It is further classified into two subtypes: monophasic PB, which is also called well-differentiated fetal adenocarcinoma (WDFA), and classic biphasic PB (CBPB) containing tissue of both fetal adenocarcinoma (typically of low grade) and primitive mesenchymal stroma [
8,
9]. The existence of partially-overlapping genetic abnormalities in PPB, CBPB and WDFA has been proved [
10], and the original pathological grouping and histological characteristics of these three subtypes are similar and coherent. Due to the rarity of PB, there are few researches exploring the long-term outcome of these populations. Most previous studies are case reports and literature reviews focusing on a small number of subjects, the results are ambiguous and even controversial. The aims of our study were to describe the epidemiological features of malignant PB in detail and to investigate the independent prognostic factors for PB patients.
Discussion
Although PB has been known for over 70 years, its prognostic factors remain largely unknown. Limited evidence suggests that age of onset, gender, anatomical location, tumor size and stage, histologic subtype, comorbidities and metastasis status and surgical resection may be associated with different outcome, but these results warrant further validation [
2,
6‐
9]. PB is previously reported to be an aggressive tumor with relatively poor prognosis. Some previous literature mentions that two-thirds of PB patients die within 2 years of diagnosis, only 16 and 8% survive 5 and 10 years post diagnosis, respectively [
13,
16,
17]. But in our study, nearly half of the PB patients achieved long-term survival, the 5 and 10-year survival rate in all PB patients were 58.2 and 48.5%, even 40% of patients with metastatic PB achieved long-term survival over 5 years. It could be seen that the survival rate of PB in our study was quite higher than that in previous reports [
18]. In addition, we found a slight female preponderance in the incidence of PB, and female patients were more common in all three histological subtypes. Whereas, the clinical outcomes between two gender groups indicated no significant difference. Nearly a quarter of PB patients were associated with other malignancies, which had not been reported before. Considering the previously published papers were almost case reports and literature reviews with small sample size, our study was more informative.
The three subtypes of PB, CBPB, PPB and WDFA, are reported to be distinguished on morphological, immunohistochemical and radiographical and clinical outcome grounds. The World Health Organization (WHO) classification of lung tumors in 2004 qualifies CBPB as lung sarcomatoid carcinoma, PPB as pulmonary soft tissue tumor and WDFA as a lung adenocarcinoma variant [
4]. Patients with CBPB generally present with common symptoms of lung cancer and larger diameter tumors [
19]. WDFA often radiographically manifests as peripheral asymptomatic nodules with mixed solid and cystic components [
20]. The biological characteristics of PPB are unique, and the tumors often undergo a transition from cystic to solid based on different subtypes and disease progresses, of which type I is associated with better prognosis and type III has the worst prognosis [
21]. The 5-year survival for CBPB was reported about 15% versus 62% for PPB and about 75% for WDFA [
2,
5,
11,
20]. It was worth noting that the 5-year survival rate between different histological subtypes in our study did not show such huge disparity despite statistical differences (Fig.
2b), and the mortality gap among three subtypes was even smaller when it comes to disease-specific death (Fig.
3d). Further multivariate analysis also indicated that histological subtype was not an independent predictor of prognosis in PB patients.
As our results suggested, peak ages of onset in three subtypes were quite different. PPB occurred almost exclusively in children aged 14 years or younger, which was why the OS and DSS of PPB patients were almost identical. On the contrary, CBPB occurred in all ages and mostly in middle-aged and old patients, and the chances of dying from other factors other than PB itself were increasing dramatically with age (Fig.
2b). Other-caused deaths even accounted for 30% of overall deaths in patients 65 years or older at diagnosis (9 of 30). Undoubtedly, the difference in mortality between different histological subtypes could be influenced by the uneven distribution of the number of patients at different ages. The impact of PB on OS was much more potent in the older cohort. New molecular data indicates that PB patients share some overlapping molecular profiles, and DICER1 mutations are found to be important drivers and are likely to be associated with the later presentation of both CBPB and WDFA, as well as PPB [
10]. The similarities and differences among three subtypes of PB should be explored further.
Surgical excision is regarded as the optimal treatment choice for well-localized mass and regional disease, 86.4% of the patients in our study performed surgery. Consistent with previous reports [
22,
23], surgery treatment significantly prolonged the survival time of PB patients, and the cumulative incidences of disease-specific death in operated patients was much lower than that in non-operated patients. Expanded resection plus lymph node dissection is the preferred method of PB treatment, and the specific range of operations should be customized according to individual clinical features. Postoperative radiochemotherapy can be performed when lymph node metastasis or surrounding tissue involvement is observed. However, it’s reported that only a few cases were sensitive to radiotherapy [
24]; Cutler et al. summarized the clinical outcome of 468 patients who underwent postoperative chemotherapy and found that the effect of single or combined medication was not satisfactory, and the median survival of these patients was only 14.7 months [
25]. Some scholars believe that the survival time of PB is mainly related to the degree of resection and the prognosis of patients with complete resection is better. While some other scholars think that, the effect of PB surgery largely relies on the differentiation of mesenchymal components. Patients with immature, undifferentiated and embryonic-like tumor tissues have the better prognosis. Because there are few cases of continuous long-term follow-up before and after surgery, the optimal therapeutic regimen of PB needs to be further explored.
In this registry-based cohort study, SEER database, a large population-based resource, was applied to provide valuable information of these low-incidence malignancies. To our knowledge, this study had the largest number of subjects among all researches conducted so far on the long-term clinical outcome of patients with malignant PB. Our results filled some previous gaps in terms of epidemiology of PB, as well as added new evidence to current controversial issues about the prognosis of PB patients. Another highlight of the study was that we used two different statistical methods to analyze the overall survival and disease-specific mortality of PB patients during various follow-up period. As we all know, there are multiple endpoint events in prospective observational cohort study, and if one event may affect the probability of another event or completely hinder its occurrence, they will be competitive risk events for each other. The standard Kaplan–Meier analyses reflect mortality from the event of interest without the consideration of competing events. This approach of treating failures from competing events as censored will lead to an overestimation of the absolute risk of the event of interest and is less clinically relevant [
26]. Therefore, we applied the competitive risk model, an analytical method designed for the survival data with multiple potential outcomes, to calculate the disease-specific mortality in a condition of retaining the underlying risk set for patients who died due to competing causes of death. As we mentioned above, similar findings were observed in the competitive risk model analysis. And the independent prognostic factors for PB predicted by two different statistical models were the same, which further showed the robustness of our results.
Our study had several limitations. First, this was a retrospective study based on administrative information from the SEER database. Therefore, clinical variables such as tumor morphology, chemoradiotherapy information, complications and medication use were lacking. In addition, details from the surgery procedures and preoperative TNM-classification were not available. Second, as with any other retrospective study, we could not exclude the possibility of residual or unmeasured confounding. Third, although SEER is designed to approximate the national distribution of cancer characteristics by collecting cancer incidence data from population-based cancer registries in the USA, it is derived from 18 states and covers only 34.6% of the U.S. population, which may lead to over- or under-representation of certain hospital types and limit its generalizability to other population. Another limitation of this study was its small sample size due to the low incidence rate of PB, resulting in the compromise in quality of estimates. Nevertheless, the unique strengths in this study were the preciseness of statistical analyses and the long follow-up time, which partially increased the power of test.
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