Genetic heterogeneity and predictive biomarker for pulmonary sarcomatoid carcinomas
Introduction
Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC), accounting for about 0.4% of all lung malignancies [1]. PSC is defined as poorly differentiated NSCLC which contains a component of sarcoma or sarcoma-like element [2]. Histologically, PSC is manifested as biphasic malignancies, combining the carcinoma component and sarcomatoid component, sometimes with heterologous sarcomatous tissue. Hence, PSC was classified as pathologically heterogeneous group. Both epithelial and mesenchymal elements of tumor could be shown using immunohistochemistry (IHC). According to the most recent 2015 World Health Organization (WHO) classification, five subtypes of PSCs have been identified as follows: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma[3]. PSC patients are often found in heavy smokers, with an elderly male predominance [1]. Compared to common NSCLC, PSC has a worse prognosis, higher resistance to chemotherapy and radiotherapy, and shorter disease-free survival (DFS) after surgical resection [4]. The median overall survival (OS) and 5-year survival rate of PSC are 7 months and 19.5%, respectively [5]. However, the main causes leading to these events remain unclear. Besides, it is still unclear whether tumor heterogeneity might affect the recurrence and treatment-resistance of PSC.
Recently, genomic profiling has been applied to investigate new strategies for improving the prognosis in patients with PSC [6,7]. Tyrosine kinase inhibitor (TKI) has been recommended for the treatment of NSCLC patients with epidermal growth factor receptor (EGFR) mutation or fusions involving anaplastic lymphoma kinase (ALK). Moreover, a novel and promising immune checkpoint inhibitor targeting the PD-1/PD-L1 axis has been recommended as first-line therapy for those with wild-type EGFR and ALK while overexpressing PD-L1 [8]. However, new therapeutic targets and biomarkers of immunotherapy response have not been well investigated for PSC. Previous studies reported the MET mutation leading to exon 14 skipping in 8 (22%) out of 36 PSC cases [9,10]. Moreover, deep sequencing analysis revealed that KRAS mutation is a potential biomarker of poor prognosis in PSC patients [11,12].
Immunotherapy offers a new therapeutic option for sarcoma patients, but its therapeutic effect needs to be further investigated in clinical trials [13]. Therefore, through the identification of genetic profiling using NGS technology, followed by detection of PD-L1 expression, treatment for tumor subsets can be facilitated by personalizing therapies.
In this study, carcinomatous and sarcomatous components were identified in 6 PSC patients who underwent surgery. Using a customized panel covering exons of 425 cancer-relevant genes and selected introns of 32 fusions genes, NGS was performed to interrogate genetic profiling. In order to provide evidence for the clonal origin of the carcinomatous, sarcomatous components and alternative therapeutic targets for immunotherapy, genetic alterations and tumor mutation burden (TMB) were evaluated. In addition, PD-L1 expression was assessed by IHC, SP263 antibody was used to identify whether PSC patients may benefit from anti-PD-1/PD-L1 immunotherapy.
Section snippets
Sample collection
We retrospectively collected 24 consecutive patients with resected PSC at Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) between January 2013 and February 2017. All patients were diagnosed with PSC, and all the diagnoses were confirmed histologically on the basis of the WHO classification [3]. Tumor stage was defined according to the 8th edition of the TNM classification for lung cancer [14].
The selective flowchart of PSC patients is displayed in Fig. 1.
Patient characteristics
The tumor samples of surgically resected biphasic PSC were collected from 6 patients. All specimens were heterogeneous (separative carcinomatous and sarcomatous components were observed). The enrolled patients were all male, with age ranging from 55 to 74 years (mean ± standard deviation [SD], 64.67±7.23 years old). Four of them were heavy smokers (≥ 20 packs/year), and two had no smoking history (Table 1). Pathological analysis indicated that the maximum tumor diameter (mean ± SD) was
Discussion
Pulmonary sarcomatoid carcinoma is a rare histopathologically heterogeneous disease. However, its genetic heterogeneity and origin are not well defined. A reliable diagnosis of PSC requires a postoperative analysis of tumor specimens. In our current study, postoperative specimens of PSC were classified by epithelial and sarcomatoid component. Previous studies have reported that with the exception of carcinosarcoma and biphasic pulmonary blastoma, PSC shares remarkable similarities with common
Declaration of Competing Interest
The authors report no conflicts of interest in this work. Junrong Yan is the employees of Geneseeq Technology Inc.
Acknowledgments
This study was supported by Wu Jieping Medical Foundation (320.6750.17251), and Zhejiang Province Traditional Medical Science Project of China (Nos 2018ZB026).
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The Medical Ethical Committee of Zhejiang Cancer Hospital approved this study. This study is a retrospective study, and four patients have died. Exempt written informed consent was approved by the Ethics Committee of Zhejiang Cancer
References (44)
- et al.
Outcomes of sarcomatoid carcinoma of the lung: a surveillance, epidemiology, and end results database analysis
Surgery
(2012) - et al.
Pulmonary sarcomatoid carcinoma
Ann Pathol
(2016) - et al.
The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification
J Thorac Oncol
(2015) - et al.
Pulmonary sarcomatoid carcinoma: experience from SEER database and Shanghai pulmonary hospital
Ann Thorac Surg
(2020) - et al.
Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma
J Thorac Oncol
(2013) - et al.
Characteristics and clinical outcomes of sarcomatoid carcinoma of the lung
Clin Lung Cancer
(2016) - et al.
Deep sequencing analysis reveals that KRAS mutation is a marker of poor prognosis in patients with pulmonary sarcomatoid carcinoma
J Thorac Oncol
(2016) - et al.
International association for the study of lung cancer S, prognostic factors committee AB, participating I, international association for the study of lung cancer S, prognostic factors committee advisory B, participating I. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer
J Thorac Oncol
(2016) - et al.
Immunohistochemical study of 36 cases of pulmonary sarcomatoid carcinoma–sensitivity of TTF-1 is superior to napsin
Hum Pathol
(2014) - et al.
Multiparametric molecular characterization of pulmonary sarcomatoid carcinoma reveals a nonrandom amplification of anaplastic lymphoma kinase (ALK) gene
Lung Cancer
(2012)
High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the lung carta panel: exploring therapeutic targets
Ann Oncol Off J Eur Soc Med Oncol
Efficacy of Crizotinib among different types of ROS1 fusion partners in patients with ROS1-rearranged non-small cell lung cancer
J Thorac Oncol
Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1)
J Thorac Oncol
Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages
Lung Cancer
Pulmonary sarcomatoid carcinomas commonly harbor either potentially targetable genomic alterations or high tumor mutational burden as observed by comprehensive genomic profiling
J Thorac Oncol
Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas
Eur J Cancer
DNA mismatch repair deficiency in surgically resected lung adenocarcinoma: microsatellite instability analysis using the promega panel
Lung Cancer
Genomic origin and EGFR-TKI treatments of pulmonary adenosquamous carcinoma
Ann Oncol Off J Eur Soc Med Oncol
Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities
Ann Oncol Off J Eur Soc Med Oncol
Sarcomatoid carcinoma of the lung: the mayo clinic experience in 127 patients
Clin Lung Cancer
Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
N Engl J Med
Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations
J Clin Oncol
Cited by (7)
A Metastatic Pulmonary Sarcomatoid Carcinoma Patient Harboring KIF5B-RET Fusion Responds to First-Line Pralsetinib Treatment: A Case Report
2023, Cancer Management and ResearchThe efficacy and safety analysis of first-line immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma
2022, Frontiers in ImmunologyThe treatment of advanced pulmonary sarcomatoid carcinoma
2022, Future OncologyMolecular and expressional characterization of tumor heterogeneity in pulmonary carcinosarcoma
2022, Molecular CarcinogenesisMultimodality Treatment of Pulmonary Sarcomatoid Carcinoma: A Review of Current State of Art
2022, Journal of Oncology
- 1
Both the authors contributed equally to this work.