ABSTRACT
Many cases of non‐small cell lung cancer (NSCLC) transforming to small cell lung cancer (SCLC) after targeted therapy have been reported, most of which are associated with acquired resistance mutations. Herein, we report the first documented case of phenotypic conversion to SCLC in a patient with advanced pulmonary sarcomatoid carcinoma (PSC) who received pemetrexed, carboplatin, and camrelizumab only, with no targeted agents administered. Through comparative analysis of two serial pathological biopsies and genetic profiling, our findings suggest that PSC may undergo clonal evolution or alternative transformation mechanisms under therapeutic pressure. TP53 and RET mutations may be implicated in this phenotypic transition. This case provides new insights into the biological mechanism underlying the evolution of PSC to SCLC.
Keywords: pulmonary sarcomatoid carcinoma, RET, small cell lung cancer, TP53, tumor heterogeneity
This is the first reported case of pulmonary sarcomatoid carcinoma undergoing conversion to small cell lung cancer. Genetic profiling of serial biopsies suggests clonal evolution or alternative transformation mechanisms.
1. Introduction
PSC is a poorly differentiated subtype of non‐small cell lung cancer (NSCLC) characterized by both epithelial and mesenchymal differentiation [1]. During NSCLC progression, a subset of cases may undergo histological transformation into small cell lung cancer (SCLC), defined as transformed SCLC (T‐SCLC) [2]. However, to date, no published reports have described pulmonary sarcomatoid carcinoma (PSC) transformation to SCLC in patients that only received chemotherapy and immunotherapy.
2. Case Presentation
A 66‐year‐old male was admitted to our hospital with intermittent fever, chest tightness, dyspnea, cough, whitish sputum, and palpitations. He had a 40‐year smoking history of approximately 20 cigarettes per day. Chest computed tomography (CT) revealed an approximately 38 × 22 mm space‐occupying lesion in the right upper lobe with cavitary changes, accompanied by multiple metastatic lymph nodes in the mediastinum, right axilla, and right hilum. Nodular pleural thickening in the right lung suggested pleural metastasis. Bone scintigraphy (BS) indicated increased metabolic activity in the right ilium, raising suspicion of bone metastasis (Figure 1). Contrast‐enhanced brain magnetic resonance imaging (MRI) and abdominal CT showed no metastatic lesions. A percutaneous biopsy of the right upper lobe confirmed sarcomatoid carcinoma (Figure 2). Immunohistochemistry demonstrated positivity for cytokeratin (CK), vimentin, and thyroid transcription factor‐1 (TTF‐1), whereas P40 and synaptophysin (Syn) were negative. Programmed death‐ligand 1 (PD‐L1) expression was assessed at 85%. The serum level of neuron specific enolase (NSE) was 5 ng/mL, carcinoembryonic antigen (CEA) was 3.76 ng/mL, carbohydrate antigen 125 (CA125) was 127.7 U/mL. Next‐generation sequencing (NGS) of the biopsy specimen identified a missense mutation in TP53, TP53 p.R282W, with a variant allele frequency (VAF) of 34.05% (Figure S1). Based on the clinical and radiological findings, the patient was diagnosed with PSC of the right upper lobe, staged as cT3N2M1b‐IVb, with metastases to the lung, bone, hilar, and mediastinal lymph nodes.
FIGURE 1.
Single‐photon emission computed tomography (SPECT/CT) image shows abnormal tracer uptake in the right ilium (arrow). Radiopharmaceutical: 99mTc‐MDP; Dose: 30 mCi.
FIGURE 2.
Pulmonary sarcomatoid carcinoma with epithelioid components and spindle‐shaped tumor cells. (A, B) Hematoxylin and Eosin staining at ×10 (A) and ×40 (B) magnification. (C–I) Expression of epithelial‐mesenchymal transition (ESCT)‐related markers in the tumor immunohistochemistry (IHC), ×20. Positive expression: Vimentin (C), cytokeratin (D), NAP (E), and thyroid transcription factor‐1 (F), PD‐L1 (G) ×40; Negative expression: Synaptophysin (H) and P40 (I). Images were acquired using a LEICA DM2500 LED microscope camera.
The patient received four cycles of pemetrexed plus cisplatin. Follow‐up chest CT after the fourth cycle showed an increase in lesion size; however, the overall response was classified as stable disease (SD) (Figure 3). Despite high PD‐L1 expression, the patient had concurrent chronic obstructive pulmonary disease (COPD) and interstitial lung changes. Therefore, after the patient's condition stabilized, his treatment regimen was adjusted at the fifth cycle to pemetrexed combined with carboplatin and camrelizumab. On July 9, 2024, dynamic monitoring of tumor marker levels revealed a significant elevation of neuron‐specific enolase (NSE) to 90.81 ng/mL. The patient completed the sixth cycle of treatment, and a follow‐up chest CT performed on July 31, 2024, demonstrated disease progression, with NSE levels decreasing to 61.93 ng/mL (Table S1). Given the high heterogeneity of PSC, a repeated biopsy of the tumor of the right upper lobe lung tumor was performed on August 1, 2024. Pathological results confirmed SCLC (Figure 4).
FIGURE 3.
(A) Timeline of diagnosis and treatment, including radiological findings of the thoracic mass. PR, Partial response; SD, Stable disease; PD, Progressive disease; PSC, Pulmonary sarcomatoid carcinoma; SCLC, Small cell lung cancer. (B) Time‐course curves of five tumor markers: Carcinoembryonic antigen (CEA), cytokeratin antigen 211 (CYFRA 21‐1), neuron‐specific enolase (NSE), carbohydrate antigen 125 (CA125), and carbohydrate antigen 50 (CA50).
FIGURE 4.
Small cell lung carcinoma showing scanty cytoplasm and fine granular chromatin. (A, B) Hematoxylin and Eosin staining at ×10 (A) and ×40 (B) magnification. (C–L) The tumor demonstrates positive expression of epithelial and stromal component markers in the IHC, ×20. Positive expression: Ki‐67 (C), CD56 (D), CD117 (E), synectin (F), cytokeratin (G), CK8/18 (H), INSM1 (I), and thyroid transcription factor‐1 (J); Negative expression: CgA (K) and vimentin (L). Images were acquired using a LEICA DM2500 LED camera.
Immunohistochemistry demonstrated positive for CK, CK8/18, TTF‐1, Syn, CD56, insulinoma‐associated protein 1 (INSM1), and the tyrosine‐protein kinase receptor (CD117). In contrast, chromogranin A (CgA) and vimentin were negative. The Ki‐67 proliferation index was 70%. NGS of SCLC specimens identified four missense mutations, TP53 p.R282W (VAF: 87.09%), RET p.V804M (VAF: 45.41%), PIK3CA p.E542K (VAF: 46.8%), and RAF1 p.R143P (VAF: 37.12%) (Figure S2). Following multidisciplinary team discussion, the chemotherapy regimen was adjusted to etoposide plus carboplatin, based on the hypothesis that tumor heterogeneity likely led to the transformation of PSC into small cell lung carcinoma. However, given the high malignancy and poor prognosis, further treatment modifications or long‐term efficacy evaluation were not feasible.
3. Discussion
This case report described a rare phenomenon of phenotypic transition from PSC to SCLC. Two sequential biopsies performed during the course of treatment revealed distinct histological differences, suggesting that the tumor may have undergone clonal evolution.
The two sequential biopsies confirmed PSC at the first sampling and SCLC at the second. Compared with the results pre‐ and post‐treatment, vimentin expression was lost whereas Syn, CD56, and Ki‐67 became positive. Meanwhile, serum NSE levels showed a gradual upward trend, CA125 and CA50 exhibited a declining trend throughout the treatment period, while CEA and CYFRA 21‐1 remained at low levels throughout the observation period. Additionally, genetic testing revealed that the abundance of TP53 mutations at the same locus increased from 34.05% to 87.09%, with persistent positivity for TTF‐1 and CK expression, suggesting that the tumor origin was consistent and essentially ruling out the possibility of double primary tumors or metastasis.
The transformation of NSCLC into SCLC may involve multiple signaling pathways. Previous studies have shown that most PSC harbor MET alterations, particularly exon 14 skipping and MET amplification, which can promote epithelial–mesenchymal transition (EMT) and neuroendocrine differentiation [3]. In cases with epidermal growth factor receptor (EGFR) mutation [4], ROS1 fusion [5] or ALK rearrangements [6], concurrent loss of TP53 and RB1 represents the classic driver event for SCLC transformation [7]. Moreover, SMAD4 deficiency has been shown to accelerate this transformation by inducing a neuroendocrine phenotype, independent of RB1 status in NSCLC cells with TP53 loss‐of‐function mutations [8]. There have also been reports of RET‐rearranged NSCLC transforming into SCLC after the application of selective RET tyrosine kinase inhibitors (TKIs) [9]. However, in the present case, two biopsies from the patient only identified a TP53 missense mutation, with no RB1 mutations detected and no prior exposure to selective TKIs. This type of transformation event is therefore particularly rare.
PSC itself exhibits marked heterogeneity, harboring both epithelial and mesenchymal components. During EMT, cancer stem cells (CSCs) are generated and drive malignant tumor progression. PSC and SCLC may arise from a common CSC population with multidirectional differentiation potential. During tumor progression and therapeutic intervention, changes in stem cell properties and therapy‐induced alterations in the tumor microenvironment may give rise to distinct pathological phenotypes [10]. Julie George et al. reported that TP53 mutations accompanied by genetic damage were significantly associated with shorter relapse‐free survival following chemotherapy. During first‐line chemotherapy, ancestral clones with acquired platinum‐related DNA damage may emerge, leading to expanded intratumoral genomic heterogeneity and spatial clonal diversity, thereby promoting branched evolution and reversion to ancestral clones [11]. In the present case, the patient received continuous platinum‐based chemotherapy, and two sequential biopsies showed an increased TP53 mutation burden, which may have affected intratumoral heterogeneity and contributed to the clonal evolution of PSC into SCLC.
In summary, PSC retains the potential to transform into SCLC even under conventional treatment, underscoring the importance of dynamic monitoring of tumor tissue during therapy.
Author Contributions
Qi Si: visualization. Haitao Zhou: writing – review and editing. Wen Jiang: writing – original draft. Yuwei Zhang: data curation. Youfeng Ma: conceptualization. Zhaohuan Ye: visualization. Jianwei Huang: supervision. Ge Zhang: funding acquisition, project administration. Xingmei Li: data curation. Chao Zhang: supervision.
Funding
This study was financially supported by the project of State Key Laboratory of Neurology and Oncology Drug Development (SKLSIM‐20250437), Henan Province Science and Technology Research Program (252102310270, 232102310108, LHGJ20230816 and LHGJ20230828), Henan Province Joint Fund for Science and Technology Research and Development Program (252103810351), Shanghai Guokang Targeted Traditional Chinese Medicine Research Institute (SHGK2021ZS001 and SHGK2022ZS001), Henan Province Engineering Research Center of Pulmonary Diseases Multi‐omics Precision Diagnosis and Treatment (DZXGCZXYN01 and DZXGCZXYN04), and Luoyang Key Medical and Health Projects (2302009A). The article processing fee is funded by the project of Henan Province Science and Technology Research Program (252102310270).
Ethics Statement
The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Luoyang Central Hospital on December 22, 2025 (Protocol Number: 2025‐LWLL‐12‐22‐01).
Consent
Written informed consent was obtained from the patient's son for participation in this study. Written informed consent was also obtained for the publication of any potentially identifiable images or data included in this article.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: Positive genes identified by next‐generation sequencing in pulmonary sarcomatoid carcinoma.
Figure S2: Positive genes identified by next‐generation sequencing in small cell lung carcinoma.
Table S1: Tumor marker change over time (Red is higher than normal value).
Data Availability Statement
The primary data supporting the findings of this study are included in the article and its Supporting Information. The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2025) in National Genomics Data Center (Nucleic Acids Res 2025), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA: HRA015985) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa. Data are unrestricted and publicly accessible.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Positive genes identified by next‐generation sequencing in pulmonary sarcomatoid carcinoma.
Figure S2: Positive genes identified by next‐generation sequencing in small cell lung carcinoma.
Table S1: Tumor marker change over time (Red is higher than normal value).
Data Availability Statement
The primary data supporting the findings of this study are included in the article and its Supporting Information. The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2025) in National Genomics Data Center (Nucleic Acids Res 2025), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA: HRA015985) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa. Data are unrestricted and publicly accessible.