Tumor Shrinkage and Symptom Relief with Doxorubicin and Ifosfamide in Thoracic SMARCA4-Deficient Undifferentiated Tumor with Airway Obstruction: A Case Report

Abstract

Introduction

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently recognized, rare, and highly aggressive malignancy. No standard treatment has been established for unresectable disease, and the prognosis is generally poor. These tumors often grow rapidly, and bulky masses can cause clinically significant symptoms.

Case Presentation

A 52-year-old man with a history of heavy smoking presented with chest and back pain. Imaging revealed a large mediastinal mass. A CT-guided biopsy demonstrated an undifferentiated neoplasm with complete loss of BRG1 (SMARCA4) expression, a high proliferative index (Ki-67 labeling index, 80%), and no evidence of specific lineage differentiation, findings consistent with SMARCA4-UT. Subsequent comprehensive genomic profiling revealed a SMARCA4 nonsense mutation and a high tumor mutational burden. The tumor was clinically unresectable and showed rapid progression, resulting in severe dyspnea and syncope due to marked extrinsic airway compression. Because a high-grade sarcoma was initially suspected before the final diagnosis of SMARCA4-UT was established, first-line doxorubicin plus ifosfamide (AI) therapy was administered, resulting in rapid symptomatic relief and a partial response. However, after three cycles of AI therapy, the disease progressed clinically with a left adrenal metastasis. Subsequent treatment with the immune checkpoint inhibitor (ICI) atezolizumab plus carboplatin and paclitaxel showed no objective response, and the patient died 6 months after the initiation of systemic therapy.

Conclusion

This case suggests that doxorubicin plus ifosfamide may provide rapid but transient tumor shrinkage and symptomatic improvement in thoracic SMARCA4-UT with airway obstruction. This regimen may be considered when urgent tumor reduction is required to relieve impending airway compromise. However, early diagnosis may also be important because first-line ICI-containing regimens have been associated with improved clinical outcomes in thoracic SMARCA4-UT.

Introduction

SMARCA4 is a tumor-suppressor gene encoding BRG1, the core ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin-remodeling complex [1]. The SWI/SNF complex plays a pivotal role in regulating the expression of genes involved in cell division, DNA replication, and DNA repair. Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) was first described in 2015 [2]. This recently recognized and extremely rare tumor typically presents as a large thoracic mass involving the mediastinum, lungs, and pleura, and it most commonly occurs in young to middle-aged men with a history of heavy smoking [3]. Initially considered a subtype of sarcoma, thoracic SMARCA4-UT is currently categorized as a distinct entity within pulmonary epithelial tumors in the fifth edition of the World Health Organization (WHO) Classification of Thoracic Tumours [4]. Thoracic SMARCA4-UT is highly aggressive, and treatment options are limited. Surgical resection has been associated with a high recurrence rate, and radiotherapy has shown limited efficacy [3]. Among patients treated with cytotoxic chemotherapy, responses are generally poor, with a reported median overall survival of approximately 4–7 months [4]. A large tumor burden may also cause significant local symptoms, such as airway obstruction, which can impair quality of life and may be life-threatening. Herein, we report a case of thoracic SMARCA4-UT with airway obstruction in which doxorubicin plus ifosfamide (AI) therapy provided rapid but transient tumor shrinkage and symptom relief.

Case Presentation

A 52-year-old man presented to our hospital with chest and back pain. He had a 32-pack-year smoking history, a history of urinary calculi, and a family history of oral cancer in his father. There were no relevant prior interventions or treatments. A CT scan revealed a 93 × 78 mm mass in the mediastinum, with no evidence of distant metastasis (Fig. 1a). Serum tumor marker testing showed elevated levels of neuron-specific enolase (NSE; 77.8 ng/mL) and soluble interleukin-2 receptor (sIL-2R; 698 U/mL), whereas other tumor markers, including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), squamous cell carcinoma antigen (SCCA), alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II), and pro-gastrin-releasing peptide (proGRP), were within normal limits.

Fig. 1.

Computed tomography of the chest. a Non-contrast CT at initial presentation, acquired in the lateral decubitus position due to back pain and rotated 90° for display. b Non-contrast CT at hospitalization for airway obstruction, also acquired in the lateral decubitus position and rotated 90°. c Non-contrast CT showing severe extrinsic tracheal compression by a mediastinal mass. d Contrast-enhanced CT after two cycles of doxorubicin plus ifosfamide (AI) therapy showing tumor shrinkage.

A CT-guided percutaneous core needle biopsy was performed. Histologically, approximately half of the specimen showed extensive coagulative necrosis. In the viable areas, round to oval atypical cells with enlarged hyperchromatic nuclei and eosinophilic cytoplasm were arranged in solid nests (Fig. 2a). Immunohistochemical analysis revealed loss of BRG1 (SMARCA4) expression in the tumor cells (Fig. 2b). The tumor cells were positive for vimentin and weakly positive for synaptophysin, whereas chromogranin A was negative. Epithelial markers, including pancytokeratin (Fig. 2c), CK7, and CK20, were all negative. Melanocytic markers (S100 and SOX10), the hematolymphoid marker CD45, and the muscle marker desmin were also negative. Programmed death-ligand 1 (PD-L1) expression was not assessed, and additional immunohistochemical analyses for SMARCA2, CD34, and SALL4 were not performed. The Ki-67 labeling index was approximately 80% (Fig. 2d). Next-generation sequencing using the FoundationOne^® genomic profiling test was performed on tumor tissue. The analysis demonstrated microsatellite stability, a high tumor mutational burden (13 mutations/Mb), an SMARCA4 nonsense mutation (p.E686*), a CDKN2A nonsense mutation (p.E33*), and a TP53 missense mutation (p.C176F). A high-grade sarcoma was initially considered on the basis of high-grade undifferentiated morphology with extensive necrosis, lack of epithelial marker expression, and vimentin positivity. However, the thoracic location, solid undifferentiated growth pattern, extensive necrosis, loss of BRG1 (SMARCA4) expression, exclusion of other tumor lineages by immunohistochemistry, and the presence of an SMARCA4 nonsense mutation supported the final diagnosis of thoracic SMARCA4-UT according to the WHO Classification of Thoracic Tumours, 5th Edition.

Fig. 2.

Histopathological findings of thoracic SMARCA4-UT (high-power views; scale bar, 100 µm). a Hematoxylin and eosin staining. b BRG1 (SMARCA4) immunohistochemistry. c Pancytokeratin immunohistochemistry. d Ki-67 immunohistochemistry.

The tumor was considered unresectable due to encasement of the aortic arch, and palliative chemotherapy was initially planned. One month after the biopsy, the patient was hospitalized with dyspnea and syncope. Vital signs were within normal limits, with no evidence of oxygen desaturation. No abnormal findings were detected on auscultation, and no palpable masses or lymphadenopathy were noted on physical examination. Severe chest and back pain made it difficult for the patient to remain in the supine position. A subsequent CT scan revealed that the mediastinal tumor had increased in size to 128 × 98 mm and was causing marked tracheal compression (Fig. 1b, c). Oxygen therapy was initiated, and corticosteroids and morphine were administered to relieve dyspnea.

At the time treatment was initiated, a regimen for malignant soft tissue sarcoma was selected because the tumor had not yet been diagnosed as thoracic SMARCA4-UT and was tentatively classified as sarcoma, unspecified. AI therapy consisting of doxorubicin (20 mg/m², IV, on days 1–3) and ifosfamide (2,000 mg/m², IV, on days 1–5) was administered every 28 days. After one cycle of AI therapy, the tumor decreased in size, resulting in relief of airway obstruction and improvement of dyspnea, chest pain, and back pain. The Eastern Cooperative Oncology Group (ECOG) performance status improved from 3 to 1. During the first cycle, the patient experienced grade 4 neutropenia, grade 3 nausea, and grade 2 stomatitis according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. For subsequent cycles, the doses of doxorubicin and ifosfamide were reduced to 80% of the initial doses.

Two months after the initiation of AI therapy, a follow-up CT scan demonstrated tumor shrinkage to 89 × 80 mm, indicating a partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (Fig. 1d). At this point, local radiotherapy was considered. However, it was not performed because airway obstruction and tumor-related symptoms had improved, and the additional benefit of radiotherapy was considered limited relative to the need to continue effective chemotherapy without interruption or delay. After three cycles of AI therapy, the patient was hospitalized because of worsening chest and back pain. CT revealed regrowth of the mediastinal tumor and a left adrenal metastasis, with no other apparent distant metastasis.

Based on a regimen used for non-small cell lung cancer, the patient received atezolizumab (1,200 mg, IV, on day 1), carboplatin (AUC 5, IV, on day 1), and paclitaxel (200 mg/m², IV, on day 1) as second-line treatment every 21 days. Bevacizumab, an anti-vascular endothelial growth factor antibody, was not used because the patient was receiving treatment for an active thrombosis in the brachial vein. After three cycles, the patient showed no response to second-line treatment. He died of intracerebral hemorrhage due to brain metastasis 6 months after the initiation of chemotherapy. The overall clinical course, including the treatment timeline and serial radiographic changes in the mediastinal tumor on chest radiography, is summarized (Fig. 3).

Fig. 3.

Clinical timeline and serial chest radiographs.

Discussion

A complete response to an AI regimen has been reported in a patient with an SMARCA4-deficient gastric tumor [5]. Doxorubicin-containing regimens have also shown clinical activity in thoracic SMARCA4-deficient tumors and SMARCA4-deficient non-small cell lung cancer [6, 7]. The present case provides further evidence that doxorubicin-based chemotherapy may induce rapid tumor shrinkage and symptom relief in thoracic SMARCA4-UT.

In SMARCA4-deficient tumors, the SWI/SNF chromatin-remodeling complex is inactivated, leading not only to transcriptional dysregulation but also to defective DNA repair [8]. The SWI/SNF complex participates in double-strand break (DSB) repair via homologous recombination and non-homologous end joining [9]. The patient in the present case received an AI regimen consisting of doxorubicin, an anthracycline, and ifosfamide, an alkylating agent. Doxorubicin inhibits topoisomerase II and stabilizes topoisomerase II-DNA cleavage complexes, thereby resulting in replication fork collapse and subsequent induction of DSBs [10]. Alkylating agents form DNA interstrand crosslinks that block replication and can be processed into DSBs during repair [11]. These mechanisms may have contributed to the rapid initial tumor shrinkage observed in this case; however, further investigation is needed to clarify this possibility.

Despite the initial response described above, the tumor rapidly progressed within 1 month. SMARCA4 deficiency is also known to suppress the expression of inositol 1,4,5-trisphosphate receptor type 3, which is involved in mitochondrial apoptotic signaling [12]. Therefore, even when DNA damage occurs, the downstream apoptotic machinery may not be effectively activated, allowing tumor cells to survive despite such damage. Clinically, SMARCA4-deficient tumors are typically associated with a high Ki-67 labeling index and poor differentiation [3]. The resulting local tumor microenvironment may be hypoxic and characterized by abnormal vasculature, which may compromise perfusion and limit the delivery of cytotoxic agents [13]. These factors may have contributed to the short duration of response in the present case.

As second-line treatment, an immune checkpoint inhibitor (ICI)-containing regimen was administered based on prior reports suggesting the potential efficacy of ICIs in thoracic SMARCA4-UT [14]. Responses have also been reported in patients with PD-L1-negative tumors [14]. In a retrospective study, first-line ICI plus chemotherapy was associated with longer progression-free survival than chemotherapy alone (26.8 months vs. 2.73 months), whereas the objective response rate was comparable (71.4% vs. 66.7%) [15]. In addition, patients who received ICI-containing therapy in the first-line setting had longer overall survival than those who received it in later lines [15]. The mechanisms underlying the benefit of ICIs in SMARCA4-UT remain unclear; however, a high tumor mutational burden and genomic instability may partly explain this clinical finding. In the present case, no clear response to ICI-containing chemotherapy was observed. This lack of response does not necessarily contradict the potential benefit of ICI-containing regimens, given that responses to ICIs are not uniformly observed in all patients and that the present patient received ICI-containing therapy as second-line treatment.

Conventional cytotoxic agents have generally shown limited efficacy in thoracic SMARCA4-UT, and no standard therapy has been established [4]. Recent reports have suggested the potential benefit of multimodal strategies, including ICI-containing chemotherapy, antiangiogenic therapy, chemoradiotherapy, and surgical resection [16, 17]. In this context, the clinical course of the present case suggests that a doxorubicin- and ifosfamide-based regimen may be considered when objective tumor shrinkage and symptom relief are urgently required. The principal limitation of this report is its single-patient design. As illustrated by the present case, early clinical and histopathological diagnosis of SMARCA4-deficient tumors can be challenging. Nevertheless, early diagnosis may be important because first-line ICI-containing regimens may improve clinical outcomes. Further accumulation of similar cases and prospective studies are needed to clarify the role of doxorubicin- and ifosfamide-based chemotherapy and the optimal treatment strategy for thoracic SMARCA4-UT.

Acknowledgments

The authors used ChatGPT 5 (GPT-5; OpenAI, San Francisco, CA, USA) to assist with improving the clarity and grammar of the manuscript. No patient data or personal information was shared with AI tool. All content was reviewed and approved by the authors.

Statement of Ethics

This case report was approved by the Ethics Committee of Ishinomaki Red Cross Hospital (Approval No. 25-9). Written informed consent for publication of the details of this case and any accompanying images was obtained from the patient’s next-of-kin (sister). This case report was prepared in accordance with the CARE Guidelines, and the CARE Checklist is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/cro/abzag029).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Conceptualization, investigation, and writing – original draft: R.U. Data curation and writing – review and editing: R.U., Y.R., S.E., Y.I., and A.O. Supervision: A.O.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All relevant data that support the findings of this case report are included in this article. Additional information is available from the corresponding author upon reasonable request.