Thoracic SMARCA4-deficient undifferentiated tumor: A case report in a 40-year-old male without a smoking history

Abstract

Thoracic SMARCA4-deficient undifferentiated tumor is a recently identified aggressive malignancy characterized by inactivating mutations leading to the loss of SMARCA4 protein expression. First classified in the 2021 World Health Organization Classification of Thoracic Tumors, thoracic SMARCA4-deficient undifferentiated tumor typically presents in men in their fourth to sixth decade of life, often with a history of smoking, though a subset of cases occurs in nonsmokers. We present a rare case of stage IV thoracic SMARCA4-deficient undifferentiated tumor in a 40-year-old male without a smoking history, presenting with spinal metastases. The patient experienced right upper back pain, chest pain, and dyspnea. Imaging revealed a right lung mass, multiple hilar and supraclavicular lymph nodes, and spinal metastases. A computed tomography-guided biopsy of the right lung mass initially suggested small cell carcinoma, but subsequent lymph node excision and expert pathologic review confirmed thoracic SMARCA4-deficient undifferentiated tumor, characterized by rhabdoid morphology and loss of SMARCA4 expression. Treatment included concurrent chemoradiotherapy with cisplatin and etoposide, followed by a regimen of carboplatin, etoposide, and atezolizumab, with maintenance therapy using atezolizumab. Despite complications such as a femoral neck fracture and pancytopenia, imaging showed a reduction in tumor size. This case highlights the diagnostic complexity and treatment approaches for thoracic SMARCA4-deficient undifferentiated tumors.

Introduction

Thoracic SMARCA4-deficient undifferentiated tumor (TSDUT) is a recently reported entity, first described as a distinct diagnosis in the 2021 World Health Organization Classification of Thoracic Tumors. It is caused by an inactivating mutation leading to a deficiency in SMARCA4 protein expression, a key component of the switch/sucrose-non-fermentable (SWI/SNF) chromatin remodeling complex. This loss of SMARCA4 protein expression results in a high-grade malignant neoplasm with an undifferentiated rhabdoid phenotype.^1,2 It most often occurs in men in their fourth to sixth decades of life with a smoking history.

While most cases are associated with smoking-induced DNA damage, ~10% occur in patients without a smoking history, suggesting alternative injury pathways, such as environmental exposures, germline mutations, or other epigenetic alterations.^3,4 Recent studies hypothesize that in nonsmokers, TSDUT may arise from chromatin instability induced by other mechanisms, including aberrant methylation or interactions with oncogenic signaling pathways, such as PI3K/AKT or WNT/β-catenin. These alternative pathways underscore the complexity of tumorigenesis in nonsmokers and warrant further investigation.^5,6 Recent work by Nambirajan and Jain has emphasized the molecular heterogeneity of SMARCA4-deficient thoracic tumors, especially in nonsmokers, where epigenetic disruptions and alternative chromatin remodeling pathways may contribute to oncogenesis. ⁷

Here, we report the diagnosis and management of a case of stage IV TSDUT in a 40-year-old male without a smoking history, with spinal metastasis at the time of diagnosis. Currently, the patient is receiving palliative care 15 months after the initial discovery of a pulmonary mass on imaging and 10 months after the established diagnosis with biopsy.

Case presentation

A 40-year-old man without a tobacco use history presented with right upper back pain, chest pain, and dyspnea over a 2-month period. He also endorsed numbness in the medial aspect of his right arm for 5 days. The patient had been evaluated for chest pain and dyspnea 5 months prior at an outside facility and was found to have a right lung mass on imaging. However, a biopsy was not performed, and the patient was lost to follow-up. Computed tomography (CT) of the chest with intravenous contrast demonstrated a 4.9 cm mass at the right lung apex, multiple right hilar masses or lymph nodes, measuring 1.4 cm in diameter, and a right supraclavicular lymph node measuring 1.7 cm in diameter (Figure 1(a) and (b)). Magnetic resonance imaging with intravenous contrast demonstrated metastasis to S1 and minimal involvement of L5 vertebral bodies with a 12 mm thick anterior epidural component at the S1 level, causing sacral nerve compression (Figure 1(c)).

Figure 1.

Imaging results. (a) Right supraclavicular lymph node present measuring 1.7 cm in short axis prior to treatment; (b) right lung apex mass measuring 4.9 cm in transverse dimension prior to treatment. (c) MRI T1 weighted sagittal image of lumbar spine with contrast showing enhancement of L5 vertebral body and the sacrum corresponding with body metastasis. Also seen is enhancing epidural soft tissue causing a significant mass effect on the thecal sac at the level of the sacrum. (d) Right upper lung mass measuring 3.0 cm in transverse dimension ~9 months after CT scan in (b). Findings suggestive of partial response with interval resolution of the right upper lobe mass.

A core needle biopsy of the right upper lobe lung mass was performed to obtain sufficient material for histological and immunohistochemical analysis. Although a less invasive procedure, such as a supraclavicular lymph node fine-needle aspiration, could have been considered, the lung mass was selected due to its larger size and accessibility via image-guided techniques, which increased the likelihood of obtaining adequate diagnostic tissue. The biopsy revealed scant fragments of fibrous tissue infiltrated by a population of small cells with rhabdoid morphology. This morphology was characterized by a plasmacytoid or signet ring-like appearance, with eosinophilic cytoplasm lacking mucin vacuoles. In addition, the cells appeared artifactually compressed, creating a molding-like appearance (Figure 2(a) and (b)).

Figure 2.

Histological features of the tumor. (a) Section 20× of right upper lung core biopsy showing tumor cells with rhabdoid morphology and necrosis. (b) Section 40× of right upper lung core biopsy showing fragment of tumor cells with rhabdoid morphology. These cells show monotony. (c) Section 2× of supraclavicular lymph node showing diffuse sheets of variable discohesive clusters of large epithelioid cells with vesicular chromatin and prominent nucleoli. Nuclei are relatively monotonous. (d) Section 10× of supraclavicular node showing diffuse sheets of variably discohesive, large, round, top epithelioid cells. (e) Section 20× of supraclavicular node showing epithelioid cells with vesicular chromatin and prominent nucleoli. (f) Section 40× of supraclavicular node showing epithelioid cells with relatively uniform nuclei and prominent nucleoli with mild-to-moderate pleomorphism.

A panel of immunohistochemistry was performed, and the cells of interest showed Synaptophysin and Pankeratin (OSCAR) reactivity. The initial diagnosis was descriptive, indicating that the current findings were morphologically and immunophenotypically compatible with small cell carcinoma. A clinical verbal discussion with the oncologist was held, emphasizing the rarity of small cell carcinoma in young non-smoker patients and the need for further investigation. Based on this discussion and the limitations of the core biopsy sample, which was insufficient for definitive diagnosis due to limited cellularity and the presence of crush artifacts, an excisional biopsy of the right supraclavicular lymph node was recommended.

The excisional supraclavicular lymph node biopsy revealed sheets of variably discohesive, large round-to-epithelioid cells with vesicular chromatin and prominent nucleoli. The nuclei exhibited vesicular chromatin, marked pleomorphism, and prominent nucleoli, with frequent mitoses and areas of geographic necrosis-like patterns. Occasional papillary and peritheliomatous arrangements were observed. No evidence of epithelial differentiation, such as glandular/tubular or squamous morphology, was present (Figure 2(c–f)).

The suspicion of TSDUT and undifferentiated tumors, which required immunohistochemical stains not available in our facility, along with the discrepancy in morphology, led to the case being sent out to an expert pathologist at an outside facility. The external laboratory demonstrated loss of SMARCA4 (BRG1) and SMARCA2 (BRM) expression in lesional cells. The immunohistochemistry results are shown in Table 1. The rhabdoid morphology, along with concurrent loss of SMARCA4 and SMARCA2, was consistent with the diagnosis of TSDUT, which can often express neuroendocrine markers, most notably synaptophysin. As described by Nambirajan et al., these tumors frequently demonstrate claudin-4 negativity and preserved SMARCB1, which, in conjunction with SMARCA4 loss, assists in differentiating TSDUT from sarcomatoid carcinoma and other mimics. ⁸

Table 1.

Immunohistochemistry results of tumor cells on supraclavicular lymph node.

Immunohistochemistry	Results
CAM5.2	Positive in a small subset of lesional cells
OSCAR	Positive in a small subset of lesional cells
Synaptophysin	Positive
FLI-1	Positive
Vimentin	Positive in a small subset of lesional cells
INSM1	Weakly positive in a small subset of lesional cells
INI (SMARCB1)	Preserved in lesional cells
BRG1 (SMARCA4)	Negative in lesional cells
BRM (SMARCA2)	Negative in lesional cells
CKPan, CK7, CK20, chromogranin, CD45, CD30, CD99, Oct-3/4, desmin, myogenin, CD31, ERG, claudin 4	Negative

Treatment was initiated using concurrent chemoradiotherapy using cisplatin and etoposide. After 1 month and one round of chemotherapy, the regimen was changed to carboplatin, etoposide, and atezolizumab due to extensive disease. The patient completed three cycles on this regimen over the course of 3 months. The patient also completed adjuvant radiation treatment to the right upper lung field and 10 fractions of palliative radiotherapy to the L5–S1 metastatic lesion. Five months after the initial CT scan with IV contrast depicted above, the patient was started on maintenance atezolizumab every 21 days.

Three months after the time of the biopsy, the patient suffered a right femoral neck fracture while walking in his home. CT imaging of the right femur demonstrated an irregular cortical lucency involving the lateral aspect of the right femoral neck, raising suspicion of a pathological fracture. During this hospitalization, the patient began to develop pancytopenia secondary to chemoradiotherapy, requiring multiple blood transfusions and cocurrent filgrastim with his chemoradiotherapy. Additional CT of the chest, abdomen, and pelvis with IV contrast, about 9 months from initial CT scans, demonstrated a right upper lung mass measuring 3.0 cm in transverse dimension (Figure 1(d)). Positron emission tomography (PET)–CT obtained shortly after showed right upper pulmonary mass without hypermetabolic activity ~3.3 cm in greatest dimension with coarse dystrophic calcifications. PET/CT demonstrated several sclerotic osseous lesions throughout the axial/appendicular skeleton without hypermetabolic activity and a destructive hypermetabolic soft tissue lesion involving the posterior spinous processes of T5–T7 as well as a sclerotic focus, not the right posterior T5 vertebral body.

Currently, 10 months after our initial biopsy and 15 months since the initial demonstration of the right lung mass, the patient is continuing his maintenance of atezolizumab, is on a multimodal pain management regimen, and is pending a consult with radiation oncology regarding the possibility of palliative radiation to the T5–T7 spinal lesion.

Discussion

TSDUT is an aggressive malignancy that often presents with metastatic disease and a poor outcome. Its pathogenesis involves an inactivating mutation of the SMARCA4 gene. This gene, also known as transcription activator BRG1, plays a critical role in the SWI/SNF chromatin remodeling complex, which regulates DNA nucleosome positioning. ⁵ Initially described in pediatric malignant rhabdoid tumors, SMARCA4 mutations have now been identified in various malignancies over the past decade. ⁵

Most patients presenting with TSDUT are males in their fourth to sixth decades of life with an extensive smoking history. However, as our case demonstrates, ~10% of cases occur in non-tobacco users, suggesting alternative carcinogenic pathways.^3,4 Emerging evidence implicates aberrant activation of oncogenic signaling pathways, such as PI3K/AKT and WNT/β-catenin, in promoting chromatin instability in these patients.^5,6 In addition, germline SMARCA4 mutations, associated with familial cancer syndromes, may predispose nonsmokers to TSDUT.^2,3 Epigenetic dysregulation, such as promoter hypermethylation or altered histone modification, may also contribute to tumorigenesis in these cases. ⁴

The histopathological morphology of TSDUT is characterized by poorly differentiated, medium-to-large epithelioid cells with irregular nuclei and prominent nucleoli. Rhabdoid morphology—a hallmark feature—often includes abundant eosinophilic cytoplasm and eccentric nuclei, sometimes resembling plasmacytoid or signet ring-like appearances.^3,4 However, the expression of these features can vary across tumor samples, particularly in small biopsies, which may lack the cellularity needed for diagnosis. In addition, artifacts such as necrosis or crushed artifacts can obscure key morphological features.^5,6

Small biopsies also pose diagnostic challenges because they may capture only focal areas of the tumor, potentially underrepresenting rhabdoid morphology or other hallmark features. Immunohistochemistry is crucial in these cases. TSDUT often expresses the neuroendocrine marker synaptophysin, which can mimic small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma. However, the hallmark loss of SMARCA4 and SMARCA2 expression distinguishes TSDUT from these entities.^5,6 In addition, other neuroendocrine markers are generally negative. As seen in this case, the initial core biopsy led to a descriptive diagnosis resembling SCLC. The subsequent excisional biopsy was essential in highlighting the diagnostic features of TSDUT, including more prominent rhabdoid morphology and loss of SMARCA4/SMARCA2 expression, which confirmed the diagnosis.^2,4

The patient in this case received concurrent chemoradiotherapy with carboplatin, etoposide, and atezolizumab, followed by maintenance atezolizumab. This regimen was selected based on its efficacy in high-grade thoracic malignancies such as SCLC, which share overlapping features with TSDUT, including high proliferative indices and poor differentiation. ⁶ Carboplatin and etoposide target rapidly dividing tumor cells, while atezolizumab, a PD-L1 inhibitor, enhances immune-mediated tumor suppression. ² The observed tumor regression in the primary lung lesion supports the effectiveness of this approach for this patient. Given the absence of standardized treatment guidelines for TSDUT, this combination reflects an evidence-based approach adapted from similar aggressive thoracic cancers.

Despite tumor regression in the primary lung lesion, the development of new spinal metastases suggested possible disease progression. Given the stability of other metastatic sites and the patient’s overall clinical condition, maintenance therapy with atezolizumab was continued. The patient is pending a radiation oncology consult for palliative treatment of the spinal lesions.

Emerging therapies for TSDUT are a promising area of research, particularly in the realm of targeted molecular therapies and immunotherapies. Preclinical studies have identified potential molecular targets, such as EZH2, CDK4/6, and AURKA, which play roles in chromatin remodeling and cell cycle regulation. Agents targeting these pathways are currently being evaluated in SMARCA4-deficient cancers and may offer novel therapeutic options in the future. ⁶ In addition, immune checkpoint inhibitors, such as atezolizumab, have demonstrated efficacy in this case and hold potential for broader application in TSDUT. ⁵

This patient’s survival of 15 months after tumor discovery is noteworthy, given the median survival of 4–7 months typically reported for TSDUT.^2,5 Contributing factors may include the patient’s relatively young age, good baseline functional status, and positive response to the chosen treatment regimen. While this is a single case, the extended survival observed here suggests that tailored, multimodal treatments may improve outcomes for TSDUT patients. Further research into the molecular and clinical factors associated with favorable outcomes is essential for refining treatment strategies. ⁶

Given the rarity of TSDUT, long-term follow-up strategies remain poorly defined. While this case highlights the potential benefit of concurrent chemoradiotherapy and maintenance of atezolizumab, there are no established guidelines for monitoring disease progression or recurrence in TSDUT. Follow-up care typically involves periodic imaging, such as CT or PET/CT scans, to evaluate for metastasis or recurrence, particularly in high-risk sites like the thoracic cavity, bone, and brain. Given the aggressive nature of TSDUT and its poor prognosis, a multidisciplinary approach involving oncologists, radiologists, and pathologists is critical to tailor follow-up protocols to individual patient needs. Additional studies are needed to establish evidence-based monitoring protocols, particularly for atypical presentations in nonsmokers.^3,4

Conclusion

TSDUT is an aggressive malignancy most commonly observed in male tobacco smokers, caused by an inactivating mutation in the SMARCA4 gene.^1,5 The rarity of TSDUT and the lack of standardized treatment guidelines necessitate a high index of suspicion, adequate tissue sampling, effective communication, and expert consultation to achieve an accurate diagnosis.^2,4 This case underscores the challenges in diagnosing and managing TSDUT, especially in nonsmoking patients. ³

The reported case demonstrates the value of multidisciplinary management and tailored treatment strategies in achieving tumor regression and extending survival in this aggressive cancer. ² Despite the typically poor prognosis, the patient remains alive 15 months after the discovery of the tumor and 10 months after the definitive diagnosis. The patient’s extended survival and primary lung tumor regression are significant achievements in optimizing treatment strategies for future cases.

Further research is needed to better understand the molecular mechanisms of TSDUT, especially in nonsmokers, and to explore novel therapeutic approaches, including targeted therapies and immunotherapy.^5,6 Long-term follow-up strategies, including periodic imaging and multidisciplinary collaboration, are essential for monitoring disease progression and recurrence in high-risk patients.^4,6 As knowledge of TSDUT evolves, personalized approaches to diagnosis and treatment may help improve outcomes for patients with this rare malignancy. ⁵